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Vol. 54, Issue 1, 1-42, March 2002
Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland
Abstract
I. Introduction
A. Background and Overview
B. Experimental Approaches
II. Drug Priming-Induced Reinstatement
A. Dopamine
1. Cocaine Priming.
2. Heroin Priming.
B. Opioids
1. Cocaine Priming.
2. Heroin Priming.
C. Glutamate
D. Other Neurotransmitter Systems
1. 5-Hydroxytryptamine.
2. Corticosterone.
3.-Aminobutyric Acid.
4. Noradrenaline.
5. Acetylcholine.
6. Endocannabinoids.
E. Summary
III. Cue-Induced Reinstatement
A. Discrete Conditioned Stimuli
B. Extinction Behavior
C. Discriminative and Contextual Drug Cues
1. Discriminative Drug Cues.
2. Contextual Drug Cues.
D. Summary
IV. Stress-Induced Reinstatement
A. Dopamine and Opioids
B. Corticosterone and Corticotropin-Releasing Factor
1. Corticosterone.
2. Corticotropin-Releasing Factor.
C. Noradrenaline
D. Other Neurotransmitter Systems
E. Summary
V. Discussion
A. Neural Mechanisms Underlying Relapse to Heroin and Cocaine: a Summary
1. Drug Priming-Induced Reinstatement.
2. Cue-Induced Reinstatement.
3. Stress-Induced Reinstatement.
B. Theoretical Issues
1. Drug Priming.
2. Drug Cues.
3. Stress.
4. Summary.
C. Methodological Issues
1. Prior Training for Food Reinforcement.
2. Noncontingent Priming Injections during Training.
3. Response Rates during Training.
4. Amount of Drug Exposure during Training.
5. The Drug Withdrawal Period Prior to Tests for Reinstatement.
6. Side Effects of the Pharmacological and Brain Manipulations.
7. Summary.
D. Emerging Issues
1. Does Drug Sensitization Contribute to Relapse to Heroin and Cocaine?
a. Drug Priming and Drug Cues.
b. Stress.
2. Application of the Reinstatement Model to Mice.
E. Concluding Remarks and Implications for Addiction Theories and Treatment
1. Implications for Addiction Theories.
2. Implications for Treatment.
Acknowledgments
References
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The objective of this article is to review data from studies that used a reinstatement model in rats to elucidate the neural mechanisms underlying relapse to heroin and cocaine seeking induced by exposure to the self-administered drug (drug priming), conditioned drug cues, and stressors. These factors were reported to contribute to relapse to drug use in humans following prolonged abstinence periods. In the reinstatement model, the ability of acute exposure to drug or nondrug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies in which pharmacological agents were injected systemically or intracranially to block (or mimic) reinstatement by drug priming, drug cues, and stressors. We also will review studies in which brain lesions, in vivo microdialysis and electrochemistry, and gene expression methods were used to map brain sites involved in relapse to drug seeking. Subsequently, we will discuss theoretical issues related to the processes underlying relapse to drugs and address methodological issues in studies on reinstatement of drug seeking. Finally, the implications of the findings from the studies reviewed for addiction theories and treatment will be discussed. The main conclusion of this review is that the neuronal mechanisms involved in relapse to heroin and cocaine seeking induced by drug priming, drug cues, and stressors are to a large degree dissociable. The data reviewed also suggest that the neuronal events mediating drug-induced reinstatement are to some degree dissociable from those mediating drug reinforcement.
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I. Introduction |
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A. Background and Overview
High rates of relapse to drug use following prolonged withdrawal
periods characterize the behavior of experienced heroin and cocaine
users (Mendelson and Mello, 1996
; O'Brien, 1997). In heroin- or
cocaine-free individuals, drug craving and relapse to drug use can be
triggered by exposure to the self-administered drug (Meyer and Mirin,
1979; Jaffe et al., 1989; de Wit, 1996), by stimuli previously
associated with drug taking (Childress et al., 1992; Carter and
Tiffany, 1999), or by exposure to stressors (Kosten et al., 1986; Kreek
and Koob, 1998; Sinha et al., 1999).
Over the last several decades, some laboratories have been using an
animal model, termed the reinstatement model, to study factors that underlie relapse to heroin and cocaine seeking induced by
exposure to the self-administered drug, drug cues, and stressors. The
use of this procedure has become increasingly popular as indicated in
Fig. 1, which depicts the number of
studies that used the reinstatement model from 1971 to 2001 in
laboratory animals. In the learning literature, reinstatement
refers to the resumption of a previously extinguished conditioned
response after acute noncontingent exposure to the unconditioned
stimulus (Bouton and Swartzentruber, 1991; Catania, 1992). In the
studies reviewed below, reinstatement typically refers to the
resumption of extinguished lever-pressing behavior after noncontingent
exposure to drug or nondrug stimuli (Stewart and de Wit, 1987). In
studies on cue-induced reinstatement (Section III.),
reinstatement also refers to the resumption of drug seeking after
exposure to the drug cues following extinction of the lever-pressing behavior in the absence of these cues. Common terms used in
reinstatement studies are defined in Table
1.
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In the reinstatement model, laboratory animals are initially trained to
self-administer drugs by pressing a lever for intravenous drug
infusions in operant conditioning chambers. Subsequently, the
drug-reinforced behavior is extinguished by substituting the drug
solutions with saline or by disconnecting the infusion pumps. After
extinction of the drug-reinforced behavior, the ability of acute
exposure to drugs (i.e., drug priming) or nondrug stimuli to reinstate
drug seeking is determined under extinction conditions (Stretch et al.,
1971; Stewart and de Wit, 1987). There are two main dependent variables
during tests for reinstatement: nonreinforced responses on a lever that
previously delivered the drug, the active lever; and
responses on a lever not associated with drug infusions, the
inactive lever. Responses on the active lever are
interpreted to reflect reinstatement of drug seeking. Inactive lever
responses are typically interpreted to reflect nonspecific activity,
but they may also reflect response generalization (Catania, 1992).
It has been argued that the reinstatement model does not mimic most
situations in humans that lead to drug abstinence and thus may not be
suitable to model relapse (Marlatt, 1996; Bergman and Katz, 1998). In
addition, based on data demonstrating different neurochemical and
behavioral effects of contingent versus noncontingent drug injections
(Dworkin et al., 1995; Hemby et al., 1997; Markou et al., 1999), it has
been argued that the effect of priming drug injections in the
reinstatement model may not be relevant to drug addiction (Everitt and
Robbins, 2000). Furthermore, it has not been established that opioid
withdrawal, which is associated with relapse in humans (Himmelsbach,
1943; O'Brien et al., 1986; Wikler, 1973), can reinstate heroin
seeking in the reinstatement model. Naloxone-precipitated withdrawal
does not reinstate heroin seeking following extinction (Stewart and
Wise, 1992; Shaham and Stewart, 1995b; Shaham et al., 1996). In
contrast, spontaneous 24-h heroin withdrawal was found to reinstate
heroin seeking, but it cannot be concluded from this study whether this
effect was due to the motivational effects of opioid withdrawal or from
state-dependent mechanisms (see Shaham et al., 1996).
Despite these limitations, the reinstatement model has good predictive
validity because conditions that reliably reinstate heroin and cocaine
seeking in laboratory animals such as drug re-exposure, drug cues, and
stress (Self and Nestler, 1998; Shaham et al., 2000a; Stewart, 2000)
also were reported to provoke drug relapse and craving in humans (see
above). Thus, the model can be used to study neuronal mechanisms
underlying relapse to drugs despite the fact that the conditions that
lead to drug abstinence in laboratory animals are different from those
in humans.
In this review we will summarize data from studies that used the
reinstatement model in laboratory rats on the role of specific neurotransmitter systems in relapse to heroin and cocaine seeking. Although most studies used heroin or cocaine as the self-administered drug, several studies in which rats were trained to self-administer amphetamine or morphine also are reviewed. Studies using the
reinstatement model with monkeys or those using this model with
alcohol-trained rats are not reviewed here Lê and Shaham, 2002);
for recent reviews, see (Spealman et al., 1999 . The section below
provides an overview of several procedures used in reinstatement studies.
B. Experimental Approaches
Using monkeys, initial studies on reinstatement of amphetamine or
cocaine seeking by drug priming were conducted by Stretch and Gerber in
the early 1970s (Stretch et al., 1971; Stretch and Gerber, 1973; Gerber
and Stretch, 1975). Goldberg, Schuster, and colleagues also have shown
that stimuli paired with morphine or cocaine injections in monkeys
reinstate drug-taking behavior after the lever-pressing behavior is
extinguished in their absence (Schuster and Woods, 1968; Kelleher and
Goldberg, 1977; Goldberg et al., 1981). Davis and Smith (1976) and de
Wit and Stewart (1981, 1983) were the first to study reinstatement of
drug seeking in rats. Over the years, several types of reinstatement
procedures were used (Fig. 2).
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Stretch et al. (1971) and Davis and Smith (1976) used a
"between-session" reinstatement method, in which
training for drug self-administration, extinction of the
drug-reinforced behavior, and tests for reinstatement were conducted
during different daily sessions. The advantage of the between-session
model is that it mimics somewhat the human situation of relapse to
drugs at times that are beyond the acute withdrawal phase. A limitation
of this method, however, is that repeated testing under extinction
conditions results in the attenuation of responding to the reinstating
stimulus. Thus, subjects that are trained for prolonged periods cannot
be tested after extinction more than two to three times, leading to the
use of many subjects.
de Wit and Stewart (1981) introduced a "within-session"
reinstatement method. In this method, rats are initially trained to self-administer cocaine or heroin. Subsequently, tests for
reinstatement are carried out several times a week in a daily session
of 1 to 2 h of drug self-administration, 3 to 4 h of
extinction of the drug-reinforced behavior, and a subsequent test for
reinstatement. Rats are given regular drug self-administration training
between the test days. The advantage of this method is that rats can be repeatedly tested for reinstatement (de Wit and Stewart demonstrated that neither tolerance nor sensitization is evident after repeated testing with priming drug injections). The limitations of the within-session method are that it does not simulate long-term relapse
in humans, and the rats are not "truly" drug-free at the time of
testing (i.e., they are tested several hours after last exposure to drug).
A more recent variation of the reinstatement procedure is the
"between-within" method (Tran-Nguyen et al., 1998). In this method,
rats are initially trained for drug self-administration. Subsequently,
extinction training and tests for reinstatement are conducted on the
same day after different days of drug withdrawal. The advantage of this
method is that it can be used to study the relationship between the
duration of the drug withdrawal period and reinstatement of drug
seeking (see Section V. Discussion). At present, however, it
is not clear whether this method is suitable for repeated testing.
Thus, different groups of rats, tested at each withdrawal period, are
needed for a clear interpretation of the data (Tran-Nguyen et al.,
1998).
Two other reinstatement models were developed in recent years.
Ettenberg and colleagues introduced a "runway " reinstatement model to study the role of discriminative drug cues in
relapse (Ettenberg, 1990; Ettenberg et al., 1996; McFarland and
Ettenberg, 1997). In this model, the dependent measure is the
"run time " from a "start box " to a
"goal box " where a drug infusion is given. During the
initial discrimination training (Catania, 1992), rats are given a drug
injection when they reach the goal box in the presence of one
discriminative cue (e.g., specific odor) or saline injections in the
presence of a different cue. The discriminative cues are presented at
the start box. Over time, rats decrease their run time in the presence
of the drug predictive cue, but not the saline cue. Rats are then given
sessions in the absence of the discriminative cues and the drug during
which run time progressively increases (extinction). During testing, a
single presentation of the drug-associated cue leads to a decrease in the run time to reach the goal box (cue reinstatement). In addition, a
single drug infusion in the goal box during extinction decreases the
run time on the subsequent drug-free day (drug reinstatement).
The advantage of the runway method is that the impact of drug priming
on behavior is studied on a subsequent, drug-free day. Thus,
alternative interpretations for the effects of pharmacological manipulations given prior to drug priming (e.g., locomotor
activation/sedation) on behavior during testing can be ruled out. The
limitation of the runway model is that rats are not exposed to more
than several drug infusions/day, and consequently drug intake is much
lower than in self-administration studies. Thus, the runway model can only mimic some aspects of recreational drug use but not compulsive use
of high amounts of drugs. This model also reveals a complex behavioral
pattern in cocaine-trained animals, which do not decrease their run
time during training, presumably due to the "anxiogenic" effects of
cocaine (Ettenberg and Geist, 1991, 1993). Thus, this model is not
suitable for studying relapse to cocaine because it is difficult to
establish that cocaine serves as a reinforcer in this model. Finally,
rats are given the drug priming contingently when they reached the goal
box during an extinction session. Thus, the priming manipulation in the
runway method is different than that of the traditional reinstatement method.
Most recently, several laboratories have developed a conditioned place
preference (CPP2)
reinstatement model (Mueller and Stewart, 2000; Parker and McDonald, 2000). In these studies, rats are initially trained to associate one
distinctive environment with a drug injection and a different environment with a saline (vehicle) injection. Following training, rats
spend more time in the drug-paired environment, when given a choice
between the two environments, on a drug-free test day. This acquired
preference for the drug-paired environment can be extinguished by daily
injections of saline in the previously drug-paired environment
(extinction). It was found that after extinction, injections of cocaine
(Mueller and Stewart, 2000) or morphine (Parker and McDonald, 2000)
reinstate the extinguished CPP for the drug. Finally, it was recently
reported that both morphine injections and footshock stress
"reactivate" CPP for morphine (that is no longer observed) after 9 (Wang et al., 2000) or 36 (Lu et al., 2000) drug-free days, during
which the rats are not exposed to extinction conditions. The advantage
of the CPP reinstatement model is that nonspecific motor effects of
pharmacological manipulations are less likely to influence behavior
because the dependent measure is not lever-pressing behavior. This
model also does not require the expertise of intravenous surgery and
the need to maintain catheter patency. However, as in the case of the
runway model, total drug exposure is low and thus the relevance of this
model to compulsive and chronic drug use is limited.
In conclusion, several experimental procedures can be used to study reinstatement of drug seeking in rats, each with its advantages and disadvantages. In the sections below, we will review studies that used these different procedures.
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II. Drug Priming-Induced Reinstatement |
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Many studies have reported reliable heroin- or cocaine-induced
reinstatement using the different reinstatement methods described above
(Self and Nestler, 1998; Stewart, 2000). The drug priming effect also
was reported in alcohol- and nicotine-trained rats (Chiamulera et al.,
1996; Shaham et al., 1997a; Lê et al., 1998). As described below,
this effect is demonstrated following systemic and intracranial
administration. Agents from the same pharmacological class of the
self-administered drug reliably reinstate heroin and cocaine seeking
(Carroll and Comer, 1996; de Wit, 1996). Several studies, however, also
demonstrated "cross-reinstatement" with drugs that are from
different classes than the self-administered drug (Davis and Smith,
1976; De Vries et al., 1999). The magnitude of drug-induced
reinstatement is positively correlated with the priming dose. In
addition, doses that are higher than the unit dose of the
self-administered drug are needed to reliably reinstate the behavior
(de Wit, 1996). Also, at higher doses, peak responding occurred later
and continued for longer periods than with low doses (de Wit and
Stewart, 1981). Finally, Lynch and Carroll (2000) reported that female
rats are more responsive to cocaine-induced reinstatement than male
rats. However, the priming effect is reliably observed with male rats,
which were used in most of reinstatement studies. In the section below,
we describe studies in which pharmacological and neurochemical methods
were used to elucidate the role of specific neurotransmitter systems
underlying reinstatement by heroin and cocaine priming. Table
2 summarizes data from
substitution (cross-reinstatement) studies in which the effect of
pharmacological agents on reinstatement of heroin and cocaine seeking
was determined. Table 3
summarizes data on the effect of pharmacological agents on
reinstatement induced by heroin or cocaine priming.
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A. Dopamine
A large body of evidence indicates that the mesocorticolimbic
dopamine (DA) system (Fallon and Moore, 1978) contributes to the acute
reinforcing effects of heroin and cocaine (Koob and Bloom, 1988; Wise,
1996b). Cocaine, an indirect DA agonist, increases DA release by
blocking the DA transporter (Heikkila et al., 1975). Heroin and other
µ-opioid receptor agonists increase DA release in terminal regions by
inhibiting GABAergic neurons in the VTA, which provide tonic inhibition
of DA neurons, resulting in increased DA release in terminal regions
(Di Chiara and North, 1992). The data reviewed indicate that the
mesocorticolimbic DA system also is involved in reinstatement by
cocaine or heroin priming.
1. Cocaine Priming.
The effect of cocaine priming on
reinstatement is mimicked by systemic injections of amphetamine (a DA
reuptake blocker and a DA releaser), DA reuptake blockers (GBR-12909,
methylphenidate) and D2-like receptor agonists
(7-hydroxy-2-dipropylaminotetralin, quinpirole, bromocriptine) (de Wit
and Stewart, 1981; Wise et al., 1990; Self et al., 1996; De Vries et
al., 1999; Schenk and Partridge, 1999). On the other hand, mixed DA
agonists (apomorphine) or direct D1-like agonists (SKF 82958, SKF 81297, ABT 431) do not mimic the effect of cocaine priming on
reinstatement (Self et al., 1996, 2000; De Vries et al., 1999) (Figs.
3 and 4).
Surprisingly, these direct D1-like agonists, some of which are
self-administered by rats and monkeys (Self and Stein, 1992; Weed et
al., 1993; but see Caine et al., 1999b), also block cocaine-induced
reinstatement in rats (Self et al., 1996, 2000) and monkeys (Khroyan et
al., 2000). Norman et al. (1999) reported that the D1-like antagonist, SCH 23390, attenuates cocaine-induced reinstatement. In addition, using
the runway model in amphetamine-trained rats, Ettenberg (1990) reported
that the D2-like receptor antagonist, haloperidol, attenuates
drug-induced reinstatement. These pharmacological data indicate that DA
plays a crucial role in cocaine-induced reinstatement. In addition,
although activation of D2-like receptors provokes cocaine seeking,
activation of D1-like receptors inhibits it. The reasons for this
pharmacological dissociation are not clear in light of the literature
on the similar behavioral effects of the D1- and D2-like agonists on
locomotor activity (Self et al., 1996) and cocaine reinforcement (Self
and Nestler, 1995).
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found that intra-VTA infusions of morphine reinstate cocaine
seeking (Fig. 5). A likely mechanism for
this effect is that morphine inhibits GABAergic neurons in the VTA, which provide tonic inhibition of DA neurons (Di Chiara and North, 1992). More recently, Self et al. (1998) studied the effect of manipulations of the intracellular signaling of the D1- and D2-like receptors by using an activator (SP-cAMPS) and an
inhibitor (RP-cAMPS) of protein kinase A (PKA).
These agents mimic activation of the D1- and D2-like receptors by
receptor agonists, respectively (Kebabian and Calne, 1979). They found
that intra-NAc infusions of RP-cAMPS reinstate
cocaine seeking, whereas infusions of SP-cAMPS
nonselectively increase responding on both levers. The data with the
PKA inhibitor are in agreement with those obtained with systemic
injections of direct D2-like agonists. However, it cannot be ruled out
that the effect of RP-cAMPS on reinstatement is
mediated via its action on non-DA receptors in the NAc that also
inhibit cAMP formation (e.g., µ-opioid receptors) (Taylor and
Fleming, 2001). The mechanisms underlying the effect of the PKA
activator on the lever-pressing behavior and their relationship to
DAergic activity are even less clear, as this effect is different from
that observed with D1-like agonists. Cornish and Kalivas (1999) found
that activation of AMPA receptors in the NAc reinstate cocaine seeking,
and PKA modulates AMPA receptor activity (Banke et al., 2000). Thus,
the effect of the PKA activator on cocaine seeking may be due to its
action on the AMPA receptor. More recently Cornish and Kalivas (2000) reported that direct infusions of DA into the NAc reinstate cocaine seeking. Surprisingly, these authors found that intra-NAc infusions of
the nonselective DA antagonist, fluphenazine, had no effect on
cocaine-induced reinstatement. These data, together with the data
described above suggest that DA neurotransmission in components of the
mesocorticolimbic DA system other than the NAc is involved in
cocaine-induced reinstatement. In agreement with this idea, McFarland
and Kalivas (2001) recently found that infusions of fluphenazine into
the medial prefrontal cortex (mPFC) attenuate cocaine-induced
reinstatement.
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) and the amygdala (Tran-Nguyen et al., 1998), a terminal projection of the mesocorticolimbic DA system (Fallon and Ciofi, 1992).
Di Ciano et al. (2001) reported that in rats trained to self-administer
d-amphetamine, priming injections of the drug increased DA
signal in the NAc, as measured by chronoamperometry. Finally,
Neisewander et al. (2000) reported that priming cocaine injections
increase Fos protein expression, a cellular marker of neuronal activity
(Morgan and Curran, 1991), in the VTA and several terminal DA
projections [the caudate putamen, central nucleus of the amygdala
(CeA), lateral amygdala and the anterior cingulate cortex].
Other indirect evidence for the role of DA in reinstatement comes from
studies demonstrating that caffeine (an antagonist of adenosine
receptors) reliably reinstates cocaine seeking (Worley et al., 1994).
This effect may be due to an interaction between adenosine A2a and
D2-like receptors, which are negatively coupled (Fuxe et al., 1998).
Thus, blockade of adenosine A2a receptors by caffeine can lead to
activation of D2-like receptors and consequently to reinstatement of
cocaine seeking. It has been shown that D2-like receptor antagonists
can attenuate the effects of adenosine receptor antagonists (Garrett
and Holtzman, 1995).
Converging evidence implicates the mesocorticolimbic DA system in
cocaine-induced reinstatement. Surprisingly, D1- and D2-like receptors
play fundamentally different roles in this effect. Finally, the recent
data of Cornish and Kalivas (2000), together with the previous
pharmacological data, suggest that the action of DA in regions of the
mesocorticolimbic DA system (e.g., the prefrontal cortex), other than
the NAc, mediates cocaine-induced reinstatement. Nevertheless, DA in
the NAc still plays a role as intra-NAc infusions of DA reinstate
cocaine seeking (Cornish and Kalivas, 2000).
2. Heroin Priming.
Indirect DA agonists (cocaine,
amphetamine) were found to reinstate heroin seeking after prolonged
withdrawal periods (3 weeks) (De Vries et al., 1998a, 1999) (Fig. 3).
Intra-NAc infusions of amphetamine also reinstate heroin seeking in the
within-session reinstatement procedure (Stewart and Vezina, 1988) (Fig.
5). In contrast, using the within-session procedure, it was reported that cocaine does not reliably reinstate heroin seeking (de Wit and
Stewart, 1983). The discrepant results between the effect of cocaine in
the between- and within-reinstatement procedures may be related to the
development of sensitization to the DA-dependent behavioral activating
effects of cocaine following prolonged, but not short, withdrawal
periods (De Vries et al., 1999; Vanderschuren and Kalivas, 2000).
). Interestingly, De Vries et al. (1999, 2002) found that the
D2-like agonist, quinpirole, reinstates heroin seeking following short
withdrawal periods (within 1 week) but not following 3 weeks of
withdrawal. The nonselective DA agonist, apomorphine, and the D1-like
receptor agonist, SKF 82958, do not reinstate heroin seeking (de Wit
and Stewart, 1983; De Vries et al., 1999). In other studies it was
found that D2-like receptor antagonists block heroin-induced
reinstatement (Ettenberg et al., 1996; Shaham and Stewart, 1996; Lu et
al., 2001b). Blockade of the D1-like receptors by SCH 23390 also
attenuated heroin-induced reinstatement (Shaham and Stewart, 1996).
However, nonspecific sedative effects of the relatively high dose of
the D1-like antagonist (0.05-0.1 mg/kg, i.p.) may have contributed to
this effect.
Together, the available data suggest that DA is involved in
heroin-induced reinstatement. The recent data of De Vries and colleagues suggest that activation of D2-like receptors plays an
important role in heroin reinstatement during early but not late
withdrawal. A role of D1-like receptors in heroin-induced reinstatement, however, has not been established.
B. Opioids
Activation of µ-opioid receptors is critically involved in
heroin reinforcement (Mello and Negus, 1996). The rewarding effects of
heroin are mediated via dopamine-dependent mechanisms within the VTA
(Wise, 1996b) and dopamine-independent mechanisms within the NAc (Koob,
1992). On the other hand, despite the fact that manipulations of opioid
receptors were found to alter cocaine self-administration and CPP in
several studies (Shippenberg and Elmer, 1998; Van Ree et al., 1999), it
has not been established that activation of opioid receptors is
critical for cocaine reward and in many studies opioid receptor
antagonists failed to alter cocaine reward (Mello and Negus, 1996).
Several studies have examined the effect of opioid receptor agonists
and antagonists on reinstatement of heroin and cocaine seeking.
1. Cocaine Priming.
The role of opioid receptors in cocaine
priming has not been clearly established and the data reviewed below
mirror the conflicting literature on the role of opioid receptors in
cocaine reinforcement. The preferentially µ-opioid antagonist,
naltrexone, has no effect on cocaine-induced reinstatement (Comer et
al., 1993). In addition, systemic injections of µ-opioid receptor
agonists (heroin, morphine, etonitazene), a mixed
µ-agonist/
-antagonist (buprenorphine) or a mixed µ/-agonist
(butorphanol) do not reliably reinstate cocaine seeking (de Wit and
Stewart, 1981; Comer et al., 1993; De Vries et al., 1998a; Lynch et
al., 1998). Furthermore, butorphanol, etonitazene, and buprenorphine
(Comer et al., 1993; Lynch et al., 1998), but not morphine (Lynch et
al., 1998), attenuate cocaine-induced reinstatement. However, the
interpretation of these data is complicated because in opioid-naive
rats, systemic injections of opioid agonists have a biphasic effect on
behavior: an initial sedative effect that is followed by behavioral
activation (Babbini et al., 1975). These initial sedative effects may
have masked the expression of the motivational effects of the opioid
receptor agonists on reinstatement. Thus, when morphine is infused
acutely into the VTA, where it induces behavioral activation (Joyce and
Iversen, 1979), it reinstates cocaine seeking (Stewart, 1984). More
recently, Schenk et al. (1999, 2000) reported that the -opioid
receptor agonist, U69593, decreases cocaine-induced reinstatement. This effect may be related to the inhibitory effect of -opioid receptor activation on DA release (Spanagel et al., 1990; Shippenberg and Elmer,
1998).
2. Heroin Priming.
The effect of heroin priming on
reinstatement is dependent on activation of µ-opioid receptors.
Priming injections of µ-opioid receptor agonists such as morphine
mimic the effect of heroin on reinstatement when given systemically (de
Wit and Stewart, 1983; Stewart and Wise, 1992) or intra-VTA but not
intra-NAc (Stewart, 1984) (Fig. 5). Naltrexone, a preferentially
µ-opioid receptor agonist, blocks reinstatement induced by either
systemic injections of heroin (Shaham and Stewart, 1996) or intra-VTA
morphine (Stewart, 1984). Finally, chronic occupation of the opioid
receptors with heroin given via Alzet osmotic minipumps attenuates
heroin-induced reinstatement (Shaham et al., 1996). These data suggest
that activation of DA neurons in the VTA mediates heroin-induced
reinstatement. However, there are recent reports that infusions of
opioid and GABAergic agents into the VTA also have DA-independent
rewarding effects (Nader and Van der Kooy, 1997; McBride et al., 1999). Thus, it cannot be ruled out that DA-independent mechanisms within the
VTA are involved in heroin-induced reinstatement.
C. Glutamate
Glutamate neurotransmission is involved in the development and
expression of behavioral and neurochemical sensitization to opioid and
psychostimulant drugs (Pierce and Kalivas, 1997; White and Kalivas,
1998). Based on these reports, several recent studies investigated the
effect of systemic or intracranial injections of agonists and
antagonists of ionotropic glutamate receptors (NMDA and AMPA/kainate)
on reinstatement of cocaine seeking.
De Vries et al. (1998b) reported that systemic injections of the
noncompetitive NMDA antagonist, MK-801, reinstate cocaine seeking. In
contrast, Bespalov et al. (2000) reported that the competitive NMDA
receptor antagonist, D-CPPene, and the low-affinity NMDA
receptor channel blocker, memantine, do not reinstate cocaine seeking.
These discrepant results are one of many examples of the different
effects of noncompetitive and competitive NMDA receptor antagonists on
behavior (Willetts et al., 1990). Another finding in the study of
Bespalov et al. was that pretreatment with the NMDA receptor
antagonists led to increased responding on the inactive lever. The
reasons for this nonspecific effect are not clear.
Evidence for the role of glutamate neurotransmission in cocaine
reinstatement comes from two studies by Cornish and Kalivas (1999,
2000). They found that intra-VTA infusions of AMPA selectively reinstate cocaine but not sucrose seeking. The NMDA receptor agonist (cis-ACDA) increased responding on the active lever during
testing, but also somewhat increased responding on the inactive lever. In addition, the AMPA receptor antagonist, CNQX, blocked reinstatement of cocaine seeking induced by cocaine priming (given systemically) and
intra-NAc infusions of DA. In contrast, the NMDA receptor antagonist,
CPP, had no effect on cocaine priming (Fig.
6). Thus, although activation of AMPA and
NMDA receptors in the NAc can induce reinstatement, only the former is
directly involved in cocaine-induced reinstatement.
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A study by Vorel et al. (2001) provides additional evidence for the
role of glutamate in cocaine reinstatement. Using stimulation parameters previously shown to evoke glutamate receptor-mediated changes in dopamine efflux in the NAc (Blaha et al., 1997), these investigators found that stimulation of the hippocampal-containing glutamatergic neurons in the ventral subiculum reinstates cocaine seeking. They also found that hippocampal stimulation-induced reinstatement is blocked by an intra-VTA infusion of the nonselective ionotropic glutamate antagonist, kynurenic acid, and is mimicked by
intra-VTA infusions of NMDA, a manipulation that increases DA release
in the NAc (Westerink et al., 1996). The relevance of these provocative
data to reinstatement induced by cocaine priming, however, is not known.
Recent data indicate that glutamate action on AMPA receptors within the
NAc plays a critical role in cocaine-induced reinstatement. In
addition, activation of NMDA receptors within both the NAc and the VTA
can reinstate cocaine seeking. The relationship between the
glutamatergic mechanisms within the VTA and NAc in cocaine reinstatement is an interesting question for future research. Finally,
acamprosate (calcium-acetyl homotaurinate), a compound that alters
glutamatergic neurotransmission (Spanagel and Zieglgänsberger, 1997), had no effect on heroin-induced reinstatement (Spanagel et al.,
1998). Studies on the effect of specific NMDA or AMPA receptor ligands
on heroin-induced reinstatement have not been published.
D. Other Neurotransmitter Systems
Several studies were conducted on the role of several other neurotransmitter systems in reinstatement induced by cocaine or heroin priming. These include 5-HT, corticosterone and corticotropin-releasing factor (CRF), GABA, noradrenaline (NA), acetylcholine, and the endocannabinoids.
1. 5-Hydroxytryptamine.
Manipulations of brain 5-HT systems
can alter the behavioral effects of cocaine, including drug
self-administration and discrimination (Walsh and Cunningham, 1997).
Several studies examined the effect of 5-HT agents on cocaine
priming-induced reinstatement. The selective serotonin reuptake
inhibitor (SSRI), fluoxetine, which increases 5-HT levels in terminal
regions (Perry and Fuller, 1992), has no effect on cocaine-induced
reinstatement (Baker et al., 2001). The 5-HT1a
antagonist, WAY 100635, which increases 5-HT cell firing and release
(Mongeau et al., 1997), attenuates cocaine-induced reinstatement. In
addition, the 5-HT2C agonist Ro 60-0175 (Grottick et al., 2000), but not the 5-HT2 antagonist
ritanserin (Schenk, 2000), attenuates cocaine-induced reinstatement. Ro
60-0175 may attenuate cocaine-induced reinstatement by decreasing DA
levels in the NAc and frontal cortex (Millan et al., 1998; Di Matteo et
al., 1999). Finally, Tran-Nguyen et al. (2001) reported that 5-HT
lesions by 5,7-dihydroxytryptamine shift the dose-response curve
of cocaine priming to the left. These data suggest that 5-HT acts on
5-HT2C receptors to attenuate cocaine-induced
reinstatement. However, the observation that fluoxetine has no effect
on cocaine priming is not in agreement with this idea. Thus, the role
of 5-HT in cocaine-induced reinstatement remains to be determined.
2. Corticosterone.
The stress hormone, corticosterone, which
is released following activation of the hypothalamic-pituitary adrenal
(HPA) axis (Selye, 1956), plays an important role in cocaine
reinforcement (Piazza and Le Moal, 1998). Cocaine activates the HPA
axis (Sarnyai et al., 2001), and inhibition of circulating
corticosterone decreases intravenous cocaine self-administration in
rats (Goeders, 1997; Piazza and Le Moal, 1997). The data reviewed
below, however, suggest that corticosterone secretion does not play a
major role in cocaine- (or heroin-) induced reinstatement. The removal
of corticosterone by adrenalectomy (ADX) or the administration of CRF
receptor antagonists had no effect on cocaine- or heroin-induced
reinstatement (Shaham et al., 1997b; Erb et al., 1998). In addition,
synthesis inhibitors of corticosterone (ketoconazole or metyrapone) had
no effect on cocaine- or heroin-induced reinstatement (Shaham et al.,
1997b; Mantsch and Goeders, 1999b). Recently, however, the nonselective CRF receptor antagonist, 
-helical CRF, and the selective
CRF1 receptor antagonist, CP-154,526 (Schulz et
al., 1996) but not the CRF2 receptor antagonist
antisauvagine-30, were reported to attenuate reactivation of morphine
CPP by drug priming after 28 days of withdrawal (Lu et al., 2000). Lu
et al. (2001a) also reported that -helical CRF, but not CP-154,526
or antisauvagine-30, attenuates reactivation of cocaine CPP by cocaine
priming. The reasons for the different effects of the CRF receptor
antagonists in the CPP model versus the self-administration model are
not clear.
3. 
-Aminobutyric Acid.
Roberts and Brebner (2000) found
that the GABAB receptor agonist, baclofen,
attenuates cocaine reward. Campbell et al. (1999) reported that
baclofen also attenuates cocaine-induced reinstatement (Campbell et
al., 1999). This effect may be due to the inhibitory action of baclofen
on DA neurons in the VTA (Westerink et al., 1996).
4. Noradrenaline.
Several studies found that manipulations of
central NA have an effect on opioid and psychostimulant
self-administration behavior (Davis et al., 1975; Harris et al., 1996).
However, based on other studies, it is generally believed that the
involvement of central NA neurons in drug reinforcement is minimal
(Wise, 1978, 1996b). Erb et al. (2000) found that the -2
adrenoceptor agonists, clonidine and lofexidine, have no effect on
cocaine-induced reinstatement at doses that decrease NA release in the
amygdala and prefrontal cortex. These data suggest that the action of
cocaine on the NA transporter (Blakely et al., 1994) is not involved in
its effect on reinstatement. The role of NA in heroin-induced
reinstatement has not been determined.
5. Acetylcholine.
Cholinergic neurons modulate
mesocorticolimbic DA neurotransmission in the NAc and the VTA (Di
Chiara et al., 1994; Sarter et al., 1999). Nicotine increases DA
release in the NAc (Damsma et al., 1989), an effect mediated via the
activation of nicotine receptors in the VTA (Nisell et al., 1994). The
available data, however, do not implicate nicotinic acetylcholine
receptors in cocaine-induced reinstatement. Schenk et al. (1999) found
some effect of nicotine on reinstatement of cocaine seeking, but Wise et al. (1990) did not.
6. Endocannabinoids.
The endocannabinoid system has been
implicated in several neuropsychiatric conditions, including drug
addiction (Gardner and Vorel, 1998; Piomelli et al., 2000). The active
ingredient of marijuana, 
9-THC, activates the mesocorticolimbic DA
system (Chen et al., 1991; Tanda et al., 1997). In addition, DA through
activation of D2-like receptors, releases endogenous cannabinoids in
the striatal complex (Giuffrida et al., 1999). Based on these findings, two studies determined the effect of activation or blockade of cannabinoid receptors on cocaine seeking. Using the within-session method, Schenk and Partridge (1999) found that 9-THC has no effect on cocaine seeking. In contrast, using the between-session method, De
Vries et al. (2001) found that the nonselective cannabinoid agonist,
HU210, potently reinstates cocaine seeking following 2 to 3 weeks of
withdrawal, whereas the CB1 receptor antagonist SR141716A attenuates
cocaine-induced reinstatement. These discrepant results may be due to
the time of testing (several hours versus several weeks of withdrawal)
and the longer duration of action of HU210 compared with 9-THC.
E. Summary
| 1. | Cross-reinstatement or reinstatement by a drug other than the self-administered drug is most commonly observed within a given drug class. This effect, however, also is observed across drug classes and is often not symmetrical (i.e., psychostimulants are more likely to reinstate opioid seeking than vice versa). |
| 2. | DA receptors are critically involved in cocaine and heroin-induced reinstatement, whereas opioid receptors are involved in heroin but not cocaine reinstatement. |
| 3. | D1- and D2-like receptors play different roles in cocaine reinstatement. Activation of D2-like receptors provokes cocaine seeking, whereas activation of D1-like receptors inhibits it. |
| 4. | Glutamate within the VTA and the NAc appears to play an important role in cocaine reinstatement. Surprisingly, within the NAc, blockade of AMPA but not DA receptors attenuates cocaine-induced reinstatement. These data suggest that mesocorticolimbic DA projections to areas other than the NAc mediate the behavioral effects of the systemic injections of DA receptor ligands in the reinstatement model. |
| 5. | Recent studies suggest that activation of GABAB or 5-HT2C receptors attenuates cocaine-induced reinstatement, but future studies are needed to verify the role of GABA and 5-HT in drug-induced reinstatement. The studies reviewed also indicate that cocaine-induced NA and corticosterone release does not contribute to cocaine-induced reinstatement. |
| 6. | Recent data suggest that activation of endocannabinoid systems in the brain is involved in cocaine-induced reinstatement. |
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III. Cue-Induced Reinstatement |
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In an initial study Davis and Smith (1976) trained rats to press a
lever for intravenous injections of morphine; each injection was
accompanied by a buzzer presentation (a discrete conditioned stimulus,
CS). Lever pressing for morphine was then extinguished by replacing
morphine infusions with saline in the absence of the CS. During
testing, lever presses resulted in response-contingent presentations of
the CS (a conditioned reinforcer), and rats increased their
lever-pressing behavior. In contrast, de Wit and Stewart (1981) found
that noncontingent exposure to a tone cue following extinction of the
lever-pressing behavior for cocaine in the absence of the CS has a weak
effect on reinstatement. Similarly, two recent studies found that
noncontingent presentations of discrete CSs have a minimal effect on
cocaine seeking following extinction of lever pressing in their absence
(Fuchs et al., 1998; Tran-Nguyen et al., 1998). It appears that two
features are important for obtaining a reliable effect of discrete drug
CS on reinstatement (See et al., 1999; Grimm et al., 2000). First, a
compound (i.e., tone + light) cue is more effective in inducing
reinstatement than a simple tone or light cue (See et al., 1999).
Second, as predicted from the studies above, the drug cues should be
presented contingently during tests for reinstatement (Grimm et al.,
2000).
More recently, Ettenberg et al. (1996) and Weiss et al. (2000) have
developed discrimination procedures (Catania, 1992) to characterize the
role of discriminative cues, which predict drug availability, in
relapse. In these studies, discrete environmental cues (e.g., sound,
smell) predict whether drug or no drug (saline) is available during
drug self-administration training. These investigators showed that
discriminative cues that predict drug availability provoke relapse when
they are introduced after the drug-reinforced behavior is extinguished
in their absence (McFarland and Ettenberg, 1997; Gracy et al., 2000).
Using a renewal procedure (Bouton and Bolles, 1979), we
examined the role of contextual stimuli (e.g., physical characteristics of the test environment), which predict drug availability, in relapse
to drug seeking (Crombag and Shaham, 2002). In the renewal procedure,
conditioned responses to discrete CSs are recovered when they are
reintroduced in the original conditioning context (where they were
paired with the primary reinforcer) after extinction in a different
context. We found that in rats with a history of speedball (a
heroin-cocaine combination) self-administration, drug seeking is
reinstated when rats are exposed to the drug self-administration context following extinction of the lever-pressing behavior in the
presence of drug-contingent CSs (stimulus light, sound of the pump) in
a different context (Crombag and Shaham, 2002).
Finally, learning theorists view responding in the absence of a primary
reinforcer during extinction as a behavior that is controlled by the
CSs previously paired with the reinforcer (Pavlov, 1927; Skinner,
1953). From this perspective, the effect of pharmacological/lesion manipulations on rate of extinction (or resistance to extinction) can
be used to study neuronal substrates involved in discrete CS-induced
drug seeking (Fuchs et al., 1998). Studies of this type are reviewed
below. However, data from studies in which in vivo electrophysiology,
microdialysis, and electrochemistry were used during drug
self-administration, and thus samples were occasionally taken in
response to the drug cues prior to drug infusions, are not reviewed
here. Table 4 describes the data from the
pharmacological studies on cue-induced reinstatement.
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A. Discrete Conditioned Stimuli
Bespalov et al. (2000) reported a decrease in cocaine cues-induced
reinstatement following pretreatment with the NMDA receptor antagonist,
D-CPPene, but not the low affinity NMDA channel blocker, memantine. See et al. (2001) found that basolateral amygdala (BLA) intra-infusions of an NMDA receptor antagonist (AP-5) or kainate/AMPA receptor antagonist (CNQX) have no effect on cocaine cues-induced reinstatement. These data suggest that NMDA receptors in regions other
than the BLA may be involved in cocaine cues-induced reinstatement. Most recently, De Vries et al. (2001) found that the CB1 receptor antagonist SR141716A attenuates cocaine cues-induced reinstatement. These data suggest that the brain endocannabinoid system is involved in
neuronal processes underlying cue-induced relapse to cocaine seeking.
Alleweireldt et al. (2002) reported that the D1-like receptor
antagonist, SCH 23390, attenuates cocaine cues-induced reinstatement. See et al. (2001) also found that SCH 23390 but not raclopride (a
D2-like antagonist) injected into the BLA attenuates cue-induced reinstatement of cocaine seeking. These data extend previous reports by
See and colleagues on the effect of permanent (excitotoxic) or
reversible (tetrodotoxin, TTX; 3 ng/µl) lesions of the BLA on
cue-induced reinstatement of cocaine seeking (Meil and See, 1997; Grimm
and See, 2000). Interestingly, Grimm and See (2000) found that
intra-NAc of TTX (3 ng/µl), which blocks cocaine self-administration, has no effect on cue-induced reinstatement, whereas the BLA reversible lesions had no effect on cocaine self-administration (Fig.
7). These data are of theoretical
importance as they demonstrate a double neuroanatomical dissociation
between responding controlled by the primary (cocaine) versus the
secondary conditioned reinforcer. Most recently, Kruzich and See (2001)
demonstrated that TTX infusions (5 ng/µl) into both the BLA and the
CeA decreased cocaine cues-induced reinstatement. However, these data
cannot be clearly interpreted because a high dose of TTX was used,
anatomical controls for spread of the toxin were not used (see Wise and
Hoffman, 1992), and the authors did not assess whether the lesions led
to motor deficits.
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It appears that the BLA and, in particular, D1-like receptors in this
area are involved in cue-induced reinstatement of cocaine seeking.
These data are in agreement with those from studies on the role of
conditioned drug cues in cocaine seeking as measured by the
second-order schedule procedure and with those from studies on the
effect of BLA lesions on the ability of stimuli paired with natural
rewards to control behavior (Robbins et al., 1989; Everitt et al.,
1999). Finally, studies on the neuronal mechanisms underlying
cue-induced reinstatement of heroin seeking have not been reported.
Thus, an interesting question, in light of recent data on the lack of
effect of BLA lesions on responding for heroin-associated cues under
the second-order schedule (Alderson et al., 2000), is whether the
findings from studies on cocaine cues-induced reinstatement generalize
to reinstatement induced by heroin cues.
B. Extinction Behavior
Fuchs et al. (1998) found that chronic administration of the NA
reuptake blocker, desmethylimipramine, decreases lever pressing during
extinction. In two other studies it was found that the tryptophan
hydroxylase inhibitor, para-chlorophenylalanine, 5-HT lesions with 5,7-dihydroxytryptamine and chronic exposure to
fluoxetine also decrease extinction behavior (Tran-Nguyen et al., 1999,
2001; Baker et al., 2001). It is not clear, however, how to interpret these data as both decreases and increases in 5-HT neurotransmission decrease resistance to extinction.
Using in vivo microdialysis, several studies have examined the effect
of exposure to discrete cocaine cues during extinction on DA release in
the NAc. Meil et al. (1995) described a precipitous drop in DA levels
in the NAc when cocaine was removed from the syringe pumps, even when
rats continued to press for a discrete CS light during extinction.
Ranaldi et al. (1999) reported a decrease in DA levels in the NAc
during extinction when amphetamine was removed, despite an increase in
lever pressing for the drug CSs. These data are somewhat difficult to
interpret because any effect of the cues on DA release may be masked by
the decrease in DA levels due to the clearance of cocaine from the DA
transporter. Neisewander et al. (1996) reported that DA levels in the
NAc are not altered when the cocaine-associated cues are reintroduced during extinction testing following 7 days of withdrawal. Together, these data suggest that alterations in DA levels in the NAc are not
associated with the lever-pressing behavior controlled by the cocaine
cues during extinction. This conclusion is in agreement with those from
two recent studies in rats and monkeys, using the second-order
procedure, on the lack of effect of contingent cocaine cues on DA
release in the NAc (Bradberry et al., 2000; Ito et al., 2000). In
contrast, Tran-Nguyen et al. (1998) reported a significant elevation in
DA levels in the amygdala when rats returned to a self-administration
chamber and were allowed to press the lever for the discrete cocaine
cues following one month of withdrawal.
In vivo electrochemistry methods (e.g., chronoamperometry) could
potentially clarify the importance of DA in the NAc in cue-induced reinstatement due to the enhanced temporal resolution of the technique. It is possible that the larger sample intervals and sampling of extrasynaptic versus synaptic space used in microdialysis mask the
brief alterations in neurotransmitter release. One study used in vivo
chronoamperometry to study changes in DA signal in the NAc in response
to discrete amphetamine cues (Di Ciano et al., 2001). The authors
reported that whereas the amphetamine priming increased the DA signal,
the CS had no effect. The limitation of this study, however, is that
the DA response to the CS was determined after the behavioral response
to the cue was extinguished. Thus, the rats were not actively involved
in drug seeking during testing.
Recent studies examined neurochemical and genomic correlates of
extinction behavior and exposure to discrete cocaine cues during
withdrawal periods. Neisewander et al. (2000) studied Fos protein
activation following 21 days of withdrawal after one session of
extinction. Exposure to the self-administration environment enhanced
Fos expression in several brain areas, including the anterior
cingulate, BLA, hippocampal CA1 region, dentate gyrus, and NAc. Thomas
and Everitt (2001) used in situ hybridization to image PKC (an
intracellular signal correlated with neuronal activity) expression in
several brain areas during exposure to a cocaine-paired cue. They found
selective activation by the discrete CSs previously paired with cocaine
infusions in regions of the amygdala and cortex but not the NAc. The
relevance of these data to extinction behavior and cue-induced relapse,
however, is not clear because the discrete CS were given
noncontingently and lever pressing-behavior was not measured following
cue exposure.
Schmidt et al. (2001) reported that 12 days of cocaine
self-administration reduced tyrosine hydroxylase (TH) immunoreactivity in the NAc shell but not core after 7 days of withdrawal. However, TH
immunoreactivity in the NAc was restored in rats that experienced extinction training during this period. Extinction training also increased TH levels in the VTA, whereas TH was not altered in the VTA
by cocaine withdrawal alone. The authors concluded that extinction-induced normalization of NAc TH levels could involve increased TH synthesis, stability, and/or transport from the VTA to the
NAc. It should be pointed out, however, that because rats in the no
extinction group were not exposed to the self-administration environment during the 1-week withdrawal period, it is not known whether repeated exposure to the cocaine self-administration context or
the active experience of extinction training (or both) are involved in
the effects described above.
Finally, Crespo et al. (2001) studied the expression of proenkephalin
mRNA (PENK mRNA) in several brain areas following 0, 1, 5, or 10 days
of extinction. One group of rats had previously self-administered
cocaine, whereas the other two groups of rats had received either
cocaine or saline injections yoked to the rats self-administering
cocaine. The main finding in this study was a decrease in PENK mRNA in
the CeA of the rats of the contingent group following 5 and 10 days of
extinction and withdrawal and a similar decrease in the ventromedial
hypothalamus following 5 days but not 10 days. However, because in the
paired group both the duration of cocaine withdrawal and the experience
of extinction were manipulated (i.e., the rats in the late withdrawal
periods also had more extinction training), the relative contribution of these factors to the changes in PENK mRNA is not known.
Although several neurochemical and genomic correlates of extinction behavior were reported, because of the correlational nature of these studies, the neuronal mechanisms underlying drug seeking during extinction remained unknown. In addition, recent studies have shown that manipulations that alter 5-HT utilization can alter extinction behavior. However, as both increases and decreases in 5-HT levels are associated with decreased lever pressing during extinction, the role of 5-HT in extinction behavior remained unclear. Finally, recent data suggest that extinction training can alter the neuroadaptive changes associated with chronic cocaine use.
C. Discriminative and Contextual Drug Cues
1. Discriminative Drug Cues.
Using a runway model with
heroin-trained rats, McFarland and Ettenberg (1995, 1997, 1998) found
that the opioid antagonist naloxone or the preferentially D2-like
receptor antagonist haloperidol have no effect on heroin seeking
provoked by discriminative heroin cues. Naloxone and haloperidol,
however, blocked drug seeking on a test day conducted 24 h after
last exposure to heroin (Fig. 8). These
data suggest that the motivational processes underlying relapse induced
by the discriminative cues and the drug itself are dissociable
(McFarland and Ettenberg, 1997). Ciccocioppo et al. (2001) and Weiss et
al. (2001) reported that SCH 23390 and SCH 39166 (a newer selective
D1-like receptor antagonist that binds with low affinity to 5-HT
receptors) block reinstatement of cocaine seeking induced by
discriminative cues (Fig. 9). Weiss et
al. (2001) also reported a similar effect with the D2-like antagonist
nafadotride and the D2-like agonist PD 128,907 but not the D1-like
agonist SKF 81297. These data should be interpreted with caution
because the investigators used a single drug dose of each compound, the
effect of the compounds on ongoing extinction behavior (i.e., baseline
responding) was not determined, and the same group of rats was tested
with the four compounds. The data with PD 128,907 also are different
from previous reports on reinstatement of cocaine seeking by D2-like
agonists (Self and Nestler, 1998). Finally, in two important studies,
Weiss et al. (2000) and Ciccocioppo et al. (2001) reported that cocaine
cues increase DA release in both the amygdala and the NAc and that
D1-like receptor antagonists decrease cues-induced Fos expression in
the BLA and the mPFC (areas Cg1/Cg3).
View larger version (37K):
[in a new window]
Fig. 8.
Mean run times (± S.E.M.) in an operant runway
for each treatment group during 3 consecutive days: the final day of
extinction (Baseline), a single reinstatement trial (Test), and two
post-treatment (Post+ and Post 
) conditions, both of
which occurred on the same day 24 h after the test trial. Panels
A, C, and E show mean run times for animals that experienced the
heroin-associated olfactory stimulus (S+) during the
reinstatement test, whereas Panels B, D, and F show the data from
animals that experienced the saline-associated olfactory stimulus
(S
) on this trial. Subjects were pretreated with lactic
acid vehicle (A and B), 0.15 mg/kg haloperidol (C and D), or 0.3 mg/kg
haloperidol (E and F) prior to behavioral testing on reinstatement
(Test) day. 
, significantly different from baseline
(p < 0.05). Data are from McFarland and Ettenberg,
1997, reprinted ©1997 with permission from Springer-Verlag.
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2. Contextual Drug Cues.
As mentioned above, we found that,
in rats trained to self-administer speedball, exposure to the drug
self-administration environment, after extinction of the
drug-reinforced behavior in a different context, leads to renewal of
drug seeking (Crombag and Shaham, 2002). We recently tested the effect
of selective D1-like (SCH 23390) and D2-like (raclopride) antagonists
on context-induced reinstatement of cocaine seeking (H. Crombag,
J. W. Grimm, and Y. Shaham, manuscript submitted).
Pretreatment with the D1-like or the D2-like receptor antagonists
attenuated context-induced renewal of cocaine seeking at doses that had
minimal impact on high rate of operant responding for a sucrose
reinforcer. However, raclopride, but not SCH 23390, also decreased
lever pressing on the previously active lever in a control group that
remained in the extinction context. These data indicate that activation
of D1-like receptors is involved in context-induced reinstatement of
cocaine seeking. These data also suggest that activation of D2-like
receptors is involved in this effect, but we cannot rule out that some
nonspecific effects of raclopride were involved to some degree.
D. Summary
| 1. | Exposure to contingent, but not noncontingent, presentations of discrete CSs associated with drug infusions reinstates drug seeking. Similarly, exposure to discriminative or contextual drug cues, which predict drug availability, also can reinstate drug seeking. |
| 2. | Activation of D1-like receptors appears to mediate reinstatement induced by conditioned cocaine cues, including discrete CSs, discriminative cues and contextual cues. The available data suggest that the D2-like receptor is probably involved in discriminative or contextual cues-induced reinstatement of cocaine seeking, but not heroin seeking. |
| 3. | The BLA, but not the NAc, is involved in discrete CSs-induced reinstatement. This brain structure is probably also involved in reinstatement induced by discriminative cocaine cues. |
| 4. | Activation of NMDA receptors may be involved in discrete CSs-induced reinstatement, but glutamate receptors within the BLA are not involved in this effect. Recent data suggest that activation of brain endocannabinoid systems is involved in cue-induced relapse to cocaine seeking. |
| 5. | Increases in DA levels in the amygdala, but not the NAc, as measured by microdialysis, are correlated with cocaine seeking during extinction. |
| 6. | The experience of extinction increases immediate early gene expression in several limbic regions, including the BLA and PFC, and recent data suggest that this experience can alter the neuroadaptive changes associated with chronic cocaine use. |
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IV. Stress-Induced Reinstatement |
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Intermittent footshock reinstates drug seeking in rats previously
trained to self-administer heroin (Shaham and Stewart, 1995b; Ahmed et
al., 2000), cocaine (Erb et al., 1996; Ahmed and Koob, 1997; Mantsch
and Goeders, 1999a), nicotine (Buczek et al., 1999), and alcohol
(Lê et al., 1998; Martin-Fardon et al., 2000). Importantly, in
the above studies footshock was found to reinstate heroin and cocaine
seeking under different training doses, schedule requirements, shock
parameters and strains of rats (Shaham et al., 2000a). Most recently,
it was reported that footshock stress also "reactivates" morphine
or cocaine conditioned place preference following drug-free periods in
rats that were not exposed to extinction conditions (Lu et al., 2000,
2001a; Wang et al., 2000). The effect of footshock also generalizes to
an operant behavior controlled by brain stimulation reward into the
septum (Shalev et al., 2000) but not to behaviors based on food or
sucrose reinforcers (Ahmed and Koob, 1997; Lê et al., 1998;
Buczek et al., 1999). Possible reasons for the different effects of
footshock on drug versus nondrug reinforcers are discussed elsewhere
(Shaham et al., 2000a). In addition, the arousal state induced by
exposure to an appetitive stimulus (receptive female) has no effect on
reinstatement of heroin seeking, suggesting that arousal per se cannot
account for the effect of stress on reinstatement (Shaham et al.,
1997c).
Stressors other than footshock, including food deprivation (Shalev et
al., 2000) and a stress-like state induced pharmacologically by CRF
(Shaham et al., 1997b) reinstate heroin seeking. In addition, the
effect of footshock on reinstatement of heroin seeking is mimicked by
reversible inactivation of the medial septum with TTX (Highfield et
al., 2000). Septal lesions mimic to some degree physiological and
psychological responses to stress (Holdstock, 1967; Gray, 1987). In
cocaine-trained rats, Comer et al. (1995) reported that food
restriction enhances cocaine-induced reinstatement. Carroll (1985) also
reported that food restriction reinstates cocaine seeking in rats that
experienced this condition during self-administration training.
In heroin-trained rats, exposure to a novel environment, a condition
known to induce stress responses (Friedman and Ader, 1967), had no
effect on reinstatement (Shalev et al., 2000). In addition, in heroin-
and cocaine-trained rats, a conditioned fear stimulus (a tone
previously paired with footshock) was not an effective stimulus for
reinstatement of lever-pressing behavior (Shaham et al., 2000a). In
contrast, using the CPP reinstatement model, Sanchez and Sorg (2001)
found that a tone or odor CSs, previously paired with footshock,
reinstates cocaine CPP after extinction. The discrepant results of the
conditioned fear condition in the self-administration versus the CPP
models may be due to the fact that the predominant behavioral effect of
the fear stimulus is freezing (LeDoux, 2000), which is incompatible
with lever-pressing behavior. Finally, we found in heroin-trained rats
that the effect of stress on reinstatement is context and time
dependent. Footshock and restraint stressors given outside the
self-administration environment are ineffective (Shalev et al., 2000),
and the duration of the withdrawal period from heroin is a critical
factor in footshock stress-induced reinstatement (Fig. 13C) (Shalev et
al., 2000).
The phenomenon of stress-induced reinstatement is both stressor and reinforcer specific, and is critically dependent on the environmental context and the drug withdrawal period. A summary of the pharmacological studies on footshock stress-induced reinstatement is provided in Table 5.
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A. Dopamine and Opioids
Exposure to certain stressors, including intermittent footshock,
activates endogenous opioid systems (Akil and Morano, 1995). Thus,
footshock stress may induce reinstatement by releasing endogenous opioids, which would in turn activate µ-opioid receptors known to
mediate heroin-induced reinstatement. However, naltrexone has no effect
on footshock-induced reinstatement of heroin seeking, but blocks
heroin-induced reinstatement (Shaham and Stewart, 1996). Furthermore,
the occupation of opioid receptors by heroin infused through osmotic
minipumps has no effect on footshock-induced reinstatement, but
attenuates heroin-induced reinstatement (Shaham et al., 1996).
Exposure to several stressors, including footshock, also activates the
mesocorticolimbic DA system (Kalivas and Stewart, 1991; Piazza and Le
Moal, 1998), involved in reinstatement of heroin and cocaine seeking by
drug priming. Therefore, it was speculated that activation of this
system underlies both stress- and drug-induced relapse (Robinson and
Berridge, 1993; Shaham and Stewart, 1995b). In agreement with this
idea, chronic treatment with the nonselective DA receptor antagonist,
flupenthixol, attenuates footshock-induced reinstatement of heroin
seeking (Shaham and Stewart, 1996). However, selective D1- or D2-like
receptor antagonists (SCH 23390 or raclopride) have no effect on
footshock-induced reinstatement. In contrast, raclopride and SCH 23390 attenuated heroin-induced reinstatement. In addition, whereas footshock
is at least as effective a stimulus for reinstatement as heroin priming
(Shaham, 1996), heroin priming is a more effective stimulus for
inducing DA release in the NAc than footshock stress (Shaham and
Stewart, 1996). Overall, we interpreted these data to indicate that,
unlike the critical role DA plays in drug-induced reinstatement, this
neurotransmitter plays only an indirect/modulatory role in footshock
stress-induced reinstatement (Shaham et al., 2000a).
It appears that footshock-induced reinstatement is independent of the action of the stressor on the endogenous opioid system. In addition, although basal DA tone may be required for the expression of footshock-induced reinstatement, it is unlikely that brain DA is the critical substrate for this effect.
B. Corticosterone and Corticotropin-Releasing Factor
Exposure to stressors induces the release of the stress-related
hormones CRF and corticosterone (Friedman and Ader, 1967; Morimoto et
al., 1993). Corticosterone is known to be involved in a variety of
behavioral and neurochemical effects of exposure to stressors (Selye,
1956; Johnson et al., 1992). CRF receptors are widely distributed in
the brain and CRF has been shown to act at both hypothalamic and
extra-hypothalamic sites to mediate behavioral and physiological
responses of stress (Dunn and Berridge, 1990; de Souza, 1995).
1. Corticosterone.
We found that manipulations of
corticosterone levels by ADX or by pretreatment with a synthesis
inhibitor of corticosterone, metyrapone, have no effect on
footshock-induced reinstatement of heroin seeking (Shaham et al.,
1997b). In cocaine-trained rats, ADX attenuates footshock-induced
reinstatement. However, in rats with ADX + corticosterone replacement
(to maintain basal levels of the hormone) footshock reinstates cocaine
seeking (Erb et al., 1998). Thus, it appears that although
footshock-induced corticosterone release is not involved in
reinstatement of either heroin or cocaine seeking by the stressor,
basal levels of the hormone are required for footshock-induced
reinstatement of cocaine seeking. Two other studies, however, appear to
challenge the above conclusion. Deroche et al. (1997) found that
corticosterone infusions reinstate cocaine seeking. Mantsch and Goeders
(1999a) reported that inhibition of corticosterone synthesis with the
antimycotic agent, ketoconazole, which one of its actions is to inhibit
corticosterone synthesis, attenuates footshock-induced reinstatement of
cocaine seeking. The results of this study, however, are difficult to
interpret due to lack of specificity of ketoconazole, which also acts
on several other neurotransmitter and hormonal systems.
2. Corticotropin-Releasing Factor.
Acute injections of CRF
induce reinstatement of heroin seeking (Shaham et al., 1997b).
Moreover, the CRF receptor antagonists, D-Phe CRF and
-helical CRF, attenuate footshock-induced reinstatement of heroin
and cocaine seeking (Shaham et al., 1997b; Erb et al., 1998; Lu et al.,
2000, 2001a). The effect of CRF on reinstatement appears to be mediated
by the CRF1 receptor subtype. Administration of
CP-154,526, a selective CRF1 receptor antagonist,
attenuates footshock-induced reinstatement of heroin and cocaine
seeking (Shaham et al., 1998; Lu et al., 2000, 2001a). In contrast,
administration of the CRF2 receptor antagonist,
antisauvagine-30, has no effect on footshock-induced reactivation of
CPP for morphine and cocaine (Lu et al., 2000, 2001a). These data,
together with those from the studies of the lack of effect of ADX
(heroin-trained rats) or ADX + corticosterone replacement
(cocaine-trained rats) on footshock-induced reinstatement, suggest that
the effect of the CRF receptor antagonists on reinstatement is mediated
via their action on extra-hypothalamic sites, independent of their
effect on the HPA axis.
studied the role of CRF in two brain sites
involved in stress response and the behavioral effects of CRF, the bed
nucleus of the stria terminalis (BNST) and the amygdala (Davis et al.,
1997; Koob and Heinrichs, 1999). They found that infusions of CRF into
the ventral BNST reinstate cocaine seeking, whereas intra-BNST
infusions of D-Phe CRF attenuate footshock-induced reinstatement (Fig. 10). In contrast,
infusions of CRF into the amygdala (infusions were aimed at the CeA)
have no effect on reinstatement and intra-amygdala infusions of
D-Phe CRF do not attenuate footshock-induced reinstatement
(Erb and Stewart, 1999). In a subsequent study with heroin-trained
rats, however, we found that reversible inactivation of both the CeA
and the BNST with TTX blocks footshock-induced reinstatement of heroin
seeking (Shaham et al., 2000a). The CeA contains high densities of cell
bodies and projection neurons for CRF, but unlike the BNST, the density
of the CRF receptors in this area is low (Gray and Bingaman, 1996; Van
Pett et al., 2000). Thus, it may not be surprising that CRF or the CRF
receptor antagonists had little effect on reinstatement when infused
into the CeA (see also Lee and Davis, 1997). Sakanaka et al. (1986) described a CRF-containing projection from the CeA to the BNST, and it
has been speculated that this projection may account, in part, for the
increase in CRF release in the BNST following exposure to stress (Lee
and Davis, 1997).
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studied whether the CRF-containing projection from
the CeA to the BNST is involved in footshock-induced reinstatement of
cocaine seeking. They used an asymmetric lesion method (Parkinson et
al., 2000; Easton and Gaffan, 2001) to functionally disconnect the
CRF-containing pathway from the CeA to the BNST. This was achieved by
simultaneously injecting TTX into the CeA in one hemisphere and
D-Phe CRF into the BNST in the opposite hemisphere. Before
testing for footshock-induced reinstatement, rats were given asymmetric
injections of TTX (2.5 ng) and D-Phe CRF (50 ng) into the
CeA and BNST, respectively, or they were given unilateral injections of
either compound alone into the appropriate structure. Functional
inactivation of the amygdala-BNST pathway significantly reduced
footshock-induced reinstatement compared with that seen when only one
hemisphere was manipulated. However, the fact that this attenuation of
footshock-induced reinstatement was not complete implies the existence
of an additional source of CRF in the BNST other than the CeA-BNST
pathway, possibly from cells intrinsic to the BNST (Veinante et al.,
1997).
These data suggest that activation of extra-hypothalamic CRF receptors
is involved in footshock-induced reinstatement of heroin and cocaine
seeking (see also Lê et al., 2000 for similar findings in
alcohol-trained rats). In addition, this effect is probably mediated by
activation of CRF1 but not
CRF2 receptors. Finally, it appears that CRF
receptors within the BNST and possibly the CRF projection from the CeA
to the BNST are involved in footshock-induced reinstatement.
C. Noradrenaline
NA neurons are activated by stressors and are thought to mediate
psychological and physiological responses to stress (Stanford, 1995;
Bremner et al., 1996). We found that administration of the -2
adrenoceptor agonists, clonidine and lofexidine, known to inhibit NA
cell firing and neurotransmitter release (Aghajanian and VanderMaelen,
1982; Carter, 1997), attenuate footshock-induced reinstatement of
heroin, cocaine, and speedball seeking (Erb et al., 2000; Shaham et
al., 2000b; Highfield et al., 2001) (Fig. 11). In contrast, these compounds have
no effect on cocaine-induced reinstatement (Erb et al., 2000) or
discrete CSs-induced reinstatement (Highfield et al., 2001). Clonidine
and several other -2 adrenoceptor agonists also bind to the to the
imidazoline type 1 receptor (Piletz et al., 1994). However, the -2
adrenoceptor agonist guanabenz, which binds at low affinity to
imidazoline receptors, also attenuates footshock-induced reinstatement
(Erb et al., 2000). Thus, it is unlikely that clonidine and lofexidine
attenuate footshock-induced reinstatement by acting on imidazoline
receptors.
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The effect of the -2 adrenoceptor agonists on
footshock-induced reinstatement is centrally mediated. In
cocaine-trained rats, systemic injections of ST-91, a charged analog of
clonidine that does not readily cross the blood-brain barrier
(Scriabine et al., 1975), have no effect on footshock-induced
reinstatement (Erb et al., 2000). In heroin-trained rats, ventricular
injections of clonidine block footshock-induced reinstatement (Shaham
et al., 2000b).
Subsequently, we studied the brain sites involved in the effect of
clonidine on footshock-induced reinstatement of heroin seeking (Shaham
et al., 2000b). The brain NA projections arise from two groups of
cells, the locus coeruleus (LC) and the lateral tegmental nuclei. The
LC neurons project to forebrain areas via the dorsal noradrenergic
bundle and provide input to cortical areas such as the hippocampus and
frontal cortex (Moore and Bloom, 1979). The lateral tegmental nuclei
innervate a smaller number of forebrain areas (most of which are also
innervated by the LC neurons) via the ventral noradrenergic bundle
(VNAB). These include the hypothalamus, CeA, Nac, and BNST (Moore and
Bloom, 1979; Fritschy and Grzanna, 1991; Aston-Jones et al., 1999). LC
neurons are activated by stressors and play a role in responses to
stress (Tanaka et al., 1990), whereas the functions of the lateral
tegmental NA system were studied to a lesser degree (Hansen et al.,
1980; Cole and Robbins, 1987), and its role in stress responses has not
been determined. We found that bilateral injections of clonidine or ST-91 into the LC have no effect on footshock-induced reinstatement of
heroin seeking, suggesting that the effects of the -2 adrenoceptor agonists on reinstatement are not mediated by the LC neurons (Shaham et
al., 2000b).
We then studied the possible role of the lateral tegmental NA neurons
by making selective 6-hydroxydopamine lesions of the VNAB (Hansen et
al., 1980; Delfs et al., 2000) following heroin self-administration
training. These lesions reduced NA levels in the hypothalamus and BNST
by 60 to 70% and were found to attenuate footshock-induced
reinstatement (Shaham et al., 2000b). This finding does not provide
direct evidence for the site of action of the -2 adrenoceptor
agonists. However, together with the data on the lack of effect of
clonidine and ST-91 in the LC, these data suggest that certain NA
nuclei in the lateral tegmentum (e.g., A2 neurons) are involved in
footshock-induced reinstatement of heroin seeking. Additional support
for this idea is the finding that intra-BNST infusions of a mixture of
-1 and -2 adrenoceptor antagonists (betaxolol and ICI 181,555)
block footshock-induced reinstatement in cocaine-trained rats (F. Leri
and J. Stewart, unpublished data). The BNST is the main target for A2
NA neurons (Aston-Jones et al., 1999).
The data indicate that central NA neurons are involved in
footshock-induced reinstatement of drug seeking. Somewhat surprisingly, it appears that lateral tegmental NA neurons and their VNAB projections but not LC neurons are involved in this effect. Finally, a question that arises from the data reviewed above is the nature of the interaction between the NA and the CRF systems in the mediation of
footshock-induced reinstatement. It appears that two main
neurotransmitter systems, CRF and NA, and two main brain structures,
the CeA and the BNST, are involved in footshock-induced reinstatement.
Several neuronal pathways are likely to be involved in this effect: the VNAB and CRF pathways from the CeA to the BNST and/or from CRF neurons
intrinsic to the BNST. The antagonism of CRF receptors in the BNST (but
not in the CeA) or blockade of postsynaptic -adrenoceptors attenuates footshock stress-induced reinstatement, suggesting an
interaction between these two systems at least in the BNST. Studies
using tracing methods or DSP-4 injections (which selectively destroy LC
neurons) have shown that the ventral lateral region of the BNST and the
CeA are two of the main targets of the lateral tegmental NA neurons
(Fritschy and Grzanna, 1991; Delfs et al., 2000). In the vBNST, lateral
tegmental NA neurons form synaptic contact with CRF-containing neurons
(Phelix et al., 1994), whereas the nature of the synaptic interactions
in the CeA is not known. Using microdialysis, it was found that i.c.v.
infusions of D-Phe CRF (1 µg) have no effect on footshock
stress-induced NA release in the BNST (Erb et al., 2001). These data,
together with the pharmacological data with CRF receptor antagonists
and -2 adrenoceptor agonists, raise the possibility that activation
of VNAB neurons leads to the activation of CRF systems within the BNST
and CeA. One possibility is that activation of VNAB neurons by
footshock leads to activation of intrinsic CRF systems within the BNST
(see Phelix et al., 1994). Another possibility, albeit speculative, is
that activation of the VNAB neurons projecting to the CeA activates the
CRF pathway from the CeA to the BNST (see Sakanaka et al., 1986). The
data on the effect of TTX infusions in the CeA (Shaham et al., 2000a)
and on the effect of "disconnecting" the CeA-BNST CRF pathway (Erb
et al., 2001) are in agreement with the idea that such an indirect
pathway may also be involved in footshock-induced reinstatement.
D. Other Neurotransmitter Systems
Nociceptin/orphanin FQ is the endogenous ligand of the ORL1
receptor (Meunier et al., 1995), and evidence suggests that it may
serve as a functional anti-opioid peptide in the control of brain
nociceptive processes (Darland et al., 1998). This peptide has been
reported to decrease alcohol and morphine CPP and stress- and
CRF-mediated effects (Ciccocioppo et al., 2000). Martin-Fardon et al.
(2000) tested the effect of nociceptin on footshock-induced alcohol and
cocaine seeking and found that the peptide decreases footshock-induced
reinstatement in rats with a history of alcohol, but not cocaine
self-administration. The reasons for these discrepant findings are not clear.
Leptin is a recently discovered hormone, which is critically involved
in energy balance and food consumption (Friedman and Halaas, 1998). In
a recent report, leptin was found to reverse the enhancement of lateral
hypothalamus brain stimulation reward by chronic food restriction
(Fulton et al., 2000). As mentioned above, we found that acute food
deprivation reinstates heroin seeking (Shalev et al., 2000), data that
extend previous reports on the effect of food deprivation on drug
self-administration and reward (Carroll and Meisch, 1984; Carr, 1996).
The neuronal mechanisms underlying the potent effect of food
deprivation on drug-taking behavior are not known. Based on the report
by Fulton et al. (2000), we tested the effect of leptin in our model
and found that leptin attenuates acute food deprivation-, but not footshock- or heroin-induced reinstatement (Shalev et al., 2001b) (Fig.
12). This result may suggest that the
neuronal mechanisms underlying relapse induced by food deprivation are
different from those involved in the relapse induced by footshock
stress or heroin priming (see Section V.B.3.).
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E. Summary
| 1. | Footshock-induced reinstatement of heroin seeking is unaffected by opioid receptor antagonists and is relatively insensitive to dopamine receptor antagonists. |
| 2. | CRF-receptor antagonists attenuate footshock-induced reinstatement of heroin and cocaine seeking, an effect mediated by CRF receptors in the BNST. A CRF pathway from the CeA to the BNST may also be involved in footshock-induced reinstatement. |
| 3. | Stress-induced release of corticosterone is not involved in footshock-induced reinstatement of heroin or cocaine seeking, but basal levels of corticosterone are required for footshock-induced reinstatement of cocaine seeking. |
| 4. | 2-Adenoceptor agonists, which decrease
NA cell firing and release, attenuate footshock-induced reinstatement
of heroin and cocaine seeking, but not drug- or cue-induced
reinstatement. The effect of the 2-adenoceptor
agonists is centrally mediated.
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| 5. | Studies with heroin-trained rats indicate that NA neurons originating from the lateral tegmental nuclei, but not LC neurons, are involved in footshock-induced reinstatement. |
| 6. | Acute food deprivation reinstates heroin seeking, an effect that is attenuated by central infusions of the hormone leptin. |
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V. Discussion |
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In this section we summarize the data reviewed above. Subsequently, we discuss several theoretical issues related to the phenomena of drug priming-, cues- and stress-induced reinstatement. We then address methodological issues associated with the use of the reinstatement procedure. Finally, we discuss emerging issues in reinstatement studies and the implications of the data from these studies for theories of addiction and treatment.
A. Neural Mechanisms Underlying Relapse to Heroin and Cocaine: a
Summary
1. Drug Priming-Induced Reinstatement.
Activation of
µ-opioid receptors is critically involved in heroin-induced
reinstatement, and DA mechanisms (likely to be initiated within the
VTA) also are involved in this effect. In the case of cocaine priming,
the data indicate that D1- and D2-like DA receptors play fundamentally
different roles: activation of D2-like receptors promotes cocaine
seeking, whereas activation of D1-like receptors inhibits it. In
addition, activation of AMPA receptors within the NAc is involved in
cocaine-induced reinstatement. An important question for future
research, therefore, is what are the brain sites through which DA
mediates cocaine-induced reinstatement. Finally, although
pharmacological agents acting at receptors of several other
neurotransmitter systems (e.g., 5-HT2C,
GABAB) can attenuate cocaine-induced
reinstatement, this effect is probably mediated via the effect of these
receptor manipulations on DA release. 2. Cue-Induced Reinstatement.
The D1-like receptor appears to
play a critical role in cocaine reinstatement induced by discrete CSs,
discriminative and contextual cues, a finding in agreement with the
general role of this receptor in conditioned reward (Sutton and
Beninger, 1999 3. Stress-Induced Reinstatement.
The effect of footshock
stress on reinstatement is opioid-independent and DA appears to play
some modulatory role in this effect. In addition, footshock-induced
corticosterone secretion is not involved in the effect of the stressor
on reinstatement. Two main neurotransmitter systems, CRF and NA, and
two main brain structures, the CeA and the BNST, are involved in
footshock stress-induced reinstatement. The data also suggest that two
neuronal pathways are involved in this effect: the VNAB, which
originates from the lateral tegmental NA neurons, and possibly a CRF
pathway from the CeA to the BNST. Finally, the hormone leptin is
involved in reinstatement of heroin seeking induced by food deprivation stress.). In addition, it appears that the D2-like receptor also
is involved in contextual or discriminative cues-induced reinstatement
of cocaine, but not heroin seeking. A critical brain site that mediates discrete CSs-induced reinstatement is the BLA, in which D1-like, but
not glutamate, receptors are involved in this effect. Indirect evidence
from in vivo microdialysis and Fos expression studies also implicates
the BLA in cue-induced reinstatement. In contrast, a role for the NAc
in cocaine cues-induced reinstatement has not been established.
Manipulations of 5-HT neurotransmission (lesions and 5-HT reuptake
blockers) can alter lever pressing controlled by the cocaine cues
during extinction, but the exact role of 5-HT in extinction behavior is
not clear.; McFarland and
Ettenberg, 1997, 1998) have no effect on footshock-induced heroin
seeking (Shaham and Stewart, 1996). Conversely, CRF receptor antagonists and -2 adrenoceptor agonists that block
footshock-induced reinstatement have no effect on drug-induced
reinstatement (Shaham et al., 2000a). In the case of cue- and
drug-induced reinstatement, Stewart et al. (1984) suggested that drug
cues reinstate drug seeking by inducing a "drug-like" state similar
to that induced by the drug itself, which is mediated in part by
enhanced DA neurotransmission. However, whereas DA appears to be
involved in both drug- and cue-induced reinstatement (see above),
pharmacological and neuroanatomical dissociations were reported. For
example, the NAc appears to be a critical substrate for cocaine-induced
reinstatement (Cornish and Kalivas, 2000), but lesions of this
structure have no effect on discrete CSs-induced reinstatement (Grimm
and See, 2000). On the other hand, reversible lesions of the NAc, which
block cocaine self-administration, have no effect on cue-induced
reinstatement (Grimm and See, 2000). In addition, in the case of heroin
seeking, DA and opioid receptor antagonists block heroin-induced drug
seeking, but they have no effect on drug seeking provoked by
discriminative heroin cues (McFarland and Ettenberg, 1997, 1998).
). However,
cross-reinstatement between opioid and stimulant drugs is to a large
degree asymmetrical. Indirect DA agonists or D2-like agonists reinstate
heroin seeking (Wise et al., 1990; De Vries et al., 1999), whereas
µ-opioid receptor agonists (given systemically) do not reinstate
cocaine seeking (de Wit and Stewart, 1981; Comer et al., 1993).
However, the initial sedative effects of opioid agonists, given acutely
to opioid-naive rats, may mask their motivational effect as infusions
of morphine into the VTA reinstate cocaine seeking (Stewart, 1984). In
the case of footshock-induced reinstatement, the pharmacological data
suggest that similar neuronal mechanisms are involved in heroin or
cocaine seeking (Shaham et al., 2000a). One exception is that basal
levels of corticosterone are required for footshock-induced
reinstatement of cocaine but not heroin seeking (Shaham et al., 2000a).
There is very little information on similarities/differences in
cue-induced reinstatement of heroin and cocaine seeking, but it is
possible that these are not identical. For example, although the
preferential D2-like antagonist haloperidol has no effect on
discriminative cue-induced reinstatement of heroin seeking in the
runway model (McFarland and Ettenberg, 1997), selective D2-like
antagonists appear to attenuate discriminative (Weiss et al., 2001) and
contextual (H. Crombag, J. W. Grimm, and Y. Shaham, manuscript
submitted) cues-induced reinstatement of cocaine seeking. In
addition, studies using the second-order schedule procedure have shown
that manipulations that block drug seeking controlled by CSs in
cocaine-trained rats (e.g., a D3 receptor partial agonist, BLA lesions)
have no effect on cue-induced drug seeking in heroin-trained rats
(Everitt and Robbins, 2000).
Finally, the data reviewed suggest that the neuronal substrates that
mediate drug-induced reinstatement are to some degree different from
those that mediate drug reinforcement. First, although D1-like receptor
agonists substitute for cocaine in the drug self-administration method
and some of these agents produce CPP (Self and Nestler, 1995; Abrahams
et al., 1998), they do not reinstate cocaine seeking (Self and Nestler,
1998). Second, although NMDA receptor antagonists are self-administered
directly into the NAc (Carlezon and Wise, 1996), an NMDA antagonist
does not reinstate cocaine seeking (Cornish and Kalivas, 2000). Third,
Cornish et al. (1999) found that whereas NMDA and AMPA agonists have a
minimal effect on cocaine self-administration behavior, these agonists
reinstate cocaine seeking. These investigators also showed that
blockade of DA receptors in the NAc, known to be involved in cocaine
reinforcement (Wise, 1996b), have no effect on cocaine-induced
reinstatement. Fourth, although manipulations of corticosterone
secretion have a profound effect on cocaine self-administration
behavior (Piazza and Le Moal, 1996; Goeders, 1997), similar
manipulations have a minimal effect on cocaine-induced reinstatement
(Erb et al., 1998; Mantsch and Goeders, 1999b). Fifth, Vorel et al.
(2001) showed that electrical stimulation of the medial forebrain
bundle
known to be involved in reward processes (Wise, 1996a)has no
effect on reinstatement of cocaine seeking. In contrast, stimulation of
the ventral hippocampus, a brain area that has not been reported to be
involved in drug reward, potently reinstates cocaine seeking. Sixth,
although blockade of brain CB1 receptors attenuates cocaine-induced
reinstatement, this manipulation has no effect on cocaine
self-administration behavior (De Vries et al., 2001). Finally, although
DA receptor antagonists do not have a consistent effect on heroin
self-administration behavior (Ettenberg et al., 1982; Mello and Negus,
1996), they reliably attenuate drug seeking induced by heroin priming
(Shaham and Stewart, 1996; McFarland and Ettenberg, 1997).
It appears that multiple and dissociable brain systems are involved in
relapse to heroin and cocaine seeking induced by drug priming,
conditioned cues, and stress. Somewhat surprisingly, it also appears
that the neuronal events that mediate heroin- or cocaine-induced
reinstatement are to some degree different from those involved in their
reinforcing effects.
B. Theoretical Issues
In this section, theoretical issues concerned with the effects of drug priming, drug cues and stressors are considered.
1. Drug Priming.
Several explanations for the drug priming
effect have been put forward over the years. It has been suggested that
the discriminative stimuli properties of drugs mediate in part
drug-induced reinstatement (Stolerman, 1992; Bergman and Katz, 1998).
Rats can readily learn to discriminate drugs from saline in a drug
discrimination model, wherein deprived rats learn to press one lever
for food/water following drug injections and a different lever
following saline injections (Stolerman, 1992). The drug discrimination
procedure is regarded as an animal model for the subjective effects of
drugs in humans (Preston, 1991). According to a discriminative stimulus account of reinstatement, exposure to the self-administration drug
during testing elicits a selective increase in responding on the
previously active lever because certain drug effects signal the rat
that pressing this lever but not the inactive lever will lead to drug
infusions. Proponents of this view typically point out that as in the
case of drug discrimination response generalization is most likely to
occur within the same drug class.
a manipulation that induces reinstatement of
heroin seeking (Stewart, 1984)do not induce heroin-appropriate responding in the drug discrimination method (Shaham and Stewart, 1995a; Jaeger and van der Kooy, 1996; but see Shoaib and Spanagel, 1994). Jaeger and van der Kooy (1993, 1996) further showed that the
rewarding and discriminative effects of morphine are anatomically dissociable and that the discriminative drug effects are neither necessary nor sufficient for morphine's rewarding effects. Finally, the observations that indirect DA agonists and D2-like agonists reinstate heroin seeking (Wise et al., 1990; De Vries et al., 1999) is
not in agreement with most studies from the drug discrimination literature, in which generalization to the training drug is typically observed within a given drug class (Stolerman et al., 1989, 1995).
Stewart and colleagues hypothesized that reinstatement by drug priming
is due to the ability of the drug to induce an incentive motivational
state, which leads to resumed drug seeking (Stewart et al., 1984). This
incentive motivational state refers to the arousing/activating state
that occurs following exposure to an appetitive unconditioned stimulus
or to stimuli classically conditioned to the unconditioned stimulus
(Stewart et al., 1984). They postulated that drug seeking during tests
for reinstatement occurs because the presence of the drug in the body
(and brain) enhances the incentive value of the extinguished drug cues,
previously paired with the drug's rewarding effect. The findings that
both heroin and cocaine priming reinstate drug seeking via activation
of the mesocorticolimbic DA (Stewart, 2000), thought to be involved in incentive motivation and appetitive goal-direct behavior (Stewart et
al., 1984; Robinson and Berridge, 1993; Di Chiara, 1995), provide support to this idea. Additional support for Stewart's hypothesis is
the observation that the removal of the drug cues previously associated
with amphetamine during testing attenuates amphetamine-induced reinstatement (Stretch et al., 1971). Finally, as argued by Leri and
Stewart (2001), the findings that drug priming reinstates an approach
behavior toward contextual cues previously associated with the drug's
rewarding effects after extinction in the CPP model is consistent with
an incentive motivation view but not with a discriminative stimulus
view. Specifically, in the CPP procedure the drug is not associated
with a specific instrumental responding. Thus, it is unlikely that drug
priming acts to induce a habitual form of responding that is elicited
by its discriminative stimulus properties (see Bickel and Kelly, 1988).
It appears unlikely that the discriminative stimulus properties of the
priming drug injections can account for their effect on reinstatement.
In contrast, the available data appear to fit an incentive motivation
account of drug priming. It should be pointed out, however, that this
state of affairs might be due to the fact that incentive motivation is
a theoretical construct, and as such, it is difficult to design
experiments that can refute or support its role in reinstatement. It is
also likely that incentive motivation is only one of several processes
involved in relapse behavior. The data reviewed indicate that multiple
neuronal systems are involved in relapse induced by drug priming, cues,
and stress, implying that multiple psychological processes are likely
to be involved. Finally, as argued by Tiffany (1990), relapse often occurs as a result of automated processes, which are independent of
motivational processes.
2. Drug Cues.
It has long been established that
conditioned drug cues can provoke relapse in rats and monkeys
(Goldberg, 1976). Furthermore, drug-associated stimuli can modulate the
behavioral and physiological effects of drugs of abuse (Siegel, 1989;
Stewart, 1992; Robinson et al., 1998). In the last 6 years, several
laboratories have used established learning procedures, including
conditioned reinforcement, discrimination learning, and renewal
(Catania, 1992; Bouton, 1993) to study neuronal substrates underlying
relapse induced by discrete CSs (previously paired with each drug
injection) and discriminative and contextual cues, which predict drug
availability but are not specifically paired with each drug injection.
This distinction is important since previous studies indicate that
different neuronal circuits underlie the behavioral effects of discrete
CSs versus contextual stimuli (Phillips and LeDoux, 1992; Holland and
Bouton, 1999).
). Interestingly, this experimental
manipulation results in a persistent effect of the drug cues on
reinstatement over many test sessions and up to 4 months of withdrawal
periods (Ciccocioppo et al., 2001).
Even with the renewal procedure, in which one set of contextual cues
(e.g., specific smell, floor texture) is associated with drug
self-administration training and the other set of cues is paired with
extinction training while keeping the discrete CS (e.g., cue light,
sound of the pump) constant during training and extinction, the
interpretation of the data is not straightforward. One possibility is
that the effect of the drug context on renewal of drug seeking is due
to a nonspecific effect of switching rats to a different environment.
This possibility is not likely becasue we found that rats exposed to a
novel environment during testing do not resume lever-pressing behavior
(Crombag and Shaham, 2002), a finding in agreement with previous
reports (Bouton and King, 1983; Goddard, 1999; Nakajima et al., 2000).
Alternatively, contextual stimuli, because they reliably signal drug
availability, acquire excitatory conditioned stimulus (CS+) qualities,
including incentive motivational properties. In our studies, extinction
training occurred in a different environment and therefore contextual
cues would have retained their motivational value. Exposure of rats to
these (nonextinguished) contextual cues could have elicited cocaine seeking.
Another possibility is that drug-associated contextual stimuli provoke
relapse because of their occasion setter (Holland, 1992) or modulator
(Rescorla et al., 1985) properties. Unlike traditional CSs, occasion
setters do not elicit behavior by themselves, but rather modulate the
behavioral effects of other conditioned stimuli (Holland, 1992).
According to this view, contexts function as retrieval cues in cases
where the meaning of the discrete CSs is ambiguous because they have
been paired with both reinforcement and nonreinforcement (Bouton,
1993), as is the case in our studies. Thus, a question that emerges
from the above behavioral analysis is whether the DA receptor
antagonists block context-induced reinstatement of cocaine seeking by
interfering with the putative occasion setting properties of the
context or by acting on neuronal systems that underlie conditioned
behaviors elicited by discrete CSs.
Thus, unlike studies using classical conditioning paradigms on
mechanisms underlying contextual versus discrete cues on behavior (e.g., conditioned fear; conditioned activity), in studies on drug
cues-induced reinstatement, it is difficult to differentiate between
the relative contribution of discrete CSs associated with drug
infusions versus that of discriminative and/or contextual cues
associated with drug availability. It is also likely that on many
occasions an interaction between discrete CSs and contextual cues
underlies cue-induced relapse to drugs.
3. Stress.
Several mechanisms have been proposed to explain
the effect of footshock stress on relapse to drug seeking. It has been
suggested that activation of the mesocorticolimbic DA system by
stressors underlies their effect on reinstatement, thus mimicking drug
priming (Robinson and Berridge, 1993; Shaham and Stewart, 1995a). This hypothesis, however, is not likely as footshock stress- and
drug-induced reinstatement can be dissociated pharmacologically and
anatomically (Shaham et al., 2000a). It has also been argued that
footshock stress might reinstate cocaine seeking by mimicking certain
interoceptive cues of cocaine that were present during training (Ahmed
and Koob, 1997). Footshock exposure results in cocaine-appropriate
responding in drug discrimination tasks (Mantsch and Goeders, 1999a).
However, footshock is often a more effective stimulus for reinstatement than drug priming (Shaham, 1996), an observation that would not be
predicted if stressors act by mimicking the cue properties of the drug.
In addition, Mantsch and Goeders (1999a) reported that a
pharmacological manipulation (ketoconazole administration) that blocks
footshock-induced reinstatement does not alter footshock-induced cocaine-appropriate responding in a drug discrimination task. Finally,
the pharmacological dissociation between footshock- and drug-induced
relapse does not support the idea that the stressor mimics
interoceptive drug cues.
suggested that stressors induce a withdrawal-like
state, which leads to relapse to heroin use. There are similarities
between the stress response and symptoms of opioid withdrawal (Redmond
and Huang, 1979). However, this idea seems unlikely as withdrawal
precipitated by an opioid receptor antagonist does not reinstate heroin
seeking and footshock reinstates drug seeking in the presence of a
maintenance dose of heroin (Shaham and Stewart, 1995b; Shaham et al.,
1996). Finally, Highfield et al. (2000) provided some evidence that
footshock stress may provoke relapse by interfering with a neuronal
processes underlying response inhibition, whose function is to stop
ongoing activity when reinforcers are not available, as is the case
during extinction (Pavlov, 1927; Gray, 1987). Four outcomes suggestive
of the interruption of inhibitory processes, and which would be
predicted by a "disinhibitory" account of footshock-induced
reinstatement, were obtained (Highfield et al., 2000). These include:
1) reinstatement of heroin seeking by inactivation of the medial
septum, a brain area involved in response inhibition (Grossman, 1977;
Gray and McNaughton, 1983); 2) attenuation of footshock-induced
reinstatement by stimulation of the medial septum; 3) summation between
reduced activation of the medial septum and mild shock; and 4)
increased resistance to extinction by footshock stress.
Another unresolved question concerns the mechanisms underlying food
deprivation stress-induced reinstatement. We found that leptin
attenuates food deprivation-induced, but not footshock- or
heroin-induced reinstatement (Shalev et al., 2001b). Thus, it is
possible that the neuronal events that mediate acute food deprivation-induced reinstatement are dissociable from those involved in reinstatement induced by footshock or heroin priming. This hypothesis can be confirmed (or refuted) by determining the effect on
food deprivation-induced reinstatement of pharmacological agents that
block reinstatement by drug priming or footshock.
It appears that footshock stress reinstates drug seeking by mechanisms
that are probably unrelated to the ability of the stressor to induce
drug-like or withdrawal-like states. An alternative explanation is that
acute exposure to footshock disrupts neural processes that normally
exert inhibitory control over prepotent behaviors. Finally, the
mechanisms underlying food deprivation-induced reinstatement are yet to
be elucidated.
4. Summary. Although a great deal of knowledge has been accumulated on the neuronal mechanisms underlying relapse behavior, the psychological processes involved in relapse induced by drug priming, drug cues, and stressors are not clear. In the case of drug-induced reinstatement, the available data appear to support the idea that incentive motivational processes underlie this effect. In contrast, the data reviewed do not support the idea that the discriminative stimulus effects of drugs mediate drug-induced reinstatement. In the case of cue-induced reinstatement, an unresolved issue is the degree of overlap between the neuronal mechanisms underlying relapse induced by discrete CSs paired with drug injection versus discriminative or contextual cues that predict drug availability. Finally, little is known about the mechanisms underlying stress-induced reinstatement. The available data do not support the idea that footshock reinstates by inducing drug-like or withdrawal-like states. The stressor, however, may reinstate drug seeking by its actions on neuronal processes involved in response inhibition. Finally, it is not known whether food deprivation reinstates drug seeking by acting on neuronal systems involved in drug priming or footshock, or by its action on a different neuronal circuit that is yet to be elucidated.
C. Methodological Issues
In this section, we address several methodological issues that should be considered in the interpretation of data from reinstatement studies. A distinction that we will make in this section is whether the experimental variable discussed alters behavior during tests for reinstatement in a quantitative (i.e., a change in the magnitude of a given behavioral effect by the different levels of the experimental variable) or a qualitative manner (i.e., a change in the direction of a given behavior by the different levels of the experimental variable).
1. Prior Training for Food Reinforcement.
In many studies,
rats are trained to lever press for food prior to drug
self-administration training. Although these conditions facilitate drug
self-administration training (Carroll, 1999), they may introduce
confounds in reinstatement studies. Specifically, when the same
experimental setup is used for food training and drug
self-administration training, the latter condition comprises a
component of extinction training for food. Thus, resumption of
lever-pressing responding during testing may be due to reinstatement of
food seeking rather than drug seeking. This alternative explanation can
be ruled out by using a control group of rats that lever press for food
(de Wit and Stewart, 1981; Shaham et al., 1997a), but this condition
has rarely been employed in reinstatement studies.
2. Noncontingent Priming Injections during Training.
A common
practice in drug self-administration studies is to start the training
sessions with one or two priming noncontingent drug injections (Caine
and Koob, 1994). As in the case of food training, this manipulation
facilitates drug self-administration training but it introduces
confounds in the interpretation of the data. When noncontingent drug
injections are given at the start of each training session they may
become discriminative cues (Catania, 1992) that predict drug
availability. As these priming injections are not given during the
extinction phase, when drug priming is reintroduced during testing it
may reinstate drug seeking because of its discriminative stimulus
properties (i.e., it informs the rat that the drug is now available or
that subsequent lever presses will lead to contingent drug injections). Thus, when priming injections are given during training, their effect
on reinstatement after extinction may be due to their discriminative stimulus effects, incentive motivational effects (see Section V.B.1.), or both.
3. Response Rates during Training.
The effect of
pharmacological manipulations on operant behavior maintained by drugs
or nondrug reinforcers is dependent on baseline rates of responding,
the rate dependence effect (Sanger and Blackman, 1976; Witkin, 1994).
For example, DA receptor antagonists increase lever pressing for a high
unit dose of cocaine when each lever press is reinforced, a fixed
ratio-1 (FR-1) schedule (Wise, 1978; Ettenberg et al., 1982). On the
other hand, under an intermittent schedule of reinforcement (FR-15),
which leads to a high rate of responding, DA receptor antagonists
decrease lever pressing for cocaine (Caine and Koob, 1994). An
important question, therefore, is whether the rate of responding during
training leads to qualitative differences in the behavioral effects of
drug priming, drug cues, and stressors during testing. Response rates
during training can be manipulated by changing either the schedule of
reinforcement, the unit dose (i.e., the dose per infusion) of the
training drug, or both.
found that under an FR-1 schedule, the
training dose of cocaine (0.2, 0.4, or 1.0 mg/kg/infusion, which
leads to high, moderate, or low response rates, respectively) does not
alter reinstatement induced by cocaine priming in rats. In addition,
regardless of the training dose, food restriction enhanced the effect
of cocaine priming on reinstatement. Leri and Stewart (2001) trained
rats to lever press for heroin (0.025, 0.05, 0.1, or 0.2 mg/kg/infusion; FR-1 schedule) or cocaine (0.25, 0.5, 1.0, or 2.0 mg/kg/infusion; FR-1 schedule) on alternate days. They found that
response rates during training (which are high with low doses and low
with high doses) do not predict the response to cocaine or heroin
priming after extinction. In contrast, Kruzich et al. (1999) reported
that the response rate during training was negatively correlated with
the magnitude of cue-induced reinstatement. These data should be
interpreted with caution as they are based on correlational analyses
rather than on experimental manipulations.
Most important, it was found that regardless of the response rates
during training, pharmacological agents have similar effects on
reinstatement. For example, the effect of D1- and D2-like agents on
reinstatement of cocaine seeking in rats trained on a high unit dose
and an FR-1 schedule (Wise et al., 1990; Self et al., 1996), conditions
that lead to low response rates, generalizes to monkeys trained on a
second-order schedule, which leads to high rates of responding (Khroyan
et al., 2000). Furthermore, it has been shown that pharmacological
manipulations (e.g., CRF receptor antagonists) that attenuate
footshock-induced reinstatement in an operant procedure (Shaham et al.,
2000a), also attenuate reactivation of CPP by the stressor in a
classical conditioning, rate-independent paradigm (Lu et al., 2000,
2001a).
In conclusion, it does not appear that differences in response rates
within and between studies lead to qualitatively different effects on
reinstatement of drug seeking. The fact that findings from
reinstatement studies based on operant self-administration behavior
generalize to those from rate-independent CPP studies further supports
this conclusion. However, in agreement with learning studies on the
partial reinforcement effect, the increased resistance to extinction
after training with intermittent versus continuous reinforcement
schedules (Gray, 1987), it appears that reinstatement by drug or
nondrug stimuli can be enhanced when rats are trained under
intermittent schedules of reinforcement. Thus, training rats on
intermittent schedules of reinforcement leads to higher rates of
responding after exposure to cocaine priming (Tran-Nguyen et al., 1998)
or footshock stress (Mantsch and Goeders, 1999a) than those observed in
studies in which an FR-1 schedule of reinforcement was used.
4. Amount of Drug Exposure during Training.
Several recent
studies indicate that the amount of drug intake during training can
influence the effect of drug priming and footshock stress on
reinstatement. The effect of prior drug exposure during training on
reinstatement, however, is quantitative rather than qualitative.
Compared with rats trained for 6 days, Deroche et al. (1999) reported
that rats trained to lever press for cocaine for 29 days demonstrated a
shift to the left in the dose-response curve in response to cocaine
priming (0.2-1.6 mg/kg, i.v.). Sutton et al. (2000) and Baker et al.
(2001) reported that total cocaine intake during training is correlated
with the magnitude of reinstatement induced by amphetamine or cocaine
priming, respectively. In the study of Sutton et al. (2000), however,
the amount of cocaine intake during training was not correlated with
reinstatement induced by drug cues or a mild footshock. In contrast,
Ahmed et al. (2000) reported that, compared with rats trained for 1 h/day, rats trained for 11 h/day to self-administer heroin demonstrated
an enhanced response to footshock stress during testing. Thus, it
appears that the magnitude of reinstatement induced by drug priming is associated with the amount of cocaine intake during training. At
present, however, a clear picture is yet to emerge on the relationship between drug intake and reinstatement induced by stressors and drug cues.
5. The Drug Withdrawal Period Prior to Tests for
Reinstatement.
Recent studies indicate that the duration of the
withdrawal period prior to tests for reinstatement is an important
factor, which can lead to quantitative and
qualitative differences in reinstatement by drug and
nondrug stimuli. Tran-Nguyen et al. (1998) demonstrated that the
response to cocaine priming is increased after 1 month of withdrawal
compared with 1 day or 1 week (Fig. 13A). In addition, the effect of
D2-like receptor agonists on reinstatement of heroin seeking is
critically dependent on the withdrawal period. Using a within-session
model, Wise et al. (1990) found that the D2-like receptor agonist,
bromocriptine, potently reinstates heroin seeking when given several
hours after drug self-administration. De Vries et al. (2002) found that
the D2-like agonist quinpirole reinstates heroin seeking after short
periods (less than 1 week), but not after prolonged periods (greater
than 3 weeks) of drug withdrawal.
|
) (Fig. 13B). In another study with
heroin-trained rats, we found that reinstatement of lever-pressing
behavior by footshock followed an inverted U-shaped curve with maximal
responding after 6 and 12 days of heroin withdrawal (Shalev et al.,
2001a) (Fig. 13C). Surprisingly, footshock did not reinstate behavior
on day 1 of heroin withdrawal.
6. Side Effects of the Pharmacological and Brain Manipulations. An important issue in reinstatement studies is concerned with the interpretation of data from studies in which pharmacological agents and/or brain manipulations are given prior to tests for reinstatement. The question is what are the necessary control conditions to determine that decreases (or increases) in active lever responding during testing reflect the effects of the experimental manipulations on drug seeking rather than some other nonspecific effects. At present, there is no single behavioral measure that can adequately address this question. Thus, it is necessary to collect data from several dependent measures to rule out that nonspecific effects of the experimental manipulations led to changes in behavior.
A common practice is to determine the effect of the experimental manipulations on responses on the inactive lever as a measure of nonspecific activity. However, given that baseline rates of responding on this lever are low, nonspecific sedative effects cannot be adequately assessed. In addition, even if the experimental manipulations increase responding on the inactive lever, it does not necessarily indicate that it is due to nonspecific behavioral activation. When tests are conducted under extinction conditions, increased responding on the inactive lever may reflect response generalization, which commonly occurs during extinction (Catania, 1992).
Another way to assess nonspecific effects of the pharmacological/brain
manipulations is to determine their impact on lever pressing after
extinction but in the absence of the reinstating stimulus. However, as
in the case of inactive lever responses, because response rates on the
active lever are low after extinction, nonspecific sedative effects are
difficult to assess. In addition, even if an experimental manipulation
selectively increases responding on the active lever but not on the
inactive lever, the increased responding may be in part due to
nonspecific behavioral activation. Early studies on the rate dependence
effects of methamphetamine have shown that the drug does not increase
low rate baseline responding that was never reinforced (Verhave,
1958).
Potential sedative effects can be determined by examining the effect of
the experimental manipulations on ongoing high rate of responding for a
nondrug reinfrocer such as sucrose (Weissenborn et al., 1995; Erb et
al., 2000). The specificity of the experimental manipulations on drug
seeking, for example, can also be studied by determining their impact
on reinstatement of food seeking (de Wit and Stewart, 1981; Cornish et
al., 1999) or reinstatement of lever pressing previously maintained by
another drug (De Vries et al., 1999). For example, Leri and Stewart
(2001) have shown that in rats trained on alternate days to lever press
for cocaine and heroin, each with its associated lever and distinct
cues, cocaine or heroin priming selectively reinstates lever pressing on its drug-associated lever. However, although the interpretation of
the data is clear if the experimental manipulations do not alter
response rates under the above control conditions, a change in response
rates for a nondrug reinforcer or for a different drug may not be
necessarily due to nonspecific effects. To the extent that drugs of
abuse act on brain systems underlying natural rewards (Wise and Rompre,
1989), experimental manipulations that decrease drug seeking may also
decrease operant responding for food reward or reinstatement of
responding previously maintained by other drug or nondrug reinforcers.
Finally, the selectivity of a given manipulation can be studied by
determining its effect on more than one reinstating stimulus. For
example, CRF receptor antagonists selectively attenuate
footshock-induced reinstatement but not reinstatement induced by drug
priming (Shaham et al., 2000a).
The measurement of changes in responding on the inactive lever during
tests for reinstatement is not an optimal measure of nonspecific
effects. Thus, it is necessary to collect converging evidence from
several measures. These may include the effect of the manipulations on
high rate of operant responding for a nondrug reinforcer, reinstatement
of food/water seeking, and reinstatement by other stimuli.
7. Summary. A number of methodological issues should be considered in the design and interpretation of reinstatement studies. To avoid confounds in reinstatement studies, rats should not be food trained prior to drug self-administration training and should not be given noncontingent drug injections at the onset of the training sessions. Based on limited evidence, it appears that the response rate during training does not lead to qualitative changes in responding during tests for reinstatement. Training rats under intermittent schedules of reinforcement, however, can lead to increased responding during testing. Another factor associated with increased responding during tests for reinstatement is the amount of drug intake during training. Recent evidence indicates that the duration of the drug withdrawal period prior to testing is an important factor in reinstatement by drug or nondrug stimuli. Finally, to assess potential side effects of pharmacological and brain manipulations given during tests for reinstatement, data should be collected from several control conditions (e.g., operant responding for food, reinstatement of food seeking), in addition to inactive lever responses.
D. Emerging Issues
In this section we will discuss two issues that emerge from recent reinstatement studies and from other developments in the neuroscience field: the relationship between reinstatement of drug seeking and drug-induced behavior and neurochemical sensitization and the application of the reinstatement model to mice for studies on the genetic bases of vulnerability to relapse.
1. Does Drug Sensitization Contribute to Relapse to Heroin and
Cocaine?
Repeated exposure to opioid and stimulant drugs results
in enhanced behavioral and neurochemical responses to the drugs
(sensitization) or stressors (cross-sensitization) after withdrawal
periods (Kalivas and Stewart, 1991; Piazza and Le Moal, 1996). These
sensitized behavioral and neurochemical responses to drugs and
stressors peak at time points that are beyond the acute withdrawal
phase and persist for many months, and the mesocorticolimbic DA system is involved in the manifestation of these sensitized responses (Pierce
and Kalivas, 1997; White and Kalivas, 1998). These observations, and
those demonstrating that pre-exposure to drugs and stressors facilitate
the initiation of drug self-administration in rats (Goeders, 1997;
Schenk and Partridge, 1997; Piazza and Le Moal, 1998), were the basis
for the hypothesis that drug sensitization also contributes to drug
relapse (Robinson and Berridge, 1993; Piazza and Le Moal, 1996; De
Vries et al., 1998a; Kalivas et al., 1998).
found that lever pressing during tests for cocaine-induced
reinstatement is higher after 1 month of cocaine withdrawal compared
with 1 or 7 to 8 days (Fig. 13A). They also found that these
time-dependent changes in behavior are correlated with cocaine-induced
DA release in the amygdala. Second, De Vries et al. (1998a, 1999) found
a high correlation between the effect of opioid and DA agonists on
reinstatement of heroin and cocaine seeking and their ability to induce
sensitized locomotor responses after prolonged withdrawal periods.
Third, Cornish and Kalivas (2000) found that activation of AMPA
receptors in the NAc, known to be involved in the expression of
sensitization to psychostimulants after drug withdrawal (White and
Kalivas, 1998), mediates cocaine-induced reinstatement. Finally, we
found time-dependent changes in cue-induced reinstatement in the first 2 months of cocaine withdrawal (Fig. 13B), which resemble to some degree the time course of the expression of behavioral sensitization to
psychostimulant drugs after withdrawal (Paulson et al., 1991).
These data support the idea that sensitization processes within the
mesocorticolimbic DA reward circuitry are involved in relapse induced
by drug or drug-related cues after prolonged withdrawal periods.
However, it must be emphasized that the above data are correlational. Thus, a causal relationship
between the expression of locomotor sensitization and relapse has yet
to be demonstrated. Also, there is one negative report on the
relationship between behavioral sensitization and reinstatement of
cocaine seeking. Sutton et al. (2000) reported that the sensitized
locomotor responses to amphetamine following cocaine
self-administration was not correlated with the magnitude of responding
during tests for reinstatement after exposure to amphetamine, cocaine
cues, or footshock. However, it is difficult to draw conclusions from
this study because a single highly effective dose of amphetamine (0.5 mg/kg, s.c.) was used during tests for sensitization and reinstatement.
Thus, it is possible that the lack of correlation is due to a ceiling effect. In addition, the drug cues in this study were given
noncontingently, a manipulation that does not effectively reinstate
drug seeking (Grimm et al., 2000).
b. Stress.
It was hypothesized that the enhanced
responsiveness of the mesocorticolimbic DA system to stressors
following withdrawal from repeated exposure to opioid and stimulant
drugs may mediate, in part, stress-induced reinstatement (Robinson and
Berridge, 1993; Shaham and Stewart, 1995b). Unlike drug priming (and
possibly drug cues), the available data suggest that this hypothesis
cannot adequately explain stress-induced reinstatement (see
Section V.B.3.). Repeated exposure to drugs of abuse,
however, may induce neuronal adaptations or sensitize neuronal systems
involved in stress responses (Kreek and Koob, 1998; Sarnyai et al.,
2001).
Two recent studies reviewed above provide some tentative support for
this idea. Ahmed et al. (2000) reported that rats trained to lever
press for heroin for 11 h per day (long access) demonstrate higher
rates of responding during tests for footshock-induced reinstatement
than rats trained for 1 h per day (short access). In addition, we
found profound time-dependent changes in the effect of footshock on
reinstatement of heroin seeking (Shalev et al., 2001a) (Fig. 13C).
These data are in agreement with a neuroadaptation model, which argues
that drugs induce long-term neuronal changes that take time to develop
after drug withdrawal, are long-lasting, and are dependent on the
amount of prior drug exposure (Pierce and Kalivas, 1997).
It should be pointed out, however, that changes in sensitivity in brain
systems involved in footshock stress-induced reinstatement (i.e., NA
and CRF) in response to the stressor are yet to be reported, and in our
initial neurochemical characterization of the time-dependent changes in
footshock-induced reinstatement, we found that alterations in CRF mRNA
in the CeA and BNST in response to the stressor are not correlated with
the lever-pressing behavior during testing (Shalev et al., 2001a).
Thus, whereas recent behavioral evidence suggests that drug-induced
sensitization of brain systems involved in stress response may
contribute to vulnerability to stress-induced relapse, the neuronal
systems involved in these putative "sensitization" processes are
yet to be determined.
2. Application of the Reinstatement Model to Mice.
The
rat reinstatement model may not be the most suitable mean for
studying genetic factors in drug addiction and relapse. Methods for
over-expressing genes via viral vectors or inactivating genes by
antisense oligonucleotides have contributed to the understanding of the
mechanisms of drug reward in rats (Nestler, 2000, 2001). For several
reasons, however, the mouse is a more appropriate species to study
genetic factors in drug addiction. There are a number of inbred mouse
strains and several molecular genetic techniques in mice that allow
them to either inactivate (knockout methods) or over-express
(transgenic methods) specific genes potentially involved in drug
effects (Crabbe et al., 1999; Nestler, 2001). Mice self-administer
opioid (Elmer et al., 1996; Roberts et al., 1997) and stimulant (Rocha
et al., 1998; Caine et al., 1999a) drugs and also demonstrate CPP for
these drugs (Cunningham et al., 1992; Laviola et al., 1992).
trained mice (OF1
albino strain) to acquire morphine (40 mg, i.p.) place preference for 4 days. Subsequently, mice were repeatedly tested for morphine CPP in the
absence of the drug 5, 15, 20, 35, and 45 days after last exposure to
morphine (extinction). CPP for morphine was not observed on the last 3 test days, but a priming injection of morphine (40 mg/kg) led to
reinstatement of CPP 46 days after training. Itzhak and Martin (2002)
trained Swiss-Webster mice for cocaine CPP and then extinguished this
behavior by administering saline injections (8 days) in the previously
cocaine- and saline-paired compartments. Subsequently, they found
reinstatement of CPP following injections of cocaine, methamphetamine,
and methylphenidate but not phencyclidine.
We trained male mice of the 129X1/SvJ strain for 14 to 16 days to
self-administer cocaine (0.75 mg/kg/infusion, 4 h per day; infusions were paired with a light-tone compound cue). Next, the lever-pressing behavior was extinguished in the presence or absence (for subsequent tests for cue-induced reinstatement) of the cocaine cue. Subsequently, tests for reinstatement were conducted in different groups of mice after exposure to priming injections of cocaine (0, 1.5, 3.0, and 6.0 mg/kg, i.v.), response-contingent presentations of the
cocaine-associated cue or food deprivation stress (1 and 22 h). We
found that the effect of cocaine priming on reinstatement was
relatively modest and was only observed at the highest dose tested. On
the other hand, reinstatement of cocaine seeking was observed following
exposure to the cocaine-associated cue and food deprivation stress.
These data tentatively suggest that factors contributing to relapse to
drugs can be studied in the reinstatement model using the common
129X1/SvJ mouse inbred strain (D. Highfield, A. Mead, J. W. Grimm,
B. A. Rocha, and Y. Shaham, manuscript submitted). The reasons for
the weak effect of the priming cocaine injections in mice are not clear.
Although species differences in response to reinstating stimuli may
exist, both operant and classical conditioning models of reinstatement
can be used in mice. Studies using molecular genetic methods are likely
to provide information on the role of specific genes in relapse to
heroin and cocaine.
E. Concluding Remarks and Implications for Addiction Theories and Treatment
We reviewed data from studies on the neuronal mechanisms underlying relapse to heroin and cocaine. Based on the data reviewed, we conclude that the neuronal mechanisms involved in relapse induced by drug priming, drug cues, and stressors are to a large degree dissociable and also are likely to be different from those involved in the acute reinforcing effects of these drugs. The data reviewed on the time-dependent changes in the propensity to relapse following withdrawal from heroin and cocaine also suggest that the organism may be most vulnerable to relapse to drugs at time periods that are well beyond the acute drug withdrawal phase. We conclude this review by briefly discussing the potential implications of the data from reinstatement studies to addiction theories and for the treatment of relapse in humans.
1. Implications for Addiction Theories.
Negative
reinforcement theories postulate that compulsive drug use and drug
relapse occur because the addict is seeking drugs to alleviate the
aversive symptoms of drug withdrawal; symptoms that can also be
elicited by cues previously paired with drug withdrawal (Himmelsbach,
1943; Lindsmith, 1947; Wikler, 1973). Over the years, several
drug-opposite physiological and psychological adaptations have been
hypothesized to underlie habitual drug use and relapse (Goldstein and
Goldstein, 1968; Solomon and Corbit, 1974; Collier, 1980; Koob et al.,
1989; Siegel, 1989). The self-medication hypothesis, which argues that
compulsive drug use and relapse is due to the drug's effects on the
individual's well being, is another form of a negative reinforcement
model (Khantzian, 1985; Markou et al., 1998). It is beyond the scope of
this paper to describe these negative reinforcement theories in detail
and to discuss the degree to which they account for drug
self-administration behavior (see Schuster and Thompson, 1969; Stewart
et al., 1984; Wise and Bozarth, 1987). In the context of relapse to
heroin and cocaine seeking as measured in the reinstatement model,
however, we argue that there is little evidence that negative
reinforcement models are compatible with the data on relapse induced by
drug priming, drug cues, or stressors.
; Shaham et al., 1996).
Cues associated with drug administration can induce drug-opposite
withdrawal-like effects (Siegel, 1989), but there is no evidence to
date that such effect of cues can induce relapse in the reinstatement
model. Finally, in our studies, in which rats were trained for 6 to 9 h/day leading to drug intakes that are sufficient to induce withdrawal
symptoms during early withdrawal (1-2 days) from heroin (Shaham et
al., 1996) and cocaine (Sarnyai et al., 2001), we found that extinction behavior, cue-induced reinstatement, and footshock-induced
reinstatement were maximal at time points that are well beyond the
acute withdrawal phase. These data are in agreement with those from a
different model of drug seeking, the second-order schedule, in which
Arroyo et al. (1998) found that during early withdrawal from 12-h
cocaine self-administration, a decrease in lever-pressing behavior
controlled by the cocaine cues is observed.
The limitations of negative reinforcement theories in explaining
compulsive drug use led to the developments of several addiction theories, which were primarily based on the observations that drugs are
powerful positive reinforcers and maintain behavior in the absence of
physical dependence (Weeks and Collins, 1968; Schuster and Thompson,
1969). Wise and Bozarth (1987) argued that "a common brain mechanism
of psychomotor activation is stimulated by all positive reinforcers and
that the same mechanism mediates the psychomotor stimulant effects and
the positive reinforcing effects of these agents" (Wise, 1988). These
authors also argued that drugs elicit approach behavior or forward
locomotion (Glickman and Schiff, 1967; Bindra, 1974), which leads to
compulsive drug use. Stewart et al. (1984) argued that drugs or
drug-associated cues elicit a positive incentive motivational state
that leads to approach behavior toward these stimuli, and consequently
to compulsive drug use and relapse upon exposure to these stimuli. Robinson and Berridge (1993) hypothesized that incentive sensitization processes or increased responsiveness to drug and drug-associated cues
following repeated drug exposure may underlie compulsive drug use and
relapse. More recently, Di Chiara (1999) argued that compulsive drug
use occurs because repeated stimulation of DA in the NAc shell by drugs
of abuse in the presence of drug-associated cues leads to the
attribution of excessive motivational value and abnormal control over
behavior by these cues. Again, it is beyond the scope of this paper to
review these theories in detail, to discuss their similarities and
differences, the degree to which they account for compulsive drug use,
and the degree to which these theories fit with the data from studies
on the role of the mesocorticolimbic DA system in goal-directed
behavior (see Berridge and Robinson, 1998; Ikemoto and Panksepp, 1999;
Schultz and Dickinson, 2000).
However, a common denominator of all four theories is that the
mesocorticolimbic DA system is involved in compulsive drug use, albeit
via the elicitation of somewhat different motivational processes, and
that the presence of drugs in the body (and brain) rather than drug
withdrawal is the critical factor in compulsive drug use and relapse.
Stewart et al. (1984) and Robinson and Berridge (1993) also argued that
drug cues elicit drug-like effects and consequently drug seeking via
their action on the mesocorticolimbic DA system.
To a certain degree, the data reviewed are in agreement with these
theories. As mentioned above, the available data tentatively support
the view that the putative incentive motivational effects of heroin and
cocaine priming may underlie their effect on reinstatement (Stewart et
al., 1984). The findings of De Vries et al. (1998a, 1999), that the
ability of drugs to induce locomotor activity is correlated with their
effects on reinstatement, are in agreement with all four theories. In
addition, as discussed in detail above (Section V.D.1.),
recent data suggest that psychomotor sensitization (a phenomenon that
served as the basis for the incentive-sensitization theory) is
associated with drug- and possibly cue-induced reinstatement. Finally,
the observations that the mesocorticolimbic DA system is involved in
both drug priming- and cue-induced reinstatement is in agreement with
the four theories.
Importantly, however, the anatomical (Grimm and See, 2000) and
pharmacological (McFarland and Ettenberg, 1997) dissociations between
reinstatement by drug priming and drug cues are not predicted by the
theories of Stewart et al. (1984) and Robinson and Berridge (1993). In
addition, all four theories would not predict the partial dissociation
between the neuronal mechanisms underlying acute heroin or cocaine
reinforcement and drug-induced reinstatement (Section V.A.).
Furthermore, although Robinson and Berridge (1993) argued that
stressors provoke relapse by mimicking the effect of drugs on the
mesocorticolimbic DA system, this does not appear to be the case
(Shaham et al., 2000a).
Finally, Koob and Le Moal (2001) proposed an "allostasis" model of
drug addiction, in which they argued that repeated and compulsive use
of high amounts of drugs induces changes in the drug's "hedonic"
set point. Allostasis is a process wherein chronic disturbances of
homeostasis of a given physiological (and psychological) system lead to
a new stable set point (which is outside of the normal homeostatic
range) to cope with the chronic internal and/or external demands
(Schulkin et al., 1998). Ahmed and Koob (1998, 1999) provided evidence
in support of this view by demonstrating that rats given access to
cocaine for 6 h/day, but not 1 h/day, escalate their drug intake over
time. However, it does not appear that the allostasis model can account
for the results obtained in reinstatement studies. Specifically,
following 35 days of withdrawal, cocaine intake returned to normal
pre-escalating values in rats which previously self-administered
cocaine for 6 h/day (Ahmed and Koob, 1998). On the other hand, in
reinstatement studies, the time course of extinction behavior and
cocaine- and cue-induced reinstatement has an opposite pattern, i.e.,
low responding on day 1 of withdrawal and high responding following 1 to 2 months of withdrawal (Tran-Nguyen et al., 1998; Grimm et al.,
2001). In other words, drug seeking is inversely related to the changes in the putative hedonic set point.
It appears that negative reinforcement and opponent processes theories
and the recent allostasis model cannot adequately explain the data
obtained in reinstatement studies. In contrast, incentive motivation,
incentive sensitization, and psychomotor theories of addiction can
account for certain findings from reinstatement studies. However, even
these theories cannot account for the pharmacological and anatomical
dissociations between drug priming, drug cues, and stressors and for
the partial neuronal dissociation between drug-induced reinstatement
and drug reinforcement.
2. Implications for Treatment.
As mentioned in the
Introduction, the reinstatement model appears to have good predictive
validity because conditions that provoke drug relapse and craving in
humans (drug re-exposure, drug cues, and stress) also reinstate heroin
and cocaine seeking following prolonged withdrawal periods in
laboratory animals. Over the past several decades, medication
development studies have screened potential clinical compounds for
their ability to attenuate drug withdrawal symptoms, to substitute for
the abused drug in drug self-administration or discrimination models,
or to block the reinforcing or discriminative stimulus effects of the
abused drug in these models (Bhargava, 1994; Mello and Negus, 1996).
The data reviewed here, however, suggest that effective compounds
derived from the above screening methods may not prevent relapse to
drug seeking. As mentioned, the data reviewed suggest that the neuronal
processes that mediate drug-induced reinstatement are to some degree
different from those involved in drug reinforcement or discrimination.
Furthermore, even compounds that can effectively block relapse induced
by drug priming or drug cues are not likely to block stress-induced
relapse and vice versa. In addition, the recent data of McFarland and
Ettenberg (1997, 1998) on the differential effect of naltrexone and
haloperidol on heroin-induced drug seeking versus cue-induced heroin
seeking suggest that potential medications screened for the effect on
drug priming may not always alter relapse induced by drug cues.
Finally, the data reviewed suggest that a pharmacological therapy that
combines agents that are effective against relapse induced by drug or
drug cues with agents that attenuate stress-induced relapse should be
considered for relapse prevention in humans.
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Acknowledgments |
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TopPreviousNextReferences
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This review was supported by funds from the National Institute on Drug Abuse/Intramural Research Program. We thank Kelly Badger for help in obtaining the information for the tables and Drs. Jane Stewart and Jonathan Katz for helpful comments. The authors contributed equally to this article.
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Footnotes |
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1 Current address: Department of Psychology, Western Washington University, 516 High Street, Bellingham, WA 98225-9089.
Address correspondence to: Dr. Yavin Shaham, Behavioral Neuroscience Branch, IRP/NIDA/National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224. E-mail: Yshaham{at}intra.nida.nih.gov
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Abbreviations |
|---|
CPP, conditioned place
preference;
DA, dopamine;
GABA, -aminobutyric acid;
VTA, ventral
tegmental area;
PKA, protein kinase A;
NAc, nucleus accumbens;
AMPA, -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid;
mPFC, medial
prefrontal cortex;
IEG, immediate early genes;
CeA, central nucleus of
the amygdala;
NMDA, N-methyl-D-aspartate;
CNQX, 6-cyano-2,3-dihydroxy-7-nitroquinoxaline;
5-HT, 5-hydroxytryptamine;
CRF, corticotropin-releasing factor;
NA, noradrenaline;
SSRI, selective serotonin reuptake blocker;
HPA, hypothalamic-pituitary-adrenal;
9-THC, 9-tetrahydrocannabinol;
ADX, adrenalectomy;
CB1, cannabinoid type 1;
CS, conditioned stimulus;
BLA, basolateral amygdala;
PKC, protein kinase C;
TTX, tetrodotoxin;
TH, tyrosine hydroxylase;
PENK, proenkephalin;
BNST, bed nucleus of the
stria terminalis;
FR, fixed ratio;
VNAB, ventral noradrenegic
bundle;
LC, locus coeruleus;
ABT 431, ()-trans-9,10-diacetyloxy-2-propyl-4,5,5a,6,7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene
hydrochloride;
CP-154,526, butyl-ethyl-(2,5-dimethyl-7-(2,4,6-trimethylphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine;
HU210, 11-hydroxydimethylheptyl-8-tetrahydrocannabinol;
PD 128,907, S(+)(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol
hydrochloride;
SCH 23390, 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine;
SCH 39166, ()-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5a-benzo-(d)-naphtho-(2,1b)azepine;
SKF 81297, (±)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hydrobromide;
SKF 82958, (±)-6-chloro-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
hydrobromide;
SR14176A, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide;
WAY 100625, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-cyclohexane
carboxamide.
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