Effects of MDL 72222, a serotonin(3) antagonist, on operant responding forethanol by alcohol-preferring P rats

Background: Previous studies indicated that, under continuous access condit ions, the 5-HT3 antagonist MDL 72222 (MDL) effectively reduced ethanol drin king of alcohol-preferring P rats. However, MDL was without effect when sim ilar doses were tested under scheduled access conditions, unless the ethano l access period was randomly presented. This study examined the effects of MDL on operant responding for ethanol and water by adult male alcohol-prefe rring P rats. Methods: During the dark cycle, subjects in the first experiment were train ed to respond concurrently for 15% ethanol and water on a fixed-ratio 5 (FR -5) and FR-1 schedule of reinforcement, respectively. Approximately 30 min before the 1-hr operant session, rats were injected subcutaneously (sc) wit h saline or MDL (1, 3, or 5 mg/kg). A second experiment tested the effects of 1 mg/kg MDL on operant responding for 15% ethanol in 1-hr sessions when operant access was given at a fixed time each day (Fixed scheduled access, FSA group) or at variable time periods throughout the dark cycle (variable scheduled access, VSA group). Results: In the first experiment, only the 5 mg/kg dose of MDL decreased re sponding for ethanol (approximately 20%) during the first 30 min of the 4-h r session. This dose also reduced total 4-hr responding for ethanol and wat er. In the second experiment, the 1 mg/kg dose of MDL had no effect on oper ant responding by the FSA group, but significantly reduced ethanol respondi ng by the VSA group. Conclusions: These results suggest that 5-HT3 receptors may be involved in mediating the reinforcing effects of ethanol, and that temporal-environment al cues associated with the presentation of ethanol may he one factor invol ved in reducing the effectiveness of 5-HT3 antagonists to attenuate ethanol intake.