Cocaine addiction as a homeostatic reinforcement learning disorder.

Abstract

Drug addiction implicates both reward learning and homeostatic regulation mechanisms of the brain. This has stimulated 2 partially successful theoretical perspectives on addiction. Many important aspects of addiction, however, remain to be explained within a single, unified framework that integrates the 2 mechanisms. Building upon a recently developed homeostatic reinforcement learning theory, the authors focus on a key transition stage of addiction that is well modeled in animals, escalation of drug use, and propose a computational theory of cocaine addiction where cocaine reinforces behavior due to its rapid homeostatic corrective effect, whereas its chronic use induces slow and long-lasting changes in homeostatic setpoint. Simulations show that our new theory accounts for key behavioral and neurobiological features of addiction, most notably, escalation of cocaine use, drug-primed craving and relapse, individual differences underlying dose-response curves, and dopamine D2-receptor downregulation in addicts. The theory also generates unique predictions about cocaine self-administration behavior in rats that are confirmed by new experimental results. Viewing addiction as a homeostatic reinforcement learning disorder coherently explains many behavioral and neurobiological aspects of the transition to cocaine addiction, and suggests a new perspective toward understanding addiction. (PsycINFO Database Record

Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes

“…Several studies suggest that drug exposure increases homeostatic gene expression during abstinence to mitigate cocaine induced neuroadaptations 5 . To identify a master regulator of homeostatic gene expression, we profiled global transcriptomic changes in the adult mouse brain, including the NAc, VTA, and PFC, at early (1day) and late (28-days) abstinence following cocaine selfadministration ( Fig.…”

“…In human drug users, relapse is triggered by drugassociated cues 2 , stress 3 , and acute drug re-exposure 4 . To combat relapse, endogenous homeostatic mechanisms may restore and even reverse normal function to reward-related brain areas 5,6 . Both preclinical 7 and human 8 studies indicate that drug-induced synaptic plasticity and the associated drug memories are reversible.…”

Non-pharmacological factors that determine drug use and addiction

“…In a dull and familiar environment, with no or very little valuable stimulation, like that in a standard operant box, animals may also take drugs as a mean to obtain and experience some artificial stimulation. They may also use drugs as a mean to amplify or increase the gain of the brain reward circuits to otherwise neutral environmental stimuli (Ahmed and Koob, 2005;Keramati et al, 2017). Of course, in such impoverished environments, animals have also no access to alternative valuable rewards and thus their drug use could also be partly motivated by the search of novelty reward.…”

Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis

“…Using the representation of predictive relationships in the environment, acquired through trial and error, reversal learning requires animals to switch responding to a now correct stimulus while ignoring the interference of a recently rewarded, but now no-longer-correct stimulus. Reinforcement learning has been proposed as a tractable computational process underlying trial-and-error learning [30,31] with utility in modelling aspects of addiction [32,33] and stimulant administration in rodents [34,35].…”