1. ¹Section of Biopsychology, Centre for Addiction and Mental Health, Toronto, ON, Canada
2. ²Department of Psychiatry, University of Toronto, Toronto, ON, Canada
3. ³Department of Psychology, University of Toronto, Toronto, ON, Canada
4. ⁴NPS Pharmaceuticals, Toronto, ON, Canada

Correspondence: Dr PJ Fletcher, Section of Biopsychology, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada M5T 1R8. Tel: +416 535 8501, ext 4058; Fax: +416 979 6942; E-mail: Paul_Fletcher@camh.net

Received 19 December 2006; Revised 18 May 2007; Accepted 14 June 2007; Published online 25 July 2007.

Abstract

Previously, we showed that the 5-HT_2C receptor agonist Ro60-0175 reduces cocaine self-administration, and the ability of cocaine to reinstate responding after extinction of drug-seeking behavior. The present experiments extended these findings further by determining whether the effects of Ro60-0175 on self-administration were sustained with repeated treatment, and whether Ro60-0175 altered reinstatement induced by the pharmacological stressor yohimbine, or by the context in which self-administration occurred. In Experiment 1, Ro60-0175 (1 mg/kg, s.c.) reduced cocaine (0.25 mg/infusion) self-administration maintained by a progressive ratio schedule. This reduction was sustained over eight daily injections. In Experiment 2, rats self-administered cocaine in daily 2 h sessions for 15 days on a FR1 schedule. Following extinction, yohimbine (1 mg/kg, i.p.) reinstated responding, and this effect was reduced dose dependently by Ro60-0175 (0.3–3 mg/kg, s.c.). In Experiment 3, rats were trained to respond for cocaine on a FR1 schedule in a distinct environmental context (A); responding was then extinguished in a different context (B). Reinstatement tests occurred in either context A or B. Responding was reinstated only when rats were tested in the original self-administration context (A). This reinstatement was reduced dose dependently by Ro60-0175. All effects of Ro60-0175 were blocked by the 5-HT_2C receptor antagonist SB242084. Thus, Ro60-0175, acting via 5-HT_2C receptors, reduces cocaine self-administration and cocaine-seeking triggered by a stressor and by drug-associated cues. The effects of Ro60-0175 do not exhibit tolerance within the 8-day test period. These results indicate that selective 5-HT_2C receptor agonists may be a useful pharmacological strategy for treatment of drug abuse.