c-Fos facilitates the acquisition and extinction of cocaine-induced persistent changes

Development of drug addiction involves persistent neurobiological changes. The dopamineD(1) receptor is involved in mediating cocaineinduced neuroadaptation, yet the underlying intracellular mechanisms remain unclear. We examined a potential role of the immediate early gene Fos, which is robustly and rapidly induced by cocaine via D-1 receptors, in mediating cocaine- induced persistent neurobiological changes by creating and analyzing a mouse in which Fos is primarily disrupted in D-1 receptor- expressing neurons in the brain. We show that the expression levels of several transcription factors, neurotransmitter receptors, and intracellular signaling molecules induced by repeated cocaine administration are altered in Fos- deficient brains. Dendritic remodeling of medium spiny neurons induced by repeated exposure to cocaine is blunted in the mutant mice. The mutant mice exhibit attenuated behavioral sensitization after repeated exposure to cocaine and more persistent memory of cocaine- induced conditioned place preference. Our findings indicate that c- Fos produced in D-1 receptor- expressing neurons integrates mechanisms to facilitate both the acquisition and extinction of cocaine- induced persistent changes.