A major goal of drug abuse research is to understand the molecular mechanisms underlying the behavioral changes causea oy repeatea exposure to cocaine. Enduring behavioral changes, such as behavioral sensitization, can be induced in rodents by repeated cocaine administration. The neurobiological mechanisms underlying such behavioral changes are associated with the brain mesocorticolimbic dopamine (DA) pathway. Moreover, the DA D1 receptors are involved in mediating the long-term behavioral effects of cocaine. The long-lasting behavioral effects of repeated cocaine exposure are highly likely to be associated with underlying changes in gene expression. To examine this possibility, we have started to combine the use of D1 receptor mutant mice with cDNA microarrays to identify gene expression changes mediated through the D1 receptors induced by repeated cocaine administration. Our initial experiments focused on a target of the mesocorticolimbic DA pathway, the nucleus accumbens (NAc), which is the primary neural substrate for mediating the long-term effects of cocaine. We found that multiple genes are differentially expressed in wild-type and D1 receptor mutant mice after chronic cocaine treatment. Further studies are in progress to determine the physiological significance of the differential expression of these genes in chronic cocaine-induced behaviors.