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Vol. 53, Issue 2, 209-244, June 2001
Laboratory of Neuroendocrinology and Laboratory of Biology of Addictive Diseases, Rockefeller University, New York, New York (Z.S.); PsychoGenics, Inc., Hawthorne, New York (Z.S.); Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (Y.S.); and Department of Psychology, Boston College, Chestnut Hill, Massachusetts (S.C.H.)
Abstract
I. Introduction
II. Overview of Corticotropin-Releasing Factor and Brain Function
A. Anatomical Distribution of the Corticotropin-Releasing Factor Family of Peptides and Binding Sites
1. Corticotropin-Releasing Factor and Urocortin.
2. Corticotropin-Releasing Factor Binding Sites.
a. Corticotropin-Releasing Factor-1 Receptor.
b. Corticotropin-Releasing Factor-2 Receptors.
c. Corticotropin-Releasing Factor Binding Protein.
B. Role of Corticotropin-Releasing Factor in the Coordination of Hormonal and Behavioral Stress Responses
1. Hormonal Effects of Corticotropin-Releasing Factor and Urocortin.
2. Behavioral Effects of Corticotropin-Releasing Factor and Urocortin.
3. Behavioral Effects of Corticotropin-Releasing Factor Receptor Antagonists.
C. Role of Corticotropin-Releasing Factor in Neuropsychiatric Disorders
III. Role of Corticotropin-Releasing Factor in Behavioral and Hormonal Effects of Drugs of Abuse
A. Drug-Induced Activation of the Hypothalamic-Pituitary-Adrenocortical Axis
1. Psychostimulant Drugs.
2. Opioids.
3. Alcohol and Benzodiazepines.
4. Nicotine.
5. Cannabinoids.
6. Differential Adaptation of the Hypothalamic-Pituitary-Adrenocortical Axis to Chronic Drug Administration.
a. Psychostimulants.
b. Opioids.
c. Alcohol and Benzodiazepines.
d. Nicotine.
e. Cannabinoids.
7. Summary.
B. Unconditioned and Conditioned Behavioral Effects of Drugs
1. Psychostimulant Drugs.
2. Alcohol and Benzodiazepines.
3. Cannabinoids.
4. Summary.
C. Drug Self-Administration and Reward
1. Cocaine.
2. Alcohol.
3. Summary.
D. Drug Withdrawal
1. Psychostimulant Drugs.
2. Opioids.
3. Alcohol and Benzodiazepines.
4. Nicotine.
5. Cannabinoids.
6. Summary.
E. Relapse to Drug-Taking Behavior
1. Cocaine.
2. Alcohol.
3. Heroin and Morphine.
4. Summary.
IV. Alterations in Brain Corticotropin-Releasing Factor Systems in Response to Drug Exposure and Withdrawal
A. Psychostimulant Drugs
B. Opioids
C. Alcohol and Benzodiazepines
D. Nicotine and Cannabinoids
E. Summary
V. Discussion
A. Summary of Main Findings
B. Neuroanatomical Considerations
C. Drug-Induced Neuroadaptations, Corticotropin-Releasing Factor, and Vulnerability to Drug Addiction
D. Therapeutic Implications
Acknowledgments
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The goal of this article is to summarize available data examining the physiological significance of brain corticotropin-releasing factor (CRF) systems in mediating the behavioral and physiological effects of several classes of abused drugs, including opioid and psychostimulant drugs, alcohol and sedative hypnotics, nicotine, and cannabinoids. An initial discussion of CRF neurobiology is followed by consideration of the role of CRF in drug-induced activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, the behavioral effects of drugs (e.g., locomotor activity, anxiogenic-like responses), drug self-administration, drug withdrawal, and relapse to drug-seeking. Subsequently, neurochemical changes in brain CRF in response to acute and chronic drug exposure are examined. A major conclusion derived from the data reviewed is that extrahypothalamic brain CRF systems are critically involved in behavioral and physiological manifestations of drug withdrawal and in relapse to drug-taking behavior induced by environmental stressors. On the other hand, it appears that hypothalamic CRF, via its action on the HPA axis, is involved in the reinforcing effects of cocaine and alcohol, and the locomotor activating effects of psychostimulant drugs. These preclinical data may provide a rationale for the development of CRF-based pharmacotherapies for the treatment of compulsive drug use in humans.
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I. Introduction |
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Chronic exposure to stressful life events is typically associated
with adverse consequences, such as failing health and psychiatric illness (Selye, 1976
; Cohen et al., 1986). These consequences of stress
exposure were labeled as distress (Selye, 1976). However, an
antithetical and in some sense paradoxical improvement in psychological and physiological well being also is associated under certain circumstances with stress exposure, a condition termed
eustress (Selye, 1976). Interestingly, the continuum of
responses to stressor exposure from eustress to distress resembles the
profile of responses to drugs of abuse. For example, in humans,
psychostimulant drugs (such as cocaine) can produce both rewarding and
mood-elevating effects, as well as physiological and psychological
changes typically observed after exposure to environmental stressors
(e.g., sympathetic activation, release of the stress hormone cortisol,
anxiety) (Koob, 1996; Kreek and Koob, 1998; Koob and Le Moal, 2001).
Interest in the role of brain systems involved in stress responses, and
the stress neuropeptide corticotropin-releasing factor (CRF2) in
particular, in mediating the actions of drugs of abuse has largely been
driven by three main findings. First, acute administration of drugs of
abuse activates the hypothalamic-pituitary-adrenocortical (HPA) stress
axis (Sarnyai, 1998), historically the predominant biological marker
for stress reactivity (Selye, 1976; McEwen, 1998). Second, the drug
withdrawal syndrome in both animal subjects and human clinical
populations resembles physiological and behavioral changes associated
with responses to stressors, which are linked to brain CRF activation
(Koob and Heinrichs, 1999). Third, exposure to stressors is associated
with increased drug-taking behavior and relapse to drugs in both humans
(Shiffman and Wills, 1985; Brown et al., 1995) and laboratory animals
(Piazza and Le Moal, 1996; Shaham et al., 2000a).
In the last 15 years or so, a large number of studies were conducted on the effect of drugs of abuse on hypothalamic and extrahypothalamic CRF systems in the brain and on the role of CRF in the mediation of the behavioral and physiological effects of drugs of abuse. The goal of the present study is to summarize the data obtained in these studies. In Section II., we will briefly summarize the physiology of the endogenous CRF systems in the brain, the role of CRF in hormonal and behavioral stress responses, and the potential role of CRF in neuropsychiatric disorders. In Section III., we will review studies on the role of CRF in the behavioral and hormonal effects of drugs of abuse, including drug-induced activation of the HPA axis, conditioned and unconditioned behavioral effects of drugs, drug self-administration, drug withdrawal, and relapse to drug use. In Section IV., we will review studies on the effect of drug exposure and drug withdrawal on brain CRF systems. In Section V., we will summarize the findings and discuss potential brain circuits through which CRF may be involved in the effects of abused drugs. Finally, therapeutic implications of the studies reviewed will be briefly discussed.
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II. Overview of Corticotropin-Releasing Factor and Brain Function |
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The CRF family of neuroendocrine peptides and receptors orchestrates endocrine, physiological, and behavioral responses to stressor exposure. Built-in biological diversity and selectivity of CRF system function are provided by multiple endogenous ligands and receptors that are heterogenously distributed in both brain and peripheral tissues across species. In mammals, the two known native peptide agonists are CRF itself (also abbreviated CRH for corticotropin-releasing hormone) and urocortin. Presently, there are five distinct targets for CRF and urocortin with unique cDNA sequences, pharmacology, and localization. These fall into three distinct classes encoded by three different genes and have been termed the CRF1 and CRF2 receptors and the CRF-binding protein.
Significant gains in knowledge about the physiological role of CRF binding sites in the brain have emerged recently due to the proliferation of novel, high-affinity, receptor-selective pharmacological tools and knock-out and knock-in mutant mouse models. Data obtained with the use of these pharmacological and genetic methods support a role for CRF binding sites in coordinating stress reactivity, emotionality and energy balance. Here, we will review studies on the role of CRF systems in the brain in the mediation of behavioral and physiological effects of drugs of abuse.
A. Anatomical Distribution of the Corticotropin-Releasing Factor
Family of Peptides and Binding Sites
1. Corticotropin-Releasing Factor and Urocortin.
CRF is a
41-residue straight-chain peptide isolated initially in 1981 from ovine
hypothalamus (Vale et al., 1981). Immunocytochemical studies have shown
that CRF is found within the paraventricular nucleus (PVN) of the
hypothalamus and in several extrahypothalamic brain areas (Sawchenko et
al., 1993). The extrahypothalamic distribution of CRF is concordant
with an involvement of CRF in affective behavioral responses to stress,
because it is found in limbic areas [e.g., amygdala, bed nucleus of
the stria terminalis (BNST)] and brain stem nuclei [e.g., locus
coeruleus (LC), nucleus of solitary tract] involved in stress
responses and regulation of autonomic function (Sawchenko et al.,
1993).).
Urocortin/urotensin-like immunoreactivity is found in brain areas such
as Edinger-Westfall nucleus, lateral superior olive, and septal region
(Vaughan et al., 1995). Moreover, in vivo characterization of the
functional significance of urocortin reveals a pharmacological profile
somewhat distinct from that of CRF (Spina et al., 1996).
2. Corticotropin-Releasing Factor Binding Sites.
CRF
receptors belong to the family of "gut-brain" neuropeptides,
possess seven putative transmembrane domains, are positively coupled to
adenylate cyclase, and bind CRF and urocortin with high affinity
(Chalmers et al., 1996). CRF-binding protein (CRF-BP) binds both native
rat/human CRF and urocortin with higher affinity than CRF receptors
(Vaughan et al., 1995). CRF-BP circulates in humans and is expressed in
the brain of several species, where it is hypothesized to serve as an
inducible factor that regulates pituitary-adrenocortical activation, as
well as extrahypothalamic CRF neurotransmission (Kemp et al., 1998).
; Dieterich et al.,
1997). The CRF1 receptor has no known genetic polymorphism. The mRNA distribution for the CRF1 receptor correlates well
with the known distribution of CRF binding sites in that expression is
highest in the pituitary, cerebral cortex, and cerebellum (Bittencourt and Sawchenko, 2000). Moreover, when this receptor is expressed in
cells, it exhibits an identical in vitro pharmacological profile to
that previously described in the brain and pituitary. These developments led to the validation of several novel CRF
receptor-antagonist molecules with which the physiological significance
of this receptor can be probed (McCarthy et al., 1999). In particular,
the hypothesized role of CRF1 receptors in mediating
unconditioned and conditioned anxiogenic-like behavioral responses to
stressor exposure (Steckler and Holsboer, 1999) have led to studies
(see below) on the role of CRF1 receptors in drug
reinforcement and dependence.
b. Corticotropin-Releasing Factor-2 Receptors.
There are
currently four known forms of the CRF2 receptor:
CRF2
, CRFR2-tr,
CRF2
, and CRF2
. The
CRF2 receptor is a 411 amino acid protein with
approximately 71% identity to the CRF1 receptor
(Lovenberg et al., 1995b). In particular, the
CRF2 receptor is localized to subcortical
regions, including the lateral septum, and the paraventricular and
ventromedial nuclei of the hypothalamus (Lovenberg et al., 1995a). The
CRF2 receptor, which has been cloned from both
rat and mouse, is 431 amino acids in length and differs from
CRF2 in that the first 34 amino acids in the
N-terminal extracellular domain are replaced by 54 different
amino acids (Perrin et al., 1995). The CRF2
receptor is primarily localized to the heart, skeletal muscle, and in
the brain to cerebral arterioles and choroid plexus (Chalmers et al.,
1995). A third splice variant, the CRF2
receptor, has recently been identified in the human brain (Kostich et
al., 1998). Reverse transcription-polymerase chain reaction analysis of
human brain CRF2 mRNA demonstrates expression
in amygdala and hippocampus, whereas Southern blot analysis of rat
genomic DNA yielded negative results, suggesting that this subtype does
not exist in the rat. However, the most recently described novel
CRF2 receptor is a short variant of the 2-isoform cloned from the rat amygdala (Miyata et al., 1999). The
short variant of CRF2, termed
CRF2-tr, exhibits differential brain
expression and pharmacology relative to CRF2.
However, although several authors argue for receptor-selective
functional effects of CRF versus urocortin based on differential
affinity of these two ligands at CRF1 and
CRF2 receptors, a recent comprehensive study of
neuronal activation after central administration of CRF or urocortin
revealed broad activation of parenchymal cell groups that express
CRF1 and CRF2 as well as
neither CRF receptor (Bittencourt et al., 1999).
c. Corticotropin-Releasing Factor Binding Protein.
Plasma CRF is substantially elevated during the third trimester
of human pregnancy, and this process is likely to participate in a
cascade of events, which eventually leads to parturition (Smith, 1999).
The majority of this late gestational maternal plasma CRF is bound to a
high affinity (CRF-BP), which neutralizes the ability of CRF to release
adrenocorticotropic hormone (Petraglia et al., 1996). The predominant
tissues expressing CRF-BP in all species are the brain and the
pituitary gland, where the protein is hypothesized to modulate CRF
actions in response to stress exposure or glucocorticoid levels
(Turnbull and Rivier, 1997). Of note, there are several brain areas in
which CRF, CRF receptor, and CRF-BP expression overlap, including the
amygdala, pituitary corticotrophs, and the preoptic nucleus (Potter et
al., 1992; Kemp et al., 1998), in which roughly 40-60% of
CRF/urocortin bound to CRF-BP (Behan et al., 1995). Recent data suggest
that CRF-BP mediates a profile of neural activation distinct from that
induced by CRF receptor agonists, although the physiological role of
CRF-BP has not yet been established (Chan et al., 2000).
B. Role of Corticotropin-Releasing Factor in the Coordination of
Hormonal and Behavioral Stress Responses
1. Hormonal Effects of Corticotropin-Releasing Factor and
Urocortin.
All known CRF receptor agonists, including CRF and
urocortin, are potent stimulators of anterior pituitary
proopiomelanocortin-derived peptides, primarily adrenocorticotropin
hormone (ACTH) and 2. Behavioral Effects of Corticotropin-Releasing Factor and
Urocortin.
Administration of a CRF receptor agonist into the
central nervous system produces a wide range of behavioral effects, and the behavioral pharmacological profile resulting from exogenous administration of these neuropeptides depends on the baseline level of
arousal (Koob and Heinrichs, 1999-endorphin (Rivier and Plotsky, 1986). Moreover,
several studies indicate that CRF is the principal physiological
regulator of pituitary ACTH secretion in many species, including humans
(Turnbull and Rivier, 1997). This concept derives from localization of
CRF synthesis within endocrine motoneurons of the PVN, high-affinity
CRF1 receptors present in the anterior pituitary
gland, and the fact that blockade of these pituitary
CRF1 receptors reduces ACTH secretion.). In nonstressed rats, under low
arousal conditions (e.g., a familiar environment), CRF or urocortin
administration produces behavioral activation, including increases in
locomotor activity, and rearing and grooming (Jones et al., 1998). The
CRF-induced behavioral activation is not observed after systemic
administration of CRF, and is not blocked by hypophysectomy (Eaves et
al., 1985) pretreatment with dexamethasone (Britton et al., 1986a,b),
or peripheral CRF immunoneutralization (Merlo Pich et al., 1993),
suggesting that this behavioral activation is mediated by CRF
originating from extrahypothalamic brain sites. When animals are
exposed to a more stressful environment, the profile of the behavioral
effects of exogenously administered CRF and urocortin changes to
reflect an enhanced behavioral response to stress. The same
intracerebroventricular (i.c.v.) doses that produce marked behavioral
activation in a familiar environment produce behavioral suppression in
a novel, presumably stressful environment. Rodents pretreated with CRF
show decreases in exploration in an open field, in a multicompartment
chamber, and in an elevated plus maze test (Dunn and Berridge, 1990).
Urocortin shares the activating and anxiogenic-like properties of CRF,
a putative CRF1-mediated effect (Steckler and
Holsboer, 1999), as shown by exploratory inhibition in several animal
models of anxiety, including the open field, the elevated plus maze
test, and the light-dark test (Moreau et al., 1997).;
Diamant et al., 1992; Spina et al., 1996). The stress-like effects of
CRF clearly have aversive properties in that CRF, and urocortin at high
doses, can produce both taste aversions and place aversions (Cador et
al., 1992; Benoit et al., 2000). Thus exogenously administered CRF and
urocortin produce a stress-like behavioral state. Of note, several
reports identify a higher potency of urocortin versus CRF in
suppressing food intake in a behaviorally specific manner such that low
anorexic doses of urocortin do not induce anxiogenic responses and
aversion (Benoit et al., 2000; Spina et al., 1996). This suggestion of
behavioral specificity of urocortin has recently been supported by
evidence that a novel urocortin-like ligand, urocortin II, suppresses
nocturnal food intake without producing locomotor activation (Reyes et
al., 2001). Moreover, since urocortin II binds selectively to
CRF2 but not CRF1 receptors
(Reyes et al., 2001), available pharmacological results support
different efficacy profiles for the two known CRF receptor subtypes.
3. Behavioral Effects of Corticotropin-Releasing Factor Receptor
Antagonists.
Additional evidence for a role of endogenous
CRF-family neuropeptides in mediating the behavioral response to
stressors comes from the demonstration of "antistress" actions of
CRF receptor antagonists (Koob and Heinrichs, 1999). Studies using
competitive CRF receptor antagonists, such as -helical
CRF9-41 (-helical CRF) and D-Phe
CRF12-41 (D-Phe CRF) provide support
for the hypothesis that brain CRF systems play a role in mediating behavioral responses to stress (Dunn and Berridge, 1990). These two
peptide antagonists have high affinity for both the
CRF1 and CRF2 receptors
(Behan et al., 1996). In rats, centrally administered -helical CRF
reverses the attenuation of feeding induced by stress and attenuates
stress-induced fighting (Krahn et al., 1986; Tazi et al., 1987). In
mice, -helical CRF reverses the suppression in exploratory behavior
produced by restraint stress (Berridge and Dunn, 1987), and in rats
this CRF receptor antagonist produces a more rapid emergence from a
small dark enclosure into a large open field and more exploration of
the unfamiliar open field (Takahashi et al., 1989). Subsequent studies
have shown that CRF receptor antagonists reverse stress-induced
decreases in exploration of the open arms of an elevated plus maze test
(Heinrichs et al., 1994).
C. Role of Corticotropin-Releasing Factor in Neuropsychiatric Disorders
CRF plays a major role in regulating behavioral and hormonal
responses to stress in animal models. Therefore, changes in activity of
CRF systems are thought to be involved in stress-related psychiatric disorders. In particular, the role of CRF hypersecretion in depression, especially major depression with melancholic features, has long been
proposed (Nemeroff, 1996). This has been supported by results showing
elevated plasma cortisol levels, blunted ACTH and cortisol responses to
acute administration of dexamethasone (a synthetic glucocorticoid
agonist), attenuated ACTH response to CRF infusion, elevated CRF levels
in the cerebrospinal fluid, decreased CRF receptor binding in the
frontal cortex, and increased number of CRF neurons in the PVN in
depressed patients (Nemeroff, 1998; Plotsky et al., 1998; Gold and
Chrousos, 1999; Wong et al., 2000). This increase in CRF neuronal
activity is also believed to mediate certain behavioral symptoms of
depression, including sleep and appetite disturbances, reduced libido,
and psychomotor changes. The hyperactivity of CRF neuronal systems
appears to be a state marker for depression because HPA axis
hyperactivity normalizes after successful antidepressant treatment
(Mitchell, 1998; Arborelius et al., 1999). However, atypical depression
with hypersomnia, hyperphagia, lethargy, fatigue and relative apathy
has been associated with concomitant hypofunctioning of the CRF systems
(Gold et al., 1996; Gold and Chrousos, 1999).
In obsessive-compulsive disorder, a decrease in cerebrospinal fluid CRF
concentrations has been found in some (Altemus et al., 1992), but not
in other, studies (Fossey et al., 1996). In Tourette's syndrome in
which tic severity is related to anxiety, an increase in cerebrospinal
fluid CRF was reported (Chappell et al., 1996). In Alzheimer's
disease, there are dramatic reductions in the content of CRF;
reciprocal increases in CRF receptors, and morphological abnormalities
in CRF neurons in affected brain areas, such as frontal cortex and
hippocampus (De Souza et al., 1987; Nemeroff et al., 1991; Davis et
al., 1999). Cognitive impairment in Alzheimer patients is associated
with a lower cerebrospinal fluid concentration of CRF (Pomara et al.,
1989). A recent study also showed that CRF levels are significantly
reduced in patients with both mild and severe dementia, suggesting that
CRF can serve as a potential neurochemical marker of early dementia and
Alzheimer disease (Davis et al., 1999).
The clinical and post-mortem data reviewed above suggest that altered
activity of brain CRF systems, either hyper- or hypoactivity, may play
a crucial role in neuropsychiatric disorders in which affect, mood,
motivation, emotion, and cognition are disturbed. This raises the
possibility that CRF systems may also contribute in an important way to
drug addiction, in which these modalities of higher brain function are
affected (APA, 1994). In the following sections, we review preclinical
data that lend support to this idea.
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III. Role of Corticotropin-Releasing Factor in Behavioral and Hormonal Effects of Drugs of Abuse |
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A. Drug-Induced Activation of the Hypothalamic-Pituitary-Adrenocortical Axis
Activation of the HPA axis is the primary neuroendocrine response
of the body to a challenge from the environment. Hormonal changes
involving increased peripheral glucocorticoid levels and release of CRF
in different brain sites initiate a cascade of biological responses to
counteract the altered homeostatic balance of the organism in response
to stress. The HPA axis has long been implicated in different aspects
of drug addiction. Early clinical studies on methadone-treated heroin
addicts (Dole et al., 1966) indicate atypical stress responsivity in
both active and long-term abstinent heroin addicts. More recently,
similar atypical stress response of the HPA axis has been found in
abstinent cocaine addicts (Kreek, 1992). Thus, it has been hypothesized
that an atypical response to stressors may contribute to compulsive
drug use (Kreek and Koob, 1998). In an intriguing series of studies,
Piazza et al. (1989) have demonstrated that rats with higher
levels of behavioral and neuroendocrine response to stress develop
psychostimulant drug self-administration more rapidly than low
responders (Piazza and Le Moal, 1997). Moreover, corticosterone, the
major glucocorticoids endproduct of HPA axis activation in rodents, is
self-administered by rats (Piazza et al., 1993). Furthermore,
pharmacological manipulations of the circulating corticosterone levels
altered cocaine self-administration behavior (Goeders et al., 1998).
Clinically, pharmacological blockade of glucocorticoids synthesis by
metyrapone in long-term abstinent opioid and cocaine addicts has led to
drug-like subjective effects (Kreek, 1996). These results suggest that
the activity of the HPA axis may play a role in the different phases of
drug addiction. The sections that follow review the literature on the
effects of drugs of abuse on the HPA axis.
1. Psychostimulant Drugs.
Considerable evidence demonstrates
that acute psychostimulant administration produces a stress-like
activation of the HPA axis in rodents. An early study found that
amphetamine (AMPH) increases plasma corticosterone in rats (Knych and
Eisenberg, 1979). The effective dose range of AMPH to increase plasma
corticosterone is between 1 and 5 mg/kg subcutaneously (s.c.) (Swerdlow
et al., 1993). Corticosterone levels peak about 30 min after a single AMPH injection with relatively high levels at 60 min and restoration of
baseline levels by 120 min post-AMPH (Knych and Eisenberg, 1979;
Swerdlow et al., 1993). ACTH secretion is also stimulated by AMPH, with
a peak effect at 30 min that returns to baseline by 60 min (Swerdlow et
al., 1993).
; Rivier and Vale, 1987), and this
finding has been confirmed and extended (Borowsky and Kuhn, 1991b; Levy
et al., 1991; Sarnyai et al., 1992a; Sarnyai et al., 1993b; Schmidt et
al., 1995). Cocaine (3.75-30 mg/kg) administered intravenously (i.v.)
or intraperitoneally (i.p.) increases plasma corticosterone levels
(peak effect about 30 min postcocaine administration). The ACTH
response to cocaine precedes the elevation in plasma corticosterone,
with a peak response 10 to 20 min after intravenous cocaine injection
(Rivier and Vale, 1987; Borowsky and Kuhn, 1991b; Levy et al., 1991).
Intracerebroventricular, intrahypothalamic (Saphier et al., 1993), or
intraventral striatum (Ikemoto and Goeders, 1998) administration of
cocaine also activates the HPA axis in rat as measured by elevations in
plasma corticosterone. Peak corticosterone levels were measured 20 min
after central administration of 50 µg of cocaine into the lateral
ventricles or immediately above the PVN of the hypothalamus,
respectively (Saphier et al., 1993), supporting a central mechanism of
action of cocaine on the HPA axis.
Initial studies, however, did not resolve the question of whether
cocaine activates the pituitary-adrenocortical axis through hypothalamic CRF release or through a direct effect of cocaine on
anterior pituitary ACTH secretion. One study (Moldow and Fischman, 1987) suggests that cocaine might stimulate ACTH release at the level
of the anterior pituitary. These researchers found that the
pharmacological blockade of CRF release did not attenuate the effect of
cocaine on ACTH and corticosterone secretion, and that hypothalamic CRF
content after cocaine administration was not altered. However, other
investigators (Rivier and Vale, 1987) did not find changes in ACTH
release from the anterior pituitary in vitro in response to cocaine.
These investigators also found that pretreatment with a CRF antiserum
blocks cocaine-induced ACTH release in rats (Rivier and Vale, 1987). In
addition, central administration of a CRF antiserum or a CRF receptor
antagonist blocks the corticosterone response to cocaine in rats
(Sarnyai et al., 1992a). Moreover, cocaine was found to release CRF
from hypothalamic explants in vitro (Calogero et al., 1989). These results clearly show that the action of cocaine on the HPA axis is
mediated via CRF receptors and depends on the release of endogenous hypothalamic CRF (Fig. 1).
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). The potential role of
vasopressin as a mediator of the cocaine's effects on ACTH release has
been suggested since cocaine increases plasma vasopressin levels in
rats (Sarnyai et al., 1992c). In addition, in animals with
lesions of the PVN that spared a small portion of
vasopressin-synthesizing neurons, cocaine was still able to increase
plasma ACTH (Rivier and Lee, 1994). However, passive immunization with
vasopression antiserum does not alter cocaine-induced ACTH secretion,
suggesting that cocaine-induced vasopressin release may not play a role
in HPA activation in rats (Rivier and Lee, 1994). Finally, the lack of
effect of cocaine on oxytocin release to the peripherial blood argues
against its involvement cocaine-induced activation of the HPA axis
(Sarnyai et al., 1992c). Overall, these data suggest that in rodents,
psychostimulants activate the HPA axis through CRF released from the
median eminence, resulting in the released of ACTH and corticosterone.
The effects of cocaine on the HPA axis have also been studied in
nonhuman primates and in humans. The possible involvement of
hypothalamic CRF was studied by using an indirect method, the measurement of micropulsatile ACTH release (Sarnyai et al., 1995b, 1996). ACTH and cortisol/corticosterone are secreted in frequent (2-3
pulses/h) micropulses in rats, rhesus monkeys, and humans (Carnes et
al., 1988, 1990; Iranmanesh et al., 1990; Sarnyai et al., 1995b, 1996).
It was shown that in rats an increase in the amplitude of
micropulsatile ACTH release is inhibited by i.v. administration of a
CRF antiserum, whereas the frequency of the release episodes remained
unchanged. These data suggest that the amount of ACTH that is secreted
into the circulation during each of the micropulsatile ACTH release
episodes, but not the frequency of these episodes, is under
hypothalamic CRF control (Carnes et al., 1990). In male rhesus monkeys,
cocaine (0.8 mg/kg i.v.) increases ACTH and cortisol pulse amplitude,
whereas the frequency of pulsatile hormone release remains unchanged
(Sarnyai et al., 1996). Data suggest that, as in rodents, CRF mediates
the effect of cocaine on ACTH and cortisol secretion in nonhuman
primates. Finally, it has recently been demonstrated that both
experimenter-administered cocaine injections, as well as i.v. cocaine
self-administration at doses as low as 0.03 mg/kg/injection increase
ACTH and cortisol release in rhesus monkeys (Broadbear et al., 1999a).
The stimulatory effect of an acute dose of cocaine on
pituitary-adrenocortical hormones has been demonstrated in humans.
Plasma cortisol levels are increased by cocaine (40 mg i.v.) in
experienced drug users (Baumann et al., 1995). In drug-naive subjects,
intranasal cocaine (2 mg/kg) also increases cortisol levels (Heesch et
al., 1995). Other investigators (Mendelson et al., 1992) reported that acute cocaine (30 mg i.v.) administration increases plasma ACTH levels
within 5 min in cocaine-dependent men. Analysis of cocaine and ACTH
pharmacokinetics, and cardiovascular and subjective effects of i.v.
cocaine in occasional cocaine users have revealed an almost identical
time to maximal concentration for cortisol and ACTH (Sholar et al.,
1998). Furthermore, cardiovascular and subjective effect measures were
correlated with concurrent increases in plasma cocaine and ACTH levels
(Sholar et al., 1998). One study addressed the mechanisms of action of
cocaine on the human HPA axis (Teoh et al., 1994). Similar to studies
in rhesus monkeys (Sarnyai et al., 1995b,c, 1996), the parameters of
pulsatile release (e.g., amplitude, frequency) of ACTH were measured
after i.v. cocaine administration. Cocaine increased the ACTH pulse
amplitude, presumably a CRF-dependent event, without altering pulse
frequency. This observation suggests a central role of CRF in the
mediation of cocaine's effects on human's HPA axis activation (Teoh
et al., 1994) (Fig. 2).
|
2. Opioids.
Opioids, such as morphine and heroin, modulate
the pituitary-adrenocortical activity in experimental animals and
humans. However, whereas the effect of psychostimulants on the HPA axis
is stimulatory in both rodents and primates, including humans (see
above), opioids, given acutely, exert species-specific
stimulatory effects in rodents and inhibitory effects in primates.
Early reports in the rat studied the effect of morphine on the in vivo
and in vitro secretion of ACTH by the pituitary gland and CRF by the
hypothalamus (Buckingham, 1982). A single injection of morphine caused
a rise followed by a fall in hypothalamic CRF content and increases in the concentrations of ACTH in the plasma and adenohypophysis. The
production of ACTH by pituitary segments in vitro was not affected by
the addition of morphine to the incubation medium. However, morphine
stimulated the secretion of CRF by isolated hypothalami, and its effect
was antagonized by both mu- and kappa-, but not by delta-, opioid
receptor antagonists (Buckingham, 1982; Buckingham and Cooper, 1986).
These results indicate that morphine evokes HPA axis activity by
stimulating mainly mu- and kappa-receptors (Buckingham and Cooper,
1986). Importantly, over repeated injections, however, rapid and
complete tolerance develops to the stimulatory effects of opioid
agonists on the HPA axis (Pechnick, 1993).
). However,
acute morphine administration did not alter CRF content in the PVN
(Milanes et al., 1997) or basal CRF release from hypothalamic explants,
whereas it inhibited CRF release induced by a variety of
neurotransmitters, in vitro (Tsagarakis et al., 1989). The inhibitory
effect of morphine is attenuated by mu- and kappa-, but not delta-,
opioid receptor antagonists (Tsagarakis et al., 1990). Thus, it seems
that, in rodents, direct stimulation of opioid receptors in the
hypothalamus inhibits CRF release, whereas acute in vivo administration
of opioids in general, stimulates HPA axis activity, probably through
actions on other neurotransmitter systems that in turn alter CRF release.
The opioid regulation of the primate, including humans, HPA axis seems
to be different from that of rodents. Opioid receptor antagonists,
naloxone and naltrexone, increase plasma cortisol levels in talapoin
monkeys (Meller et al., 1980), cynomolgus monkeys (McCubbin et al.,
1993), and in the chimpanzee (Gosselin et al., 1983). In humans,
morphine (oral slow-release tablet) suppresses basal ACTH and cortisol
levels and decreases CRF-stimulated release of ACTH and cortisol
(Allolio et al., 1987). Morphine (10 mg), methadone (10 mg),
pentazocine (30 mg), nalorphine (10 mg), and met-enkephalin analog,
DAMME (0.25 mg), all decrease serum cortisol in healthy human subjects
(Delitala et al., 1983). Finally, the opioid antagonist, naloxone,
increases ACTH and cortisol levels in humans, which, together with
other results, further support earlier findings that stimulation of
opioid receptors in humans inhibits HPA axis activity (Kreek and Koob,
1998). The mechanisms underlying the opposing effects of acute opioid
administration in rodent and primate HPA axis are not known.
3. Alcohol and Benzodiazepines.
Early observations of the
effects of ethanol on corticosterone secretion in rats (Ellis, 1966)
were extended to show that acute administration of alcohol (i.p.) to
freely moving, nonanesthetized rats increases plasma ACTH and
corticosterone levels (Rivier et al., 1984). An i.v. injection of a CRF
antiserum blocks this stimulatory effect, suggesting a CRF-dependent
mechanism for the effect of alcohol on the release of ACTH. Acute
exposure of cultured pituitary cells to 0.2% alcohol does not modify
basal or CRF-induced ACTH release, whereas pretreatment of the cells
with alcohol for 24 h decreases both spontaneous and stimulated
ACTH secretion. It is, therefore, possible that long-term exposure to
alcohol may result in an increase of CRF release by the median
eminence, as well as in some loss of pituitary responsiveness. These
investigators hypothesized that the acute alcohol-induced activation of
the HPA axis probably takes place at the level of CRF-secreting neurons (Rivier et al., 1984).
). Acute exposure of superfused rat pituitaries to alcohol (20-200
mg/dl) produced dose-related increases in ACTH. The response to each
dose was multiphasic, consisting of three peaks of ACTH in the 28-min
sampling period after the addition of alcohol. Lesions of the PVN
attenuate, but do not abolish the stimulatory effects of alcohol (1.5 mg/kg i.p.) on ACTH release in rats (Rivest and Rivier, 1994). Because
the PVN is the major source of CRF in the median eminence, this
observation suggests that extra-PVN brain regions, and/or ACTH
secretagogues other than CRF (e.g., vasopressin), mediate ACTH
stimulation by alcohol. This hypothesis was tested by determining the
effect of vasopressin immunoneutralization on ACTH release in rats with
PVN lesions (Ogilvie et al., 1997b). Removal of endogenous vasopressin
diminished alcohol-evoked ACTH secretion in both sham-operated and
PVN-lesioned animals, indicating that vasopressin from outside the PVN
partially mediates the pituitary-adrenocortical response to alcohol.
To identify the role of hypothalamic CRF and pituitary CRF receptors in
alcohol-induced HPA axis activation, one study (Rivier et al., 1996)
used two CRF receptor antagonists: -helical CRF and astressin. The
-helical CRF peptide is very effective in interfering with
biological responses mediated by brain CRF receptors, but is relatively
weak in its effect on pituitary CRF receptors (Fisher et al., 1991). In
contrast, astressin, a member of the newer generation of CRF receptor
antagonists, effectively blocks both brain and pituitary CRF receptors
(Hernandez et al., 1993). Intravenous administration of astressin, at
doses shown to block CRF-induced ACTH release, reduces the ACTH
response to alcohol (1.5 or 3 g/kg i.p.). The ACTH response to alcohol
was modestly, but not significantly, attenuated by central infusion of
-helical CRF. Similarly, the stimulatory effect of alcohol on
hypothalamic neuronal activation, measured by increases in the
immediate early gene NGFI-B mRNA levels, was only slightly altered by
blockade of hypothalamic CRF receptors. Taken together, these results
suggest that the stimulatory effect of alcohol on ACTH release depends on the activation of CRF synapses in the hypothalamus and that functional pituitary CRF receptors are essential for the ACTH response
to the drug. The data reviewed also indicate that low doses of alcohol
act directly on the pituitary to induce ACTH release, whereas higher
doses may have their primary site of action on the hypothalamus.
Benzodiazepine (BDZ) drugs act on the GABA-BDZ receptor complex to
modulate the state of the chloride ion channels. These drugs exert
anxiolytic effects in experimental animals and humans (Ticku, 1990).
Alcohol has been proposed to interact with the same receptor complex to
produce acute anxiolytic effects (Mihic and Harris, 1995). The activity
of the HPA axis can be altered by both acute and chronic BDZ
administration. The effects of acute BDZ agonists on the HPA axis are
dose-dependent (Pohorecky et al., 1988). A series of studies have shown
that lower, anxiolytic doses (below 5 mg/kg) of BDZ agonists, i.e.,
chlordiazepoxide (CDP) and clorazepate, attenuate HPA axis activity in
rats and mice (Mormede et al., 1984; Pericic et al., 1984; Pivac and
Pericic, 1993). However, CDP and other BDZ agonists, at doses higher
than 5 mg/kg, usually increase plasma ACTH and corticosterone levels (Freeman and Thurmond, 1986; Lakic et al., 1986; McElroy et al., 1987;
Matheson et al., 1988; Calogero et al., 1990; De Boer et al., 1990,
1991; Kalman et al., 1997). Activation of the HPA axis by stress,
however, is attenuated by CDP treatment (De Boer et al., 1991; Pericic
and Pivac, 1996; Kalman et al., 1997).
The effects of BDZs on the HPA axis may be mediated through
hypothalamic CRF secretion, since a BDZ agonist increased CRF release
from hypothalamus in vitro (Calogero et al., 1990) and in several brain
regions, including amygdala, LC, and median eminence in vivo (Wilson et
al., 1996). However, it seems that in vivo administration of BDZs in
anxiolytic doses decreases HPA axis activity. For example, alprazolam,
a triazolobenzodiazepine anxiolytic drug, has been shown to decrease
ACTH secretion (Owens et al., 1991). Moreover, CRF levels are decreased
in the LC in response to alprazolam (Owens et al., 1991). The
differential effects of BDZ agonists on CRF concentration could also be
a function of dose, the brain region investigated, or the type of BDZ
ligand administered. Overall, the preclinical data preclude a clear
conclusion concerning the effect of BDZ on the HPA axis.
4. Nicotine.
Nicotine, the addictive substance in tobacco,
has been shown to stimulate HPA activity in rodents, leading to
elevated levels of plasma ACTH and corticosterone (Cam et al., 1979;
Andersson et al., 1983; Conte-Devolx et al., 1985). When given
systemically, nicotine increases the release of ACTH and corticosterone
via its effect on hypothalamic CRF (Matta et al., 1998). Intravenous administration of nicotine increases plasma levels of ACTH within 7 min
after administration. On the other hand, cystine, which is as potent
peripherially on the nicotinic acetylcholine receptors as nicotine, but
does not cross the blood-brain barrier, is ineffective (Matta et al.,
1987). Nicotine dose dependently stimulates ACTH release when
administered i.c.v. (Matta et al., 1987). Furthermore, the effect of
nicotine on ACTH release is blocked by a centrally active nicotinic
receptor antagonist, mecamylamine, but not by hexamethonium, a
quaternary amine that does not cross the blood-brain barrier (Matta et
al., 1990). Nicotine, tested in a wide dose range, does not alter ACTH
secretion from anterior pituitary cultures in vitro (Matta et al.,
1987). In contrast, nicotine has been shown to stimulate CRF-containing
neurons in the PVN as measured by Fos protein activation (Matta et al.,
1998), and to release CRF from medial hypothalamic explants in vitro
(Karanth et al., 1999). Overall, data from studies with rodents
indicate that nicotine stimulates the HPA axis through the activation
of hypothalamic CRF.
; Seyler et
al., 1984). However, intense smoking was necessary to elicit activation
of the HPA axis in humans. One regular-strength cigarette (1 mg of
nicotine per cigarette) does not produce a measurable increase in
plasma cortisol (Gilbert et al., 1992). It seems that at least two
regular-strength cigarettes are required to elicit significant
elevation of salivary cortisol levels in men, an indicator of free
cortisol in the plasma (Kirschbaum et al., 1992). Nicotine has been
shown to be the main, if not the only, component of smoked tobacco to
activate HPA axis. Increased plasma cortisol levels were measured after
i.v. administration of nicotine (Newhouse et al., 1990). Similarly,
intranasal aerosol delivery of nicotine reverses the expected diurnal
decrease of plasma cortisol levels (Pomerleau et al., 1992). Overall,
it can be concluded that nicotine stimulates the HPA axis in rodents and humans. In addition, studies in rats indicate that hypothalamic CRF
plays a major role in mediating nicotine's effects on the ACTH and
glucocorticoid secretion.
5. Cannabinoids.
Early studies, using plasma corticosterone
levels as a measure of HPA activity, showed that tetrahydrocannabinol
(THC) and related cannabinoids are potent stimulators of this system
(Johnson et al., 1978; Jacobs et al., 1979; Kumar and Chen, 1983). THC administration (i.p.) increases ACTH and cortisol levels in rats 8- to
10-fold (Puder et al., 1982). THC, infused centrally, increases ACTH
and corticosterone levels in a dose-dependent manner (Weidenfeld et
al., 1994). Similar effects were exerted by anandamide
(arachidonylethanolamide), an endogenous ligand of the cannabinoid
receptor (Weidenfeld et al., 1994) and by a potent, synthetic
cannabinoid receptor agonist, HU-210 (Martin-Calderon et al., 1998).
Effects of central administration of THC on ACTH and corticosterone can
be blocked by administration of a selective cannabinoid receptor
antagonist, SR-141716A (Manzanares et al., 1999), suggesting that the
HPA-axis activating effects of THC are mediated by central cannabinoid receptors.
).
THC-induced CRF release from the median eminence is also suggested by
the findings that THC-induced suppression of luteotroph hormone is
inhibited by central administration of a CRF receptor antagonist
(Jackson and Murphy, 1997). A CRF receptor antagonist,
D-Phe CRF, had no effect on the increase in corticosterone levels induced by the cannabinoid receptor agonist, HU-210
(Rodríguez de Fonseca et al., 1996). This observation suggests
a direct pituitary target for cannabinoids to stimulate ACTH and
corticosterone release. However, complete hypothalamic deafferentation
entirely abolished the pituitary-adrenal activating (ACTH and
corticosterone) effects of THC (Puder et al., 1982), which is not
consistent with a pituitary target for THC. Taken together, while
cannabinoid receptor agonists activate the HPA axis, the degree that
this effect is CRF-dependent remained to be determined.
6. Differential Adaptation of the
Hypothalamic-Pituitary-Adrenocortical Axis to Chronic Drug
Administration.
Although most of the drugs reviewed above
stimulate the HPA axis when given acutely, the question remains if this
effect is maintained after chronic drug administration. This issue is
important in light of the proposed role of high circulating
glucocorticoids levels in the development of psychostimulant drug
self-administration (Piazza and Le Moal, 1997), and the detrimental
effect of chronic glucocorticoid hypersecretion on brain functions and
behavior (McEwen, 1998). In general, acute and chronic exposure to
different drugs of abuse have different effects on the HPA axis.
Changes in basal, stress- and drug-induced activation of the HPA axis following chronic drug administration are reviewed and compared with
changes found in response to a single drug administration.
). These data indicate a sustained hyperactivity of the HPA axis by
chronic drug treatment. Similarly, a shorter chronic "binge"
cocaine exposure in pregnant female rats also results in highly
elevated basal corticosterone levels (Quinones-Jenab et al., 2000).
Interestingly, basal corticosterone levels measured 24 h after the
last experimental session were reduced in cocaine
self-administering rats and rats receiving yoked infusions of cocaine
relative to yoked-saline controls and to preacquisition values (Mantsch
and Goeders, 2000). It is possible that long-term (30 days) and
high-dose (1.0 mg/kg/infusion) i.v. cocaine administration can lead to
a facilitated negative feedback that can be mediated by an increased
hippocampal glucocorticoid receptor density (Mantsch and Goeders,
2000).
In cocaine-dependent men, no difference in basal cortisol levels was
found, compared with healthy subjects (Jacobsen et al., 2001) or normal
values (Mendelson et al., 1998). This discrepancy can be attributed to
the fact that most of the chronic cocaine dependent subjects in the
previous studies used other drugs, including heroin, or alternatively,
to species differences in response to chronic cocaine administration.
An altered response to an acute administration of cocaine following
chronic cocaine treatment can indicate the development of either
tolerance (loss of the effect of cocaine) or sensitization (facilitated
effect of cocaine). Several preclinical studies in rats indicate that
neither tolerance nor sensitization develops as a result of chronic
cocaine administration in rats (Borowsky and Kuhn, 1991a; Yang et al.,
1992; Laviola et al., 1995). A single dose of cocaine following a
chronic treatment regimen has repeatedly been found to be as effective
in stimulating HPA axis activity as in control animals. One study with
cocaine-dependent humans reported tolerance of the HPA axis response to
cocaine (Mendelson et al., 1998). However, the cocaine-dependent
subjects in this study also met the diagnostic criteria for opioid
dependence (Mendelson et al., 1998); thus, it is difficult to draw
conclusions from this study.
Acute administration of restraint stress resulted in an increase in
plasma corticosterone levels in rats subjected to chronic "binge"
cocaine administration similar to what was found before the chronic
cocaine treatment or in control rats, suggesting the lack of
cross-tolerance and cross-sensitization to another agent that
stimulates the HPA axis (Sarnyai et al., 1998). Overall, it seems as if
chronic cocaine administration may lead to a sustained hyperactivity of
the HPA axis without the development of tolerance (or sensitization).
This might be important from the point of view of a long-term
"glucocorticoid burden" that results from chronic cocaine use and
can lead to the endangerment of different organ systems, including the
brain (McEwen, 1998).
b. Opioids.
Acute administration of opioids, similar to
psychostimulants, result in an increased activity of the HPA axis (see
above), whereas these drugs exert profoundly different effects on HPA activity when administered chronically. There is no significant tolerance in the HPA stimulatory effects of psychostimulants upon chronic administration (see above). In contrast, studies in many animal
species, including rodents, indicate the development of tolerance to
the HPA axis stimulatory effects of opioids upon chronic administration
(Pechnick, 1993). Repeated subcutaneous morphine injections and chronic
implantation of morphine pellets produced tolerance to the HPA axis
activating effects of morphine (Ignar and Kuhn, 1990; Alcaraz et al.,
1996). Furthermore, chronic i.c.v. administration of the µ-agonist
DAMGO
(D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin)
and the -agonist DPDPE
(D-Pen2,Pen5-enkephalin)
lead to the development of tolerance to their HPA axis activating
effects (Gonzalvez et al., 1991). Similarly, profound tolerance
developed in response to chronic (s.c.) injections of a 
-agonist,
UH50,488 (Ignar and Kuhn, 1990).
These results suggest that chronic stimulation of any major opioid
receptor subtype (i.e., mu, delta, and kappa) can lead to the
development of tolerance to opioids' facilitatory effects on the HPA
axis. One recent study showed that, whereas acute morphine administration resulted in an increase in ACTH concentrations in the
plasma and in the anterior pituitary as well as in elevated CRF
concentrations in the hypothalamus, chronic morphine treatment produced
little effects on ACTH and CRF concentrations, indicating the
development of tolerance (el Daly, 1996). Tolerance to the HPA axis
stimulatory effects of opioids does not occur at the level of pituitary
or adrenals, because ACTH and corticosterone responses to exogenous CRF
and ACTH, respectively, were not attenuated (Ignar and Kuhn, 1990).
This result, together with the tolerance demonstrated on
morphine-induced increase in hypothalamic CRF levels (el Daly, 1996) raises the possibility that hypothalamic or suprahypothalamic sites
mediate this phenomenon. Another intriguing mechanism of morphine-induced alterations of corticosterone levels was recently demonstrated. It was shown that chronic exposure to morphine increases the level of corticosteroid binding globulin in male rats leading to a
dramatic reduction in free, physiologically active corticosterone (Nock
et al., 1997, 1998). In summary, chronic administration of opioids
result in the development of tolerance to their HPA axis stimulating
effects, which, together with decreased corticosteroid binding globulin
levels, can lead to decreased biologically active corticosterone levels.
c. Alcohol and Benzodiazepines.
Acute alcohol treatment is a
powerful stimulus of the HPA axis (see Section III.A.3.).
Repeated administration of alcohol for 1 to 3 weeks produced signs of
hyperstimulation of the HPA axis, as indicated by adrenal hypertrophy
and thymus involution (Spencer and McEwen, 1990). In the same model, an
adaptation of the HPA axis to the repeated alcohol administration was
observed, since the corticosterone response to alcohol on the last day
of the treatment was less than on the first day (Spencer and McEwen, 1990). The development of tolerance to the HPA axis stimulating effects
of alcohol have been demonstrated repeatedly by several groups in young
adults (Guaza et al., 1983; Guaza and Borrell, 1985; Rivier, 1996;
Spencer and McEwen, 1997), but not in aged rats (Spencer and McEwen,
1997). Chronic alcohol consumption results in the development of
cross-tolerance to some other stressors, such as cytokine stimulus and
mild footshock (Lee and Rivier, 1993). Both in vitro and in vivo
administration of alcohol, when given acutely, stimulates CRF release
from the hypothalamus (Rivier et al., 1984; Redei et al., 1988).
Tolerance developed to the CRF-stimulating effect of alcohol as
measured by decreased CRF release in response to acute alcohol
administration in chronically alcohol-treated subjects (Rivier et al.,
1984; Redei et al., 1988).
It has been proposed that the activity of both CRF nerve terminals in
the median eminence, and of CRF perikarya in the PVN of the
hypothalamus, is inhibited by chronic alcohol treatment, whereas
pituitary responsiveness to CRF appears unchanged (Rivier et al.,
1984). Relatively little work has been published on the effects of
chronic benzodiazepine treatment on the activity of the HPA axis. Basal
corticosterone levels were increased in rats subjected to chronic
diazepam administration. This observation may indicate the lack of
tolerance to the HPA axis activating effects of the high dose of
benzodiazepines (Barlow et al., 1979; Chabot et al., 1982; Pericic et
al., 1987; Wilson et al., 1996).
d. Nicotine.
Acute nicotine administration has been shown to
activate HPA axis in rats and humans (see Section III.A.4.).
A very rapid desensitization of this effect seems to occur even after a
single dose of nicotine pretreatment (Sharp and Beyer, 1986). Even in the face of this acute desensitization phenomenon, several studies have
indicated that repeated, long-term nicotine treatment leads to
increased basal corticosterone levels in rats (Morse, 1989; Pauly et
al., 1992; Rasmussen, 1998). However, at least one study did not show
significant changes in basal corticosterone in response to 8 weeks of
repeated nicotine administration (Seifert et al., 1984). A challenge
with a single dose of nicotine in chronically nicotine-treated rats
resulted in an attenuated HPA response, compared with its effects in
chronically saline-treated animals, which indicates the development of
tolerance to the HPA axis activating effects of nicotine (Pauly et al.,
1992). Finally, in agreement with the idea that tolerance develops to
nicotine's neuroendocrine effects, it was recently demonstrated that
the activating effect of nicotine on the expression of Fos (an
immediate early gene product) in the PVN of the hypothalamus was
abolished by chronic nicotine administration (Salminen et al., 2000).
e. Cannabinoids.
Relatively little is known about the chronic
effects of THC on the HPA axis, but several studies suggest that
tolerance may develop after repeated administration. Acute (Cone et
al., 1986), but not repeated (Dax et al., 1989; Block et al., 1991)
administration of THC increases cortisol levels in humans.
7. Summary.
The effects of drugs of abuse on the activity of
the HPA axis and the presumed role of central hypothalamic-pituitary
CRF system can be summarized as follows:
| 1. | In rats, upon acute administration, most drugs of abuse
activate the HPA axis as measured by an increase in ACTH and
corticosterone secretion. In primates, including humans,
psychostimulants, alcohol, nicotine, and THC but not opioid
drugsactivate the HPA axis.
|
| 2. | The role of CRF synthesized by neurons in the parvocellular section of the PVN and released from the median eminence to the pituitary portal circulation has been clearly demonstrated in the HPA activating effects of psychostimulants, opioids, and alcohol in rodents. In addition, indirect evidence (i.e., micropulsatile ACTH release) suggests a role for CRF in cocaine-induced activation of the HPA axis in rhesus monkeys and humans. |
| 3. | Chronic administration of cocaine, BDZ, nicotine, and possibly alcohol, but not opioid drugs, can lead to a sustained increase in basal activity of the HPA axis in experimental animals. |
| 4. | Upon repeated exposure to opioids, alcohol, nicotine, and possibly THC administration, tolerance develops to the ability of acute injections of the drugs to activate the HPA axis. It does not appear, however, that tolerance develops to the acute effects of psychostimulant drugs on the HPA axis after repeated drug exposure (Table 1). |
|
B. Unconditioned and Conditioned Behavioral Effects of Drugs
Exposure to psychostimulant, sedative/hypnotic and opioid drugs
results in several unconditioned behavioral effects, including alterations in the levels of arousal, nociception, and appetite (Jaffe,
1992). Several studies examined the role of CRF in the unconditioned
and conditioned locomotor activating effects of psychostimulant drugs,
in the development of sensitization to the behavioral activating
effects of psychostimulants, and in the effects of alcohol and
cannabinoid drugs in animal models of anxiety.
1. Psychostimulant Drugs.
The role of endogenous CRF in the
locomotor hyperactivity induced by cocaine in rats has been examined
using immunoneutralization of endogenous CRF and CRF receptor blockade
(Sarnyai et al., 1992b). A CRF antibody, injected i.c.v., in dilutions
of 1:20 and 1:5, but not 1:100, 24 h before cocaine treatment (7.5 mg/kg s.c.) blocks the expression of cocaine-induced hyperactivity.
Similarly, -helical CRF (0.01-1.0 µg i.c.v.) inhibits the
locomotor hyperactivity induced by cocaine. Neither CRF
immunoneutralization nor CRF receptor blockade alters the hyperactivity
induced by caffeine (Sarnyai et al., 1992b). These findings suggest a
role for activation of brain CRF systems in psychostimulant motor activation.
). CRF (0.02-0.1 µg i.c.v.) was found to potentiate behavioral
stereotypy induced by amphetamine (4 mg/kg s.c.) (Cole and Koob, 1989).
In addition, physical restraint over 90 min for 5 days enhances
amphetamine-induced stereotypy (Cole and Koob, 1989). Similarly,
repeated administration of CRF (0.5-2.5 µg i.c.v.) induces a
long-lasting sensitization to the locomotor activating effect of
amphetamine (0.75 mg/kg s.c.) (Cador et al., 1993). In contrast,
-helical CRF (25 µg i.c.v.), given prior to restraint stress,
prevents the development of stress-induced sensitization to an
amphetamine (3 mg/kg s.c.) challenge, administered 5 days after last
exposure to restraint (Cole et al., 1990). Taken together, these
studies suggest that prior stressor exposure facilitates the magnitude
of unconditioned motor responses to psychostimulant drugs in a
CRF-dependent manner.
Another series of studies supports the ability of prior exposure to
psychostimulant drugs to condition behavioral activation by a mechanism
involving brain CRF stimulation (De Vries and Pert, 1998; De Vries et
al., 1998a). Rats were administered cocaine (30 mg/kg i.p.) over five
consecutive days prior to placement in a distinctive chamber for 30 min. The following day, on which cocaine was not injected, rats exposed
to the distinctive chamber for 25 min exhibited anxiogenic-like
behavior during a subsequent 5-min test in an animal model of anxiety,
the elevated plus maze test (De Vries et al., 1998a). In contrast, rats
treated centrally with -helical CRF (1 µg i.c.v.), did not display
the exploratory inhibition characteristic of untreated rats (De Vries
et al., 1998a). A separate study using similar methods, reported that contextual cues associated with cocaine administration induce locomotor
and HPA axis activation, and the latter effect was attenuated by
central administration -helical CRF prior to cue presentation (De
Vries and Pert, 1998). These findings suggest that the expression of
endocrine and behavioral arousal conditioned by prior exposure to a
psychostimulant drug requires brain CRF activation.
Spontaneous emission of locomotor behavior has been linked to the
preference for self-administration of psychostimulant drugs. Rats
characterized as high responders in terms of locomotor response to a
novel environment more readily acquire amphetamine self-administration (Piazza et al., 1989). Moreover, corticosterone administration, in
rats not predisposed to readily self-administer amphetamine, facilitates the acquisition of amphetamine self-administration (Piazza
et al., 1991). Thus, high activity in adrenocortical and 
p < 0.05) cocaine-induced increases in
corticosterone levels. B, pretreatment with 