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

Affective memories associated with the negative emotional state experienced during opiate withdrawal are central in maintaining drug taking, seeking, and relapse. Nucleus accumbens (NAC) is a key structure for both acute withdrawal and withdrawal memories reactivation, but the NAC neuron coding properties underpinning the expression of these memories remain largely unknown. Here we aimed at deciphering the role of NAC neurons in the encoding and retrieval of opiate withdrawal memory. Chronic single neuron and local field potentials recordings were performed in morphine-dependent rats and placebo controls. Animals were subjected to an unbiased conditioned placed aversion protocol with one compartment (CS+) paired with naloxone-precipitated withdrawal, a second compartment with saline injection (CS−), and a third being neutral (no pairing). After conditioning, animals displayed a typical place aversion for CS+ and developed a preference for CS− characteristic of safety learning. We found that distinct NAC neurons code for CS+ or CS−. Both populations also displayed highly specific oscillatory dynamics, CS+ and CS− neurons, respectively, following 80 Hz (G80) and 60 Hz (G60) local field potential gamma rhythms. Finally, we found that the balance between G60 and G80 rhythms strongly correlated both with the ongoing behavior of the animal and the strength of the conditioning. We demonstrate here that the aversive and preferred environments are underpinned by distinct groups of NAC neurons as well as specific oscillatory dynamics. This suggest that G60/G80 interplay—established through the conditioning process—serves as a robust and versatile mechanism for a fine coding of the environment emotional weight.

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 electrical footshock to identify individuals whose drug use is differently suppressed by punishment. Here we sought to further study individual responsiveness of drug use to punishment in rats self-administering intravenous cocaine.Rats were first trained during several weeks to self-administer cocaine under a fixed-ratio 3 schedule of reinforcement. Then, their self-administration behavior was punished with increasing intensity of footshock (i.e., from 0.1 mA to 0.9 mA, every 30 min). With increasing intensity of punishment, rats first continued to self-administer cocaine before eventually stopping near completely. When retested, however, drug use became more responsive to punishment and was suppressed by a low and initially ineffective footshock intensity (i.e., 0.1 mA). This increase in responsiveness to punishment was seen in all individuals tested, albeit with varying degrees, and was acquired after one single experience with an intensity of punishment that near completely suppressed drug self-administration. Mere passive, noncontingent exposure to the same intensity, however, had no such effect. Once acquired, increased responsiveness to punishment persisted during at least one month when rats were tested every week, but not every day. Finally, increased responsiveness to punishment was not observed after exposure to a non-painful form of punishment (i.e., histamine). Overall, this study reveals that initial responsiveness of drug use to punishment can change rapidly and persistently with experience. We discuss several possible mechanisms that may account for this change in punishment responsiveness and also draw some of the implications and future perspectives for research on animal models of compulsion-like behavior.