Interaction of noncontingent cocaine and contingent drug-paired stimuli on cocaine reinstatement

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Abstract

Both noncontingent cocaine and the presentation of cocaine-paired external stimuli will reinstate cocaine-appropriate operant responding. However, the interaction of noncontingent cocaine and cocaine-paired stimuli in producing reinstatement has not been extensively examined. In the present study, the ability of noncontingent cocaine alone, the combination of noncontingent cocaine+contingent cocaine-paired lights+tone and contingent lights+tone alone to produce reinstatement were examined. No cocaine dose (3, 10, 17 mg/kg) produced significant reinstatement in the absence of cocaine-paired lights+tone. When responding also resulted in lights+tone presentation, all doses of cocaine produced similar, significant reinstatement. Finally, when only response contingent lights+tone were presented, none of the groups showed significant reinstatement. These findings indicate that in isolation, noncontingent cocaine alone and cocaine-paired external stimuli may be insufficient to engender significant levels of reinstatement, but when presented together produce robust reinstatement. The results highlight the important interaction between drug administration and drug-paired environmental stimuli in the reinstatement model.

Introduction

Relapse to drug use following a period of abstinence is a major problem in drug abusers. Many detoxified drug abusers report that they relapsed due to craving induced by the environment that was previously associated with drug taking O'Brien et al., 1977, Sideroff and Jarvik, 1980, Wallace, 1989. Other abstinent drug abusers report that craving followed exposure to the previously abused drug McCaul et al., 1989, Chornock et al., 1992. Although both interoceptive and external environmental variables are believed to play significant roles in relapse, the interaction of the two is not well understood (Childress et al., 1993).

The drug reinstatement paradigm in animals is frequently used to explore the factors underlying relapse and has been theorized to model some aspects of human drug craving and relapse Koob, 2000, Littleton, 2000. In reinstatement studies, operant responding resulting in drug injections is extinguished after a period of drug availability. Following extinction, noncontingent presentation of the previously self-administered drug or a pharmacologically similar drug will result in renewed responding on the manipulandum that previously produced drug injections (Shaham et al., 2002). The magnitude of drug-induced reinstatement has been shown to be dose-dependent, with low doses producing less robust reinstatement than moderate or high doses (Schenk and Partridge, 1999). External stimuli, typically light and/or tones that have been repeatedly paired with drug delivery, will also reinstate operant responding when presented response contingently, and to a lesser degree when presented noncontingently during reinstatement testing Gerber and Stretch, 1975, Arroyo et al., 1998, Weiss et al., 2001. Exposure to a specific environment that has been intentionally paired with the opportunity to self-administer cocaine will also result in significant, albeit transient, reinstatement responding (Alleweireldt et al., 2001).

Few studies have explicitly examined the interaction between interoceptive drug effects and contingent drug-paired external stimuli on the magnitude of subsequent reinstatement. One experiment in squirrel monkeys found that drug-paired external stimuli combined with a noncontingent drug injection resulted in more pronounced reinstatement responding than either the external stimuli or drug alone (Spealman et al., 1999). A second study in cocaine-trained rats demonstrated that noncontingent presentation of drug-associated external stimuli in combination with an injection of d-amphetamine produced greater reinstatement and enhancement of dopamine efflux in the nucleus accumbens than d-amphetamine or noncontingent stimuli alone (Di Ciano et al., 2001).

The major goal of the present study was to determine the degree of interaction between noncontingent cocaine dose and response contingent drug-paired external stimuli on reinstatement. To examine this interaction, three different noncontingent cocaine doses were initially presented alone immediately prior to reinstatement testing. These same three doses of cocaine were subsequently presented in combination with response-contingent flashing lights+tone. Finally, only the response contingent flashing lights+tone were presented during reinstatement testing.

Section snippets

Subjects

Subjects were 32 adult, male, experimentally naı̈ve Sprague–Dawley (Charles River Laboratories, USA) rats. Animals were food-restricted to 15 g of rodent chow per day and had continuous access to water except during the experimental sessions. Rats weighed at least 275 g at the beginning of the study. The animals were individually housed in standard plastic rodent cages in a temperature-controlled (22° C) 12-h reversed light/dark cycle colony room. Studies were approved by the Institutional

Results

Rats readily acquired self-administration of 0.5 mg/kg/infusion cocaine. Averaged across rats, a mean of 15.9 (±1.1) cocaine self-administration sessions were required to reach FR5 and meet criteria for beginning extinction. A mean of 29.4 (±1.7) cocaine infusions were obtained on the last day of cocaine self-administration training. During extinction, an average of only 2.8 (±0.3) days were required to reach reinstatement testing criteria. Neither total infusions on the final day of

Discussion

The results in the present study show that under some conditions neither noncontingent cocaine nor contingent cocaine-paired external stimuli presentation may be effective in reinstating extinguished cocaine-reinforced behavior. However, their concurrent presentation may powerfully evoke such behavior beyond that expected by their individual contributions and do so repeatedly for several days. Although both noncontingent cocaine and contingent cocaine-paired external stimuli have been

Acknowledgements

This work was supported by NIDA contract N01DA-0-8801. The authors would like to thank Ms. Kelly Silver-Wade and Ms. Kelly Kinzer for their excellent technical assistance.

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