Effects of 5-HT3 receptor antagonists on daily alcohol intake under acquisition, maintenance, and relapse conditions in alcohol-preferring (P) rats

Previous research indicated that 5-HT3 antagonists can reduce ethanol drink ing in rats, but drinking conditions and other environmental manipulations influenced the efficacy of these antagonists. The current experiments were conducted to examine the effects of the 5-HT3 antagonists MDL 72222 (MDL) o r ICS 205-930 (ICS) on 24-h ethanol (10% v/v) consumption during acquisitio n, maintenance, and following a period of dt privation in selectively bred high alcohol-preferring (P) male rats. In an analysis of the acquisition of ethanol consumption, daily injections of MDL(1 mg/kg; s.c.) or ICS (1 or 5 mg/kg) were administered to separate groups of P rats during the initial 1 0 days of ethanol exposure. To examine the maintenance of ethanol drinking, these same groups of rats were allowed access to ethanol for 21 days with no pharmacological manipulations, and were then administered either saline or the 5-HT3 antagonist. To examine the effects of a 5-HT3 antagonist on re lapse of ethanol drinking, another group of P rats was allowed access to et hanol for 6 weeks and was then deprived of ethanol for 3 weeks. Prior to et hanol reinstatement, rats were treated chronically (seven daily injections) or acutely with MDL (1 mg/kg), saline, or received no injections. MDL (1 m g/kg) and ICS (1 or 5 mg/kg) reduced ethanol intake during acquisition (60- 80%) and during maintenance drinking (35-70%) in P rats pretreated with sal ine during acquisition. However, in rats pretreated with MDL or ICS during acquisition, there was a significant reduction in the effectiveness of eith er MDL or ICS to reduce ongoing ethanol drinking. Neither acute nor chronic treatment with I mg/kg MDL altered the 80% increase in ethanol consumption observed on the first day of reinstatement following a 3-week deprivation period. However, in a follow-up study, acute treatment with MDL (3 mg/kg) o r ICS (5 mg/kg) did prevent the 80% increase in ethanol consumption observe d on the first day of reinstatement. Overall, the results suggest that 5-HT 3 receptors are involved in the acquisition and maintenance of 24-h ethanol drinking, and that neuroadaptations may occur as a result of chronic treat ment with 5-HT3 antagonists, or during prolonged alcohol deprivation, which alter the involvement of these receptors in regulating alcohol drinking in the P rat. (C) 2000 Elsevier Science Inc. All rights reserved.