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 GABA(A) 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.