Significant progress has been made in the understanding of the neurobiological basis for the reinforcing actions of drugs of abuse. However, there is as yet little understanding of the mechanisms responsible for two of the defining characteristics of drug addiction: the transition from the non-dependent state to escalating and compulsive drug use, and the long-lasting vulnerability to relapse during abstinence. Better understanding of the neurobiological basis of these phenomena will be essential for treatment and prevention of drug abuse. The present proposal is designed to identify neurobiological changes associated with escalating cocaine-seeking behavior and relapse at the level of gene expression. To accomplish this, reliable animal models of escalating cocaine-seeking behavior and """"""""relapse"""""""" induced by drug-related environmental stimuli will be employed that have recently been developed in the applicants' laboratories. Taking advantage of the availability of these behavioral methodologies, state-of-the-art DNA array screening using gene chip technology will be utilized to establish the gene expression profile associated with escalating cocaine self-administration, protracted cocaine withdrawal, and """"""""relapse"""""""" as measured by the reinstatement of extinguished cocaine-seeking behavior by drug-related environmental stimuli. The experimental plan will employ a sequential approach designed to maximize cost effectiveness by combining different commercial arrays with inexpensive custom arrays printed in-house. The latter arrays will be used to more systematically investigate the expression of candidate genes identified by the commercial assays, and to determine the specificity of gene expression changes for specific aspects of cocaine seeking behavior. In addition, the data generated by this research program are expected to lead to future mechanistic investigations of the function of genes that show significant changes in expression with regard to their precise role in escalation, protracted withdrawal symptoms, and vulnerability to relapse. Overall, the proposed investigation of gene expression changes associated with critical aspects of the addictive cycle is expected to provide important insights toward the understanding of the neurobiological and molecular basis of cocaine addiction.
