Blockade of the discriminative stimulus effects of ethanol with 5-HT3 receptor antagonists

The ability of selective 5-HT₃ receptor antagonists to block the discriminative stimulus effects of ethanol was investigated in pigeons trained with food reinforcement to discriminate ethanol (1.5 g/kg; IG) from water. The 5-HT₃ receptor antagonists that are substituted tropines, ICS 205-930 (0.1–0.56 mg/kg) and MDL 72222 (3.0–17.0 mg/kg), blocked ethanol-appropriate responding, in a dose-dependent manner, suggesting that some of the discriminative stimulus effects of ethanol are mediated via the 5-HT₃ receptor. The blockade the discriminative stimulus effects of ethanol occurred in the presence of approximately 25–40 mM blood ethanol levels. Furthermore, the ethanol dose-effect function was shifted to the right by increasing doses of MDL 72222, suggesting a surmountable antagonism of the discriminative stimulus effects of ethanol. However, the benzamide zacopride (0.56–1.7 mg/kg), which is also a 5-HT₃ receptor antagonist, did not block the discriminative stimulus effects of ethanol. In addition, the dopaminergic antagonist haloperidol and the 5-HT₂ receptor antagonist ketanserin also failed to block the ethanol discrimination. The results suggest that 5-HT₃ mediated neurotransmission is an important component of ethanol's discriminative stimulus effects, but that the structural characteristics of the selective 5-HT₃ receptor antagonists influence their ability to block this action of ethanol. Furthermore, these findings implicate a significant role of 5-HT₃ activity in the behavioral effects of ethanol that may provide a pharmacological means for therapeutic intervention of alcohol abuse.