¹Department of Psychiatry, Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA

Correspondence: Dr EB Larson, Department of Psychiatry, Graduate Program in Neuroscience, University of Minnesota, MMC 392, 420 Delaware St SE, Minneapolis, MN 55455, USA. Tel: +1 612 624 4406; Fax: +1 612 624 8935; E-mail: larso323@umn.edu

Received 30 March 2006; Revised 8 August 2006; Accepted 19 September 2006; Published online 29 November 2006.

Abstract

Preclinical and clinical studies indicate that females are more vulnerable to relapse than males, and the neurobiological effects of estrogen are thought to mediate, in part, the sex differences in cocaine-taking behavior. The goal of the present study was to investigate the involvement of estrogen receptor (ER) and (ER) in estrogen-mediated increases in cocaine-induced reinstatement of extinguished cocaine-seeking behavior in ovariectomized (OVX) female rats. Rats were initially trained to self-administer cocaine (0.4 mg/kg/inf, i.v.) under a fixed-ratio 1 (FR 1) schedule of reinforcement during daily 2-h sessions. After a 10-day maintenance period, cocaine solutions were replaced with saline, and self-administration was extinguished over a 14-day period. OVX rats were then treated with either the mixed ER/ agonist estradiol benzoate (EB), the ER-selective agonist, propyl-pyrazole-triol (PPT), the ER-selective agonist, diarylpropionitrile (DPN), or a vehicle control (dimethyl sulfoxide, DMSO). Treatment lasted a total of 9 days, and during this time, rats were assessed for nonreinforced reinstatement of extinguished cocaine-seeking behavior after priming injections of saline or cocaine (5, 10, or 15 mg/kg, i.p.). OVX rats showed no differences in self-administration during maintenance or extinction. OVX rats treated with EB exhibited greater responding for cocaine during reinstatement compared to OVX+DMSO controls. Selective activation of ER with DPN also increased cocaine-induced reinstatement responding, whereas selective activation of ER with PPT did not affect cocaine-seeking behavior. These results indicate that estrogen influences the propensity for reinstatement of extinguished cocaine-seeking behavior, and that estrogen-mediated enhancement of cocaine-induced reinstatement responding involves the activation of ER.