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Effect of 5‐HT 3 Receptor Over‐Expression on the Discriminative Stimulus Effects of Ethanol
Author(s) -
Shelton Keith L.,
Dukat Malgorzata,
Allan Andrea M.
Publication year - 2004
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1097/01.alc.0000138687.27452.e2
Subject(s) - stimulus control , receptor , pharmacology , ethanol , chemistry , 5 ht receptor , receptor antagonist , stimulus (psychology) , antagonist , serotonin , psychology , biology , neuroscience , biochemistry , psychotherapist , nicotine
Background: Drug discrimination studies using selective antagonists and agonists have suggested that 5‐HT 3 receptors may modulate ethanol's discriminative stimulus effects. However, conflicting data between laboratories leaves the issue of 5‐HT 3 receptor involvement in ethanol's discriminative stimulus effects in question. The present study utilized transgenic mice that over‐express 5‐HT 3 receptors in conjunction with traditional pharmacological techniques to examine the contribution of 5‐HT 3 receptors to ethanol's discriminative stimulus. Methods: Ten 5‐HT 3 over‐expressing (5‐HT 3 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‐HT 3 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‐HT 3 OE mice were more sensitive to the rate suppressing effects of dizocilpine and MDL‐72222 than were WT mice. Neither of the 5‐HT 3 antagonist tested significantly attenuated ethanol's discriminative stimulus effects in either 5‐HT 3 OE or WT mice. Conclusions: The results of the present study are consistent with a minimal role of 5‐HT 3 receptors in transducing ethanol's discriminative stimulus effects. Over‐expression of 5‐HT 3 receptors does not alter the relative efficacy of GABA A positive modulators or NMDA antagonists for producing ethanol‐like discriminative stimulus effects. However, 5‐HT 3 receptor over‐expression does appear to modulate the response‐rate altering effects of the uncompetitive NMDA antagonist, dizocilpine, and the 5‐HT 3 antagonist, MDL‐72222.