Validation of a relapse prevention strategy based on the extinction of the con-ditioned incentive effects of cocainedécembre 2015 Directeur(s) de thèse : Serge AHMED Résumé de thèse
Craving often precedes relapse into cocaine addiction. This explains why considerable research effort is being expended to try to develop anti-craving strategies for relapse prevention. Recently, we discovered using the classic reinstatement model of cocaine craving that the reinstating or priming effect of cocaine can be extinguished with repeated priming – a phenomenon dubbed extinction of cocaine priming. Such extinction has been interpreted as evidence that the priming effect of cocaine on reinstatement of cocaine seeking depends on an interoceptive drug conditioning mechanism whereby the interoceptive cues of cocaine become reliable conditioned Pavlovian predictors of the availability of cocaine reinforcement. Regardless of the underlying mechanisms, however, extinction of drug priming has been proposed as a potential cocaine exposure therapy for relapse prevention that may complement other, more traditional exteroceptive cue exposure therapies. The goal of my PhD thesis was to measure the potential beneficial effect of this novel extinction strategy on subsequent relapse (i.e., return to the pre-extinction pattern of cocaine self-administration once the drug is made again available after extinction). Overall and contrary to our initial hope, extensive and complete extinction of cocaine priming had no major impact on relapse. This lack of effect occurred despite evidence for post-extinction loss of neuronal responsiveness to cocaine priming in brain regions causally involved in cocaine-induced reinstatement (i.e., the anterior cingulate and prelimbic prefrontal cortex, and the core of the nucleus accumbens). An effect of extinction of cocaine priming on relapse was only observed when cocaine was available for self- administration under more demanding conditions. However, this effect was modest and short-lived. Finally, we were able to trace the origin of our failure to prevent relapse to an extinction-resistant form of cocaine seeking that is commonly reported, though often overlooked, in other reinstatement studies. We propose that this behavior should become a novel target for future preclinical research on anti-craving strategies for relapse prevention.