Effect of 5-HT3 Receptor Over-Expression on the Discriminative Stimulus Effects of Ethanol

Background: Drug discrimination studies using selective antagonists and agonists have suggested that 5‐HT3 receptors may modulate ethanol's discriminative stimulus effects. However, conflicting data between laboratories leaves the issue of 5‐HT3 receptor involvement in ethanol's discriminative stimulus effects in question. The present study utilized transgenic mice that over‐express 5‐HT3 receptors in conjunction with traditional pharmacological techniques to examine the contribution of 5‐HT3 receptors to ethanol's discriminative stimulus. Methods: Ten 5‐HT3 over‐expressing (5‐HT3 OE) and 18 B6SJL wild‐type (WT) mice were trained to discriminate 1.5 g/kg ethanol from saline in daily 15 min, milk reinforced operant sessions. After training, ethanol substitution and response‐rate suppression dose response curves were determined for ethanol, midazolam, dizocilpine, cocaine, mCPP, MD‐354, YC‐30 and MDL‐72222. Antagonism tests combining ethanol with MDL‐72222 and ondansetron were also conducted. Results: The 5‐HT3 OE and WT mice learned the ethanol discrimination in a comparable number of training sessions. Similar patterns of substitution were generated in both groups of mice for most test drugs. 5‐HT3 OE mice were more sensitive to the rate suppressing effects of dizocilpine and MDL‐72222 than were WT mice. Neither of the 5‐HT3 antagonist tested significantly attenuated ethanol's discriminative stimulus effects in either 5‐HT3 OE or WT mice. Conclusions: The results of the present study are consistent with a minimal role of 5‐HT3 receptors in transducing ethanol's discriminative stimulus effects. Over‐expression of 5‐HT3 receptors does not alter the relative efficacy of GABAA positive modulators or NMDA antagonists for producing ethanol‐like discriminative stimulus effects. However, 5‐HT3 receptor over‐expression does appear to modulate the response‐rate altering effects of the uncompetitive NMDA antagonist, dizocilpine, and the 5‐HT3 antagonist, MDL‐72222.