DARPP-32: A molecular switch at the nexus of reward pathway plasticity

Abstract

Substance-related disorders represent a major burden to afflicted individuals, their families, and society. Repeated drug use can result in addiction, manifested as an intense desire for the drug, along with an impaired ability to temper its use, even in the face of serious consequences. Many tens of millions of people are addicted to drugs of abuse, and with costs to society in the many hundreds of billions of dollars per annum, there is little doubt that understanding the consummate processes (followed by advances in treatments) represents a major goal for medicine (1, 2). Although many transmitters have been implicated in the effects of the various types of drugs of abuse, dopamine and, more recently, glutamate have been most consistently associated with the reinforcing effects. Indeed, there is considerable evidence that the mesolimbic dopaminergic pathway plays a crucial role in the selection and orchestration of goal-directed behaviors, particularly those elicited by incentive stimuli. Drugs of abuse increase extracellular dopamine concentrations in limbic regions, including the nucleus accumbens (1, 2). However, a growing body of data suggests that increases in dopamine are not directly related to reward per se , but, rather, to the learned anticipation of reward and incentive salience (3). Notably, salience affects the motivation to seek the anticipated reward and facilitates conditioned learning (3). The key role of conditioned learning has focused attention on neural systems that attribute incentive salience, most notably a circuit that includes glutamate projections from the prefrontal cortex to the nucleus accumbens and dorsal striatum. This finding has led to the hypothesis that key biochemical events underlying drug-induced changes in neural plasticity should occur specifically in neurons inervated by both dopamine and glutamate inputs. In this issue of PNAS, Valjent et al. (4) provide an important link, implicating dopamine, cAMP-regulated phosphoprotein …