RALATIONSHIP BETWEEN THE DEVELOPMENT AND EXPRESSION OF COCAINE‐INDUCED BEHAVIORAL SENSITIZATION AND CHANGES IN FRA‐2 AND SIGMA RECEPTOR GENE AND PROTEIN EXPRESSION: MODULATION BY A SIGMA RECEPTOR ANTAGONIST

Repeated cocaine exposure can cause addiction, which is characterized by altered behavioral responses to the drug (e.g. sensitization). Cocaine also induces the expression of immediate early genes which trigger long‐term alterations in brain function. Using a behavioral sensitization model in mice, we measured the ability of a σ receptor antagonist BD1063 to modulate the development and expression of behavioral sensitization to cocaine. In separate studies, BD1063 significantly attenuated both the development and expression of cocaine‐induced behavioral sensitization. RT‐PCR and Western blots suggested that cocaine administration up regulated the immediate early gene fra‐2 which in turn resulted in a progressive up regulation of σ receptor gene and protein expression in brain regions involved in cocaine reward. The progressive up regulation of σ receptors in the striatum and cortex paralleled the development of cocaine‐induced behavioral sensitization, and was prevented by administration of BD1063 during the development phase of the study. Together, the data suggest that alterations in fra‐2 and σ receptor expression that are induced by cocaine play an important role in the development of behavioral sensitization, and that the functional consequences of these changes can be attenuated by σ receptor antagonism.