Changes in dopamine efflux associated with extinction, CS-induced and d-amphetamine-induced reinstatement of drug-seeking behavior by rats

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Abstract

The present experiment employed chronoamperometry with stearate–graphite paste electrodes to monitor dopamine efflux in the nucleus accumbens during extinction and subsequent reinstatement of bar-pressing for a conditioned stimulus (CS) following presentation of a CS or following a systemic injection of d-amphetamine. Rats self-administered d-amphetamine (0.25 mg/kg per infusion) for 3 h a day on 6 consecutive days. Each infusion was paired with a flashing light CS. On the 7th day, rats self-administered d-amphetamine for 1 h, followed by 10 h of extinction. Presentation of the CS 2 days following extinction induced small and transient increases in responding for the CS, with no significant associated increases in DA efflux. Lower rates of responding were observed in rats that had received random presentations of the CS during d-amphetamine self-administration, and in an experimentally-naı̈ve control group. A subsequent systemic injection of d-amphetamine increased dopamine efflux in the nucleus accumbens in all groups and was most effective in reinstating bar-pressing in the CS-d-amphetamine paired group. This is consistent with the hypothesis that exposure to psychostimulant drugs, and a drug-paired CS, can reinstate drug-seeking behavior. Together, these findings suggest that enhanced DA efflux may contribute to the reinstatement of drug-seeking behavior induced by the single administration of a psychostimulant drug, but not transient reinstatement induced by presentation of a drug-paired CS alone following extinction.

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.

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