Estrogen-modulated frontal cortical CaMKII activity and behavioral supersensitization induced by prolonged cocaine treatment in female rats

Females have been demonstrated repeatedly to be more sensitive to cocaine. The role of the frontal cortex (FCX) in mediating behavioral sensitization and the underlying signaling pathways are unclear. The study was designed to characterize the role of FCX calcium/calmodulin-dependent protein kinase II (CaMKII) activity in the behavioral supersensitization observed in female rats after prolonged cocaine exposure. Intact female rats that received cocaine for 9 days followed by 7 days of drug withdrawal constituted the model used for studying the mechanism of supersensitization. This cocaine withdrawal treatment resulted in behavioral supersensitization in intact female rats as indicated by an enhanced behavioral response to cocaine challenge assessed on day 16 (7-day withdrawal) and compared to the response on day 9 of cocaine treatment. This treatment regimen did not lead to supersensitization in male or in ovariectomized (OVX) rats. Administration of estrogen to OVX rats restored behavioral supersensitivity to repeated cocaine. FCX CaMKII activity was significantly altered by cocaine in females, and this effect was related to estrogen's presence; cocaine-induced changes in striatal CaMKII activity were, however, less estrogen-sensitive. Furthermore, estrogen-modulated FCX CaMKII activity in cocaine-supersensitized rats was dependent on D(1) dopamine receptor activation. Estrogen-modulated D(1) dopamine receptor activity mediates the effects of prolonged cocaine exposure on FCX CaMKII, and this, in turn, may contribute to the development of behavioral supersensitivity to repeated cocaine treatment in intact female rats.