Drug Addiction: The Yin and Yang of Hedonic Homeostasis

Abstract

Drug addiction is a chronic relapsing disorder, and relapse is associated with states of craving and protracted abstinence that are difficult to define but reflect some prolonged post-acute withdrawal perturbation or vulnerability to reinstatement of drug-taking behavior and ultimately compulsive use. There may be either a residual deficit state or a sensitization of the reward system to stimuli that predict drug effects or both. One could speculate that the combination would be particularly powerful as a motivator for reinstatement of drug use. Animal models of drug craving and relapse are being developed and refined and usually reflect secondary sources of reinforcement. The neural substrates for conditioned positive reinforcement may involve elements of afferent input of the extended amygdala such as the afferents from the basolateral amygdala and the mesolimbic DA system. The neural substrates for conditioned negative reinforcement are largely unknown. The challenge for future studies in the neurobiology of drug dependence will be to elucidate the neuroadaptive changes, such as changes in signal transduction function and gene expression, produced by chronic drug use in animal models of protracted abstinence and relapse. Presumably, the same molecular and cellular changes in the neurochemical systems and neurocircuitry responsible for the positive and negative reinforcement associated with chronic drug use will hold the key.