Paul Girardeau | Search bioRxiv

bioRxiv2016

Persistent vulnerability to relapse despite complete extinction of cocaine craving

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 in rats - a phenomenon dubbed extinction of cocaine priming. Here we sought 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 responses to cocaine priming in brain regions critically involved in cocaine-induced reinstatement (i.e., the dorsomedial 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 succeeded to trace the origin of our failure to prevent relapse to a persistent, extinction-resistant form of operant behavior that is not directly induced by cocaine. This extinction-resistant behavior is commonly reported, though generally ignored as causally irrelevant, in many other reinstatement studies. We propose that this behavior should become both a novel marker for long-term vulnerability to relapse and a novel target for preclinical development of potential relapse prevention interventions.

Animal Behavior and Cognition↗

bioRxiv2015

An integrated homeostatic reinforcement learning theory of motivation explains the transition to cocaine addiction

Drugs of abuse implicate both reward learning and homeostatic regulation mechanisms of the brain. Theories of addiction, thus, have mostly depicted this phenomenon as pathology in either habit-based learning system or homeostatic mechanisms. Showing the limits of those accounts, we hypothesize that compulsive drug seeking arises from drugs hijacking a system that integrates homeostatic regulation mechanism with goal-directed action/behavior. Building upon a recently developed homeostatic reinforcement learning theory, we present a computational theory proposing that cocaine reinforces goal-directed drug-seeking due to its rapid homeostatic corrective effect, whereas its chronic use induces slow and long-lasting changes in homeostatic setpoint. Our theory accounts for key behavioral and neurobiological features of addiction, most notably, escalation of cocaine use, drug-primed craving and relapse, and individual differences underlying susceptibility to addiction. The theory also generates unique predictions about the mechanisms of cocaine-intake regulation and about cocaine-primed craving and relapse that are confirmed by new experiments.\n\nSignificanceChronic use of addictive drugs renders increased motivation in planning to obtain and consume the drugs, despite their adverse social, occupational, and health consequences. It is as if addicts gradually develop a strong need for the drug and use their cognitive abilities and the knowledge of their environment in order to fulfil that need. In this paper, we build a mathematical model of this conception of addiction and show through quantitative simulations that such a model actually behaves in the same way that human addicts or laboratory animals that are exposed to cocaine behave. For example, the model shows gradually increasing motivation for drugs, relapse after long periods of abstinence, and individual differences in susceptibility to addiction.

Neuroscience↗