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NEUROPHARMACOLOGY

Alterations in Fos-Related Antigen 2 and ₁ Receptor Gene and Protein Expression Are Associated with the Development of Cocaine-Induced Behavioral Sensitization: Time Course and Regional Distribution Studies

Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (Y.L., R.R.M.); Department of Pharmacology, University of Mississippi, University, Mississippi (R.R.M.); and Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia (R.R.M.)

Repeated exposure to cocaine results in neuroadaptations that can alter the way the brain responds to subsequent stimuli. Earlier studies demonstrated that acute administration of cocaine up-regulates the immediate-early gene fos-related antigen 2 (fra-2) followed by a later up-regulation of ₁ receptor gene and protein levels in brain regions involved in addiction and reward. To test whether such alterations could have long-term consequences on behavior, the present study was undertaken. Using a cocaine-induced behavioral sensitization model coupled with gene and protein expression studies in mice, the results show that cocaine induces the expression of fra-2, which leads to a progressive increase in ₁ receptor gene and protein expression over a period of days. This progressive increase in ₁ expression corresponds to the steady increase in the locomotor response to repeated cocaine administration in mice. The cocaine-induced changes in fra-2 and ₁ receptor gene and protein expression occur in brain regions that subserve drug abuse, such as the cortex, striatum, and hippocampus, but not the cerebellum. Moreover, the prototypic ₁ receptor antagonist 1-[2-(3,4-dichloropheny)ethyl]-4-methylpiperazine (BD1063) significantly attenuates both the molecular adaptations and behavioral sensitization induced by cocaine. These data suggest that repeated exposure to cocaine elicits alterations in fra-2 and ₁ receptor-mediated mechanisms, which ultimately manifest as altered behavioral responses to cocaine.

Address correspondence to: Dr. Rae R. Matsumoto, West Virginia University, School of Pharmacy, P.O. Box 9500, Morgantown, WV 26506. E-mail: rmatsumoto{at}hsc.wvu.edu