Kotlinska Jolanta, Bochenski Marcin
Department of Pharmacology and Pharmacodynamics, Medical University School, Lublin, Poland.
Eur J Pharmacol. 2008 Nov 19;598(1-3):57-63. doi: 10.1016/j.ejphar.2008.09.026. Epub 2008 Sep 27.
The aim of the present study was to determine whether various glutamate receptor antagonists could affect ethanol withdrawal-induced anxiety-like behavior measured in the elevated plus-maze test in rats. In our study, memantine (8 and 12 mg/kg), a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, did not show any effect on ethanol withdrawal anxiety. Acamprosate (NMDA and metabotropic glutamate5 (mGlu5) receptor antagonist), at a dose of 400 mg/kg showed anxiolytic-like effect, thus increasing the percent of time spent in open arms and open arms entries. Antagonists of group I mGlu receptors, such as MTEP ([(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, mGlu5 receptor) or EMQMCM (3-ethyl-2-methyl-quinolin-6-yl-(4-methoxy-cyclohexyl)-methanone methanesulfonate, mGlu1 receptor), caused similar effects to acamprosate. In contrast to acamprosate and MTEP, EMQMCM (5 mg/kg) elevated the ethanol withdrawal-induced decrease in locomotion. When given alone to the saline-treated group, EMQMCM indicated anxiolytic-like effect. Our results imply a crucial role of mGlu5 receptor in an anxiety-like effect of ethanol withdrawal because MTEP (a selective mGlu5 receptor antagonist) and acamprosate (which also indirectly inhibits mGlu5 receptor) attenuated ethanol withdrawal anxiety-like behavior without influence on ethanol withdrawal hypolocomotion and did not show any effect in the saline-treated groups. However, difference in anxiolytic-like potency between both these group I mGlu receptors antagonists may be due to the recent experimental design. Therefore, taking into account a positive correlation between ethanol withdrawal-induced anxiety and relapse to ethanol drinking, our results suggest that mGlu receptor antagonists of group I (similarly to acamprosate) could prevent relapse to drinking and, therefore they might be useful in therapy of alcoholism.
本研究的目的是确定各种谷氨酸受体拮抗剂是否会影响在高架十字迷宫试验中测量的大鼠乙醇戒断诱导的焦虑样行为。在我们的研究中，非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂美金刚（8和12mg/kg）对乙醇戒断焦虑没有任何影响。阿坎酸（NMDA和代谢型谷氨酸5（mGlu5）受体拮抗剂），剂量为400mg/kg时显示出抗焦虑样作用，从而增加了在开放臂中花费的时间百分比和进入开放臂的次数。I组mGlu受体拮抗剂，如MTEP（[(2-甲基-1,3-噻唑-4-基)乙炔基]吡啶，mGlu5受体）或EMQMCM（3-乙基-2-甲基喹啉-6-基-(4-甲氧基环己基)-甲酮甲磺酸盐，mGlu1受体），产生了与阿坎酸类似的效果。与阿坎酸和MTEP相反，EMQMCM（5mg/kg）加剧了乙醇戒断诱导的运动减少。当单独给予生理盐水处理组时，EMQMCM显示出抗焦虑样作用。我们的结果表明mGlu5受体在乙醇戒断的焦虑样作用中起关键作用，因为MTEP（一种选择性mGlu5受体拮抗剂）和阿坎酸（也间接抑制mGlu5受体）减轻了乙醇戒断焦虑样行为，而不影响乙醇戒断引起的运动减少，并且在生理盐水处理组中没有显示任何作用。然而，这两种I组mGlu受体拮抗剂之间抗焦虑样效力的差异可能归因于最近的实验设计。因此，考虑到乙醇戒断诱导的焦虑与复饮之间的正相关关系，我们的结果表明I组mGlu受体拮抗剂（类似于阿坎酸）可以预防复饮，因此它们可能对酒精中毒的治疗有用。
