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Stress-induced relapse to heroin and cocaine seeking in rats: a review

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Abstract

Studies in humans suggest that exposure to stress increases the probability of relapse to drug use, but until recently there has been no animal model to study the mechanisms that mediate this effect. We have developed a reinstatement procedure that allows us to study the effect of stress on relapse to drug seeking in rats. Using this procedure, we have shown that exposure to intermittent footshock stress reliably reinstates heroin and cocaine seeking after prolonged drug-free periods. In the present paper, we summarize results from several studies on stress-induced reinstatement of heroin and cocaine seeking in rats. We first assess the degree to which the phenomenon of stress-induced relapse generalizes to other stressors, to behaviors controlled by other drugs of abuse, and to behaviors controlled by non-drug reinforcers. We then review evidence from studies concerned with the neurotransmitters, the brain sites, and the neural systems involved in stress-induced reinstatement of drug seeking. Finally, we consider the mechanisms that might underlie stress-induced relapse to drug seeking and the possible implications of the findings for the treatment of relapse to drug use in humans.

Introduction

Drug addiction is characterized by repeated episodes of relapse to drug self-administration, and relapse remains the primary problem for treatment [92], [139]. Until we understand the factors that determine renewed drug craving and seeking, it is unlikely that we will be able to provide effective interventions. In large part, our ideas about what controls drug self-administration and relapse stem from knowledge of the phenomenology and neurobiology of the direct actions of abused drugs, and of the effects of withdrawal from them [135]. Such knowledge may not, however, be sufficient to explain why, when drugs are unavailable for long periods of time, individuals remain vulnerable to relapse.

There are many reports that relapse to alcohol and drug use is more likely to occur in individuals exposed to high levels of life stress [19], [40], [106], [123], [189]. The reasons for this putative relationship, however, are not understood. The correlational nature of the studies in humans prevents the drawing of conclusions about a causal link between stress and relapse to drugs [140]. In addition, although individuals often report that subjective craving and relapse are associated with negative mood states [37], there are findings to suggest that this relationship is less than clear [78]. Thus, even if relapse is associated with stress, the mechanisms through which stress acts to induce relapse are not known.

In recent years, we have been using an animal model of relapse to drug seeking, known as the reinstatement procedure, to study the relationship between stress and relapse. This method was developed originally to study the ability of acute non-contingent exposure to drugs or exposure to drug-related stimuli to reinstate drug seeking after a period of extinction of the drug-reinforced behavior [41], [46], [205]. Many studies using this procedure have demonstrated that reexposure to drugs and drug-related stimuli reinstates drug seeking in rats and monkeys [29], [59], [67], [101], [125], [172], [194], [199]. The validity of this method as a model for the study of relapse [121] is reinforced by the fact that when drug-free human addicts are reexposed to drugs and to drug-related stimuli they report increased craving for drugs [32], [36], [45], [93], [127].

In initial studies of acute exposure to stress in both heroin- and cocaine-trained animals, we found that exposure to 10–15 min of intermittent footshock (0.5–1.0 mA, 0.5 s ON, a mean OFF period of 40 s) reliably reinstates drug seeking after 1–2 weeks of extinction training and after an additional 4–6-week drug-free period [55], [178]. Footshock was found to be at least as effective as priming injections of drugs in inducing high levels of responding in tests for reinstatement over a range of footshock durations and doses [177] (see Fig. 1, Fig. 2). Subsequently, similar findings were reported by a number of laboratories using different training doses, schedule requirements, footshock parameters and strains of rats [2], [3], [120], [206]. Thus, it would appear that the phenomenon of footshock stress-induced reinstatement is reproducible under a number of different experimental conditions. Furthermore, in a recent study in humans it was found that stress provokes craving for cocaine under controlled laboratory conditions [191].

Following our initial observations of stress-induced reinstatement of heroin and cocaine seeking, a number of studies were carried out to investigate the phenomenology and neurobiology of footshock-induced reinstatement. Here we review, first, studies done to determine the degree to which the phenomenon of footshock-induced reinstatement generalizes to other stressors, to other drugs, and to instrumental behaviors based on non-drug reinforcers. We then consider findings from studies done to determine the role of a number of neurotransmitter and hormonal systems in stress-induced reinstatement of heroin and cocaine seeking, and studies done to identify the brain sites mediating these effects. Finally, we consider the mechanisms that might underlie stress-induced relapse to drug use and the possible implications of the findings for the treatment of relapse to drug use in humans.

Section snippets

Can footshock-stress induce relapse to other drug and non-drug reinforcers?

Footshock has been found to induce reinstatement of drug seeking in animals trained to self-administer both alcohol and nicotine [23], [112] (Fig. 3). In the case of alcohol, when the reinstatement induced by footshock was compared directly to that induced by oral alcohol, footshock had a much greater effect on responding than did alcohol itself. In the case of nicotine, although not compared directly in the same study, the effect of footshock [23] was similar to that seen following priming

Pharmacological approaches

Using specific receptor agonists and antagonists we have studied the possible contribution of several neurotransmitter systems in stress-induced reinstatement of drug seeking. These include the opioid, dopaminergic (DA), noradrenergic (NE) and CRF systems. In addition, we have studied the possible role of the adrenal hormone, corticosterone. A summary of the results from these pharmacological studies is provided in Table 2.

Discussion

The study of stress-induced reinstatement of drug seeking has a short history and much has yet to be learned about the processes involved. In the sections below we will discuss several issues that are pertinent to the understanding of this phenomenon.

Acknowledgements

Supported by NIDA and the Medical Research Council of Canada. We thank Dr. Hans Crombag for helpful comments.

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