Effect of 5-HT3 receptor over-expression on the discriminative stimulus effects of ethanol.
Effect of 5-HT3 receptor over-expression on the discriminative stimulus effects of ethanol.
复制标题
5-HT3受体过度表达对乙醇辨别刺激作用的影响。
DOI：
10.1097/01.alc.0000138687.27452.e2
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Allan,AndreaM
中科院分区：
文献类型：
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作者：
Shelton,KeithL;Dukat,Malgorzata;Allan,AndreaM
背景：使用选择性拮抗剂和激动剂进行的药物鉴别研究表明，5‐ht3受体可能调节乙醇的鉴别刺激作用。然而，实验室之间相互矛盾的数据留下了5‐ht3受体参与乙醇的鉴别刺激效应的问题。本研究利用过表达5‐ht3受体的转基因小鼠，结合传统药理学技术，研究了5‐ht3受体对乙醇鉴别刺激的作用。方法：将10只5‐ht3过表达（5‐HT3OE）小鼠和18只B6SJL野生型（WT）小鼠进行训练，使其在每天15分钟的牛奶强化操作中区分1.5 g/kg乙醇和生理盐水。训练后，测定乙醇、咪达唑仑、二唑西平、可卡因、mCPP、MD‐354、YC‐30和MDL‐72222的乙醇替代和反应率抑制剂量反应曲线。同时进行了乙醇与MDL - 72222和昂丹司琼的联合拮抗试验。结果：5‐HT3OE小鼠和WT小鼠在相当数量的训练中学会了乙醇辨别。在两组小鼠中，大多数测试药物都产生了类似的替代模式。与WT小鼠相比，5‐HT3OE小鼠对二唑西平和MDL‐72222的抑率作用更为敏感。在5‐HT3OE或WT小鼠中，两种5‐ht3拮抗剂均未显著减弱乙醇的特异性刺激作用。结论：本研究的结果与5‐ht3受体在转导乙醇的鉴别刺激效应中的微小作用相一致。5 - ht3受体的过表达不会改变gaba阳性调节剂或NMDA拮抗剂产生乙醇样鉴别刺激效应的相对功效。然而，5‐ht3受体过表达似乎可以调节非竞争性NMDA拮抗剂二唑西平和5‐ht3拮抗剂MDL‐72222的反应率改变作用。
Background:Drug discrimination studies using selective antagonists and agonists have suggested that 5‐HT3receptors may modulate ethanol's discriminative stimulus effects. However, conflicting data between laboratories leaves the issue of 5‐HT3receptor involvement in ethanol's discriminative stimulus effects in question. The present study utilized transgenic mice that over‐express 5‐HT3receptors in conjunction with traditional pharmacological techniques to examine the contribution of 5‐HT3receptors to ethanol's discriminative stimulus.Methods:Ten 5‐HT3over‐expressing (5‐HT3OE) 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‐HT3OE 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‐HT3OE mice were more sensitive to the rate suppressing effects of dizocilpine and MDL‐72222 than were WT mice. Neither of the 5‐HT3antagonist tested significantly attenuated ethanol's discriminative stimulus effects in either 5‐HT3OE or WT mice.Conclusions:The results of the present study are consistent with a minimal role of 5‐HT3receptors in transducing ethanol's discriminative stimulus effects. Over‐expression of 5‐HT3receptors does not alter the relative efficacy of GABAApositive modulators or NMDA antagonists for producing ethanol‐like discriminative stimulus effects. However, 5‐HT3receptor over‐expression does appear to modulate the response‐rate altering effects of the uncompetitive NMDA antagonist, dizocilpine, and the 5‐HT3antagonist, MDL‐72222.