Girardeau, P. | bioRxiv Science

bioRxiv2020

Loss of resistance to punishment of cocaine use after prior experience

One behavioral feature of drug addiction is continued drug use despite awareness that this causes negative consequences. Attempts to model this feature in animals typically involve punishing drug self-administration with a brief electrical footshock and look for resistance to punishment. Though all individual animals eventually stop self-administering the drug with increasing intensity of punishment, some individuals do so at higher intensities than other individuals. The greater relative resistance to punishment of the former individuals is generally interpreted as evidence for a compulsion-like behavior. Here we show that resistance to footshock punishment is in fact not a stable individual behavioral feature. Specifically, when rats are retested for their resistance to increasing intensity of footshock punishment, they become much less resistant. As a result, they suppress their cocaine intake even when punished with an initially low and ineffective intensity. A series of original behavioral experiments reveals that this low resistance to footshock punishment is rapidly acquired after rats experience a punishment intensity that leads them to near-completely suppress their cocaine intake. Passive exposure to the same intensity does not induce this effect. Once acquired, low resistance to punishment persists during at least one month, but can nevertheless be extinguished by retesting rats on a daily basis. Interestingly, this acquired low resistance to footshock punishment does not generalize to a non-painful form of punishment (i.e., histamine) that is also seldom used in animal drug self-administration studies. We discuss some possible theoretical and methodological implications of these findings for future research on animal models of compulsion-like behavior.

neuroscience↗

bioRxiv2020

Pharmacokinetics trumps pharmacodynamics during cocaine choice: a reconciliation with the dopamine hypothesis of addiction

Cocaine is known to increase brain dopamine at supranormal levels in comparison to alternative nondrug rewards. According to the dopamine hypothesis of addiction, this difference would explain, at least in part, why the latter are eventually given up in favor of continued cocaine use during the transition to addiction. Though resting on solid neuroscientific foundations, this hypothesis has nevertheless proven difficult to reconcile with research on cocaine choice in experimental animals. When facing a choice between an intravenous bolus of cocaine and a nondrug alternative (e.g., sweet water), both delivered immediately after choice, rats do not choose the drug, as would be predicted, but instead develop a strong preference for the nondrug alternative, sometimes to the exclusion of continued drug use. Here we report converging evidence that reconciles this finding with the dopamine hypothesis of addiction. Briefly, our data suggest that cocaine is indeed supranormal in reward magnitude, as postulated by the dopamine hypothesis of addiction, but is less preferred during choice because its pharmacokinetics makes it an inherently more delayed reward than the alternative. Reframing previous drug choice studies in rats as intertemporal choice studies reveals that the discounting effects of delays spare no rewards, including supranormal ones, and that during choice, pharmacokinetics trumps pharmacodynamics. Finally, this study also reveals important gaps in our understanding of drug reward delays that need to be filled by future experimental and theoretical work.

neuroscience↗