ORIGINAL INVESTIGATION Estrogen-modulated frontal cortical CaMKII activity and behavioral supersensitization induced by prolonged cocaine treatment in female rats Xuechu Zhen & Satindra Goswami & Syed Amir Abdali & Maya Frankfurt & Eitan Friedman Received: 6 September 2006 / Accepted: 7 November 2006 / Published online: 12 December 2006 # Springer-Verlag 2006 Abstract Rationale 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. Objective 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. Materials and methods 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. Results 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 dopa- mine receptor activation. Conclusion 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. Keywords Cocaine . Estrogen . CaMKII . Frontal cortex . Behavioral supersensitization . Dopamine receptor Introduction Clinical and experimental studies indicate that females are more sensitive to cocaine exposure. Development of cocaine addiction is more rapid in female subjects as compared to males (Haney et al. 1994; Glick and Hinds 1984; Lukas et al. 1996; Lynch and Carroll 1999). Female rats exhibit greater locomotor activity (sensitization) in response to repeated cocaine than do male rats (Sircar and Kim 1999; Sell et al. 2002). Female rats also display a more robust behavioral response to acute cocaine exposure as compared to male rats (Van Haaren and Meyer 1998; Chin et al. 2002). Furthermore, ovariectomy attenuates the enhanced behavioral sensitization to chronic cocaine in female rats, whereas estrogen restores the behavioral sensitization in ovariectomized (OVX) female rats (Becker 1999; Peris et al. 1991; Hu and Becker 2003; Dunn et al. 2005). Although enhanced behavioral sensitization in females is thought to be related to ovarian hormones, the underlying molecular mechanisms remain unclear. In studies with male animals, multiple intracellular pathways, such as mitogen-activated protein kinases, cyclin-dependent kinase 5, and protein kinase A, were found to be altered by cocaine. The effects of cocaine vary depending on the duration of cocaine treatment, dosage, and brain region Psychopharmacology (2007) 191:323–331 DOI 10.1007/s00213-006-0648-0 X. Zhen (*) : S. Goswami : S. A. Abdali : M. Frankfurt : E. Friedman Department of Physiology/Pharmacology, The City University of New York at CCNY, 138th Street and Convent Avenue, New York, NY 10031, USA e-mail: xuechu@med.cuny.edu