¹Department of Psychology, Arizona State University, Tempe, AZ, USA

Correspondence: JL Neisewander, Department of Psychology, Arizona State University, PO Box 871104, Tempe, AZ 85287-1104, USA. Tel: +1 (480) 965 0209; Fax: +1 (480) 965 8544; E-mail: janet.neisewander@asu.edu

Received 7 May 2003; Revised 21 September 2003; Accepted 6 October 2003; Published online 12 November 2003.

Abstract

The 5-HT indirect agonist, d-fenfluramine, attenuates cue reinstatement of extinguished cocaine-seeking behavior. To investigate the role of 5-HT receptor subtypes in this effect, we examined whether the attenuation is reversed by either a 5-HT_1A, 5-HT_2A/C, or 5-HT_2C receptor antagonist. We also examined the effects of the antagonists alone on both cue and cocaine-primed reinstatement. Rats that had been trained to press a lever for cocaine (0.75 mg/kg/0.1 ml, i.v.) paired with light and tone cues underwent daily extinction sessions during which responding had no consequences. We then examined the effects of WAY 100635 (0–1.0 mg/kg, s.c.), ketanserin (0–10.0 mg/kg, i.p.), or SB 242,084 (0–1.0 mg/kg, i.p.) with and without d-fenfluramine (1.0 mg/kg, i.p.) pretreatment on cue reinstatement. Subsequently, we examined the effects of the antagonists on cocaine-primed (7.5 or 15.0 mg/kg, i.p.) reinstatement. The 5-HT_1A antagonist, WAY 100635, failed to alter cue reinstatement, but attenuated cocaine reinstatement. Conversely, the 5-HT_2A/C antagonist, ketanserin, attenuated cue reinstatement, but failed to alter cocaine reinstatement. The 5-HT_2C-selective antagonist, SB 242,084, did not alter cue or cocaine reinstatement, but was the only drug that reversed the d-fenfluramine-induced attenuation of cue reinstatement. The findings suggest that stimulation of 5-HT_1A receptors plays a critical role in cocaine-primed, but not cue, reinstatement. Furthermore, 5-HT_2A and 5-HT_2C receptors may play oppositional roles in cue reinstatement. The SB 242,084 reversal of the d-fenfluramine attenuation suggests that stimulation of 5-HT_2C receptors inhibits cue reinstatement, whereas the ketanserin-induced attenuation of cue reinstatement suggests that decreased stimulation of 5-HT_2A receptors inhibits this behavior.