Long-term blockade of the expression of cocaine sensitization by ondansetron, a 5-HT3 receptor antagonist

Intermittent cocaine administration induces sensitization (reverse toleranc e) to its behavioral effects. The mechanism(s) mediating sensitization is n ot clear, however, previous research has implicated 5-HT3 receptors in the expression of sensitization. The present experiment evaluated the ability o f the 5-HT3 receptor antagonist, ondansetron, administered during withdrawa l from chronic intermittent cocaine administration, to block the expression of sensitization. Rats were pretreated for 14 days by daily subcutaneous i njections of either 40 mg/kg cocaine or 0.9% saline. During the first 5 day s of withdrawal from this pretreatment regimen, all rats received a daily s ubcutaneous injection of 0-1.0 mg/kg ondansetron. On days 7, 14 or 28 of wi thdrawal from the cocaine pretreatment, the rats received a 15.0-mg/kg coca ine challenge. Ambulatory behavior was automatically recorded for 60 min. O ndansetron had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron blocked the expression of sensitization at all withdrawal time s. We thus report that it is possible to permanently block the expression o f sensitization once it has developed by administering a 5-HT3 receptor ant agonist. (C) 2000 Elsevier Science B.V. All rights reserved.