Changes in dopamine efflux associated with extinction, CS-induced and d-amphetamine-induced reinstatement of drug-seeking behavior by rats
Introduction
Use of a psychostimulant drug on a single occasion can induce relapse to drug-seeking behavior in abstinent drug users [29]. Similarly, presentation of a conditioned stimulus (CS) paired previously with self-administration of psychomotor stimulant drugs is often accompanied by ‘craving’ for the drug, and activation of drug-seeking behavior in humans [50], [2] and in experimental animals [24], [33], [46], [61]. Reinstatement of extinguished self-administration behavior in animals by presentation of drug-associated stimuli [15], [54], [57], or systemic administration of cocaine [22], [15], or d-amphetamine [5], [22], provides further evidence that drug-paired stimuli or a single infusion of drug may play important roles in drug-seeking behavior.
Direct evidence for the role of the mesolimbic dopamine (DA) system in drug-induced reinstatement is provided by the finding that microinjection of the DA agonist d-amphetamine into the nucleus accumbens (NAc) can reinstate heroin self-administration [51]. Related experiments have also shown that systemic administration of DA antagonists can block relapse induced by stress or re-exposure to heroin [48]. Recently, Ranaldi et al. [44] showed that DA levels in the NAc returned to basal levels during an extinction session immediately following d-amphetamine self-administration. A subsequent non-contingent injection of d-amphetamine following extinction, increased DA efflux and also reinstated lever pressing behavior.
Several recent reports have shown that presentation of a CS can elicit conditioned increases in DA efflux in the NAc which may be critical in the reinstatement of drug-seeking behavior by a CS. For example, presentation of a discrete onset CS paired with the presentation of either d-amphetamine or cocaine [18], [39], or presentation of a flashing light stimulus previously paired with the self-administration of either cocaine [25], [30] or d-amphetamine [19] were both effective in increasing NAc DA efflux. Of particular relevance is the recent report of robust cocaine-seeking behavior elicited by sustained (64 min) presentation of a salient discriminant stimulus that previously signaled the availability of cocaine [57]. This study also observed significant elevations in DA efflux in the NAc and amygdala, following presentation of the discriminative stimulus. These findings compliment new evidence from studies with human subjects which report changes in the DA system of chronic cocaine users [55], [56], [52], [31]. In particular, in a recent study [10], subjects who had received cocaine and were then given saline, showed activation in the NAc, which the authors attribute to experience and ‘expectancy’. These findings are compelling in that they suggest the possibility that some brain areas, in particular, the mesolimbic DA system and NAc, may show conditioned activation in response to non-contingent presentation of drug-paired cues.
Behavioral treatments for cocaine addiction often employ cue exposure as a means of degrading the motivational impact of the CS [35]. The aim of such treatments is to reduce the ability of a drug-paired CS to induce drug-appropriate responding. In this regard, it is important to note that although an extinguished CS can reinstate drug-seeking, the observed rates of responding are often lower than those observed when only the operant response had been extinguished [1]. Therefore, given the hypothesis that elevations in NAc DA efflux play a critical role in eliciting drug-appropriate responses [50], it is of interest to investigate whether an extinguished CS can induce increases in DA efflux when presented passively. If CS-induced reinstatement is not associated with significant increases in DA efflux in the NAc under these conditions, it would provide strong support for CS-extinction as an effective intervention in preventing cue-induced relapse to drug-seeking behavior [35]. However, given the evidence that psychostimulants can also induce relapse [29], and can potentiate the motivational impact of drug-paired cues [11], it is unlikely that extinction of responding for d-amphetamine would be effective in blocking drug-induced reinstatement of drug-seeking behavior, especially when responding is accompanied by presentation of a CS.
The present study employed chronoamperometry and stearate-graphite paste electrodes to monitor DA efflux in the NAc, during: (1) d-amphetamine self-administration; (2) extinction; (3) CS-induced; and (4) d-amphetamine-induced reinstatement of drug-seeking behavior. The incorporation of a CS-unpaired condition also provided a rigorous test of the role of d-amphetamine and a drug-associated CS in the reinstatement of drug-seeking behavior. Further, the electrochemical technique employed will provide finer temporal resolution than is normally available with brain microdialysis and may therefore be more sensitive in detecting brief but significant changes in DA efflux.
Portions of these data were presented as an abstract at the 27th Annual Meeting of the Society for Neuroscience, 1997, and at the Meeting of the European Behavioural Pharmacology Society, 1998.
Section snippets
Materials and methods
All experiments were conducted in accordance with the standards of the Canadian Council on Animal Care.
Histology
Fig. 1 indicates the location within the NAc of the tips of each electrochemical recording electrode used in the data analyses. Electrode placements were located in both the core and shell regions of the NAc. The number of subjects in each group were as follows: CS-paired, n=8; CS-unpaired, n=7; naı̈ve, n=6.
Discussion
The present findings confirm the important relationship between enhanced DA efflux in the NAc and self-administration of d-amphetamine by rats [20], [8], [44]. As observed previously [44], DA efflux in the NAc declined steadily throughout the extinction phase, reaching baseline levels after approximately 4 h. In a subsequent test 2 days later, presentation of the CS to rats in the CS-paired group, was accompanied by a small but significant increase in bar-press responses during the first half
Conclusions
After an extended period of extinction, reinstatement of responding induced by presentation of a CS paired previously with d-amphetamine was not accompanied by a significant increase in DA efflux, as measured by chronoamperometry. These data are consistent with the use of extinction procedures as an effective therapy in the prevention of relapse in human drug addicts [35]. However, it must also be noted that, the non-contingent administration of d-amphetamine increased DA efflux in the NAc and
Acknowledgements
This research was supported by an operating grant 36372 from the Canadian Institutes of Health Research to A.G.P. We thank Fredric LePiane for his help in drafting this manuscript.
References (63)
- et al.
Differences between responders and nonresponders to cocaine cues in the laboratory
Addict. Behav.
(1995) - et al.
Effects of response requirement upon human sedative self-administration and drug-seeking behavior
Pharmacol. Biochem. Behav.
(1976) Evaluation of stearate–graphite paste electrodes for chronic measurement of extracellular dopamine concentrations in the mammalian brain
Pharmacol. Biochem. Behav.
(1996)- et al.
Does monoamine oxidase inhibition by pargyline increase extracellular dopamine concentrations in the striatum?
Neuroscience
(1996) - et al.
Acute effects of cocaine on human brain activity and emotion
Neuron
(1997) - et al.
Involvement of the amygdala in stimulus-reward associations: interaction with the ventral striatum
Neuroscience
(1989) - et al.
Drug-induced reinstatement of extinguished self-administration behavior in monkeys
Pharmacol. Biochem. Behav.
(1975) - et al.
Dissociation of primary and secondary reward-relevant limbic nuclei in an animal model of relapse
Neuropsychopharmacol.
(2000) - et al.
Conditioned changes in nucleus accumbens dopamine signal established by intravenous cocaine in rats
J. Neurochem.
(1996) - et al.
Effects of contingent and non-contingent cocaine on drug-seeking behavior measured using a second-order schedule of cocaine reinforcement in rats
Neuropsychopharmacol.
(1999)
Dopamine overflow in the nucleus accumbens during extinction and reinstatement of cocaine self-administration behavior
Neuropsychopharmacol.
Effect of dose on cocaine self-administration behavior and dopamine levels in the nucleus accumbens
Brain Res.
Neurobehavioural mechanisms of reward and motivation
Curr. Opin. Neurobiol.
The neural basis of drug craving: an incentive-sensitization theory of addiction
Brain Res. Rev.
Repeated cocaine administration induces behavioral sensitization and corresponding decreased extracellular dopamine responses in caudate and accumbens
Brain Res.
The role of accumbens dopamine in lever pressing and response allocation: effects of 6-OHDA injected into core and dorsomedial shell
Pharm. Biochem. Behav.
A comparison of the effects of intra-accumbens injections of amphetamine and morphine on reinstatement of heroin intravenous self-administration behavior
Brain Res.
Cocaine uptake is decreased in the brain in detoxified cocaine abusers
Neuropsychopharmacol.
Increased extracellular dopamine in the nucleus accumbens of the rat during associative learning of neutral stimuli
Neuroscience
Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine
Psychopharmacol.
The effects of pipradol on the acquisition of responding with conditioned reinforcement: a role for sensory preconditioning
Psychopharmacol.
The effect of pimozide on the establishment of conditioned reinforcement
Psychopharmacol.
Critical assessment of electrochemical procedures applied to the measurement of dopamine and its metabolites during drug-induced and species-typical behaviours
Behav. Pharmacol.
Potentiation of the effects of reward-related stimuli by dopaminergic-dependent mechanisms in the nucleus accumbens
Psychopharmacol.
Effect of haloperidol on (+)-amphetamine self-administration
J. Pharm. Pharmacol.
Role of conditioned reinforcers in the initiation, maintenance and extinction of drug-seeking behavior
Pav. J. Biol. Sci.
Reinstatement of cocaine-reinforced responding in the rat
Psychopharmacol.
A motivational hypothesis of the role of mesolimbic dopamine in compulsive drug use
J. Psychopharmacol.
In vivo monitoring of dopamine in the nucleus accumbens during long-term intravenous self-administration of d-amphetamine by the rat
Behav. Pharmacol.
The relation between dopamine oxidation currents in the nucleus accumbens and conditioned increases in motor activity in rats following repeated administration of d-amphetamine or cocaine
Eur. J. Neurosci.
Cited by (38)
Effect of food training and training dose on nicotine self-administration in rats
2014, Behavioural Brain ResearchCitation Excerpt :Training paradigm was a between subjects factor and there was no difference between FT and SP animals (Fig. 5b). Consistent with earlier studies with nicotine [11] and other drugs of abuse [19–23], the result of the present study confirm and further extend the finding that prior training with another reinforcer (food) can facilitate acquisition of NSA. One significant finding from the present work is that prior FT resulted in a greater proportion of animals achieving the criteria for NSA in comparison to spontaneous acquisition.
Effects of CCK-8 on the reinstatement of morphine-induced CPP and expression of behavioral sensitization in rats
2013, NeuroscienceCitation Excerpt :To date, the role of DA in the relapse to drug-seeking behavior has focused primarily on the nucleus accumbens and produced mixed results. It has been found that chronic morphine administration changed DA levels within the nucleus accumbens (NAc), and morphine- or amphetamine-primed reinstatement is associated with reduced or enhanced DA release in the NAc (Neisewander et al., 1996; Spanagel and Weiss, 1999; Di Ciano et al., 2001; Adinoff, 2004). Data also suggest that behavioral sensitization is generally associated with enhanced dopamine signaling in the mesocorticolimbic dopamine system (Chen et al., 2009).
A new criterion for acquisition of nicotine self-administration in rats
2012, Drug and Alcohol DependenceCitation Excerpt :It has long been known that food restriction facilitates self-administration of abused drugs (Lang et al., 1977; Singer et al., 1978). In addition, prior training with natural rewards is generally employed to facilitate acquisition of operant responding for the drug upon subsequent training sessions (Ahmed et al., 2000; Baker et al., 2003; Di Ciano et al., 2001; Meil and See, 1996; Sutton et al., 2003; Weiss et al., 2000). This procedure results in higher response rates on the first day of self-administration (Bongiovanni and See, 2008; Donny et al., 1998) leading to a more rapid acquisition process (Donny et al., 1998) that is likely coupled with extinction of the initial response-reinforcer contingency.
Stress-induced reinstatement of amphetamine-conditioned place preference and changes in tyrosine hydroxylase in the nucleus accumbens in adolescent rats
2010, Pharmacology Biochemistry and BehaviorDopamine receptors in the learning, memory and drug reward circuitry
2009, Seminars in Cell and Developmental BiologyMouse model of relapse to the abuse of drugs: Procedural considerations and characterizations
2009, Behavioural Brain Research
- 1
Tel.: +44-01223-339549; fax: +44-01223-333564.