Behavioral and neurobiological consequences of intermittent exposure to addictive drugs.

Abstract

These studies were undertaken to better understand how repeated exposure to addictive drugs leads to adaptations in brain function and behavior related to the development of addiction. They are predicated on evidence that the mere presence of a drug in the body is not the sole determinant of adaptation - rather, the pattern of drug exposure is a key variable, with intermittent exposure making the brain reward system increasingly sensitive to drugs and leaving individuals susceptible to relapse. These experiments were designed to examine whether events occurring during the offset of drug action may contribute to the unique effects of intermittent drug exposure. The first series of experiments develops a set of behavioral measures that can be used to resolve and quantify a state of acute withdrawal caused by the offset of drug action. The second series of experiments utilizes these measures to investigate whether recurrent episodes of acute withdrawal contribute to the development of psychomotor sensitization - a specific consequence of intermittent drug exposure related to adaptations in the brain reward system. The final series of experiments describes a specific synaptic adaptation in a key component of the brain reward system (the nucleus accumbens) that is caused by intermittent drug exposure, related to the development of psychomotor sensitization, and reversed by experiences linked to relapse. The results of these studies suggests new and provocative interactions between neural circuits mediating reward and aversion, which may help identify and explain forms of neural plasticity that underlie the development of drug addiction.