Oka Michiko, Hirouchi Masaaki, Tamura Masaru, Sugahara Seishi, Oyama Tatsuya
Research Laboratories, Nippon Shinyaku Co., Ltd., 14, Nishinosho-monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.
Eur J Pharmacol. 2013 Oct 15;718(1-3):323-31. doi: 10.1016/j.ejphar.2013.08.014. Epub 2013 Sep 4.
Acamprosate, the calcium salt of bis(3-acetamidopropane-1-sulfonate), contributes to the maintenance of abstinence in alcohol-dependent patients, but its mechanism of action in the central nervous system is unclear. Here, we report the effect of acamprosate on ethanol-drinking behavior in standard laboratory Wistar rats, including voluntary ethanol consumption and the ethanol-deprivation effect. After forced ethanol consumption arranged by the provision of only one drinking bottle containing 10% ethanol, the rats were given a choice between two drinking bottles, one containing water and the other containing 10% ethanol. In rats selected for high ethanol preference, repeated oral administration of acamprosate diminished voluntary ethanol drinking. After three months of continuous access to two bottles, rats were deprived of ethanol for three days and then presented with two bottles again. After ethanol deprivation, ethanol preference was increased, and the increase was largely abolished by acamprosate. After exposure of primary neuronal cultures of rat cerebral cortex to ethanol for four days, neurotoxicity, as measured by the extracellular leakage of lactate dehydrogenase (LDH), was induced by incubation with glutamate for 1h followed by incubation in the absence of ethanol for 24h. The N-methyl-D-aspartate receptor blocker 5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine, the metabotropic glutamate receptor subtype 5 antagonist 6-methyl-2-(phenylethynyl)pyridine and the voltage-gated calcium-channel blocker nifedipine all inhibited glutamate-induced LDH leakage from ethanol-exposed neurons. Acamprosate inhibited the glutamate-induced LDH leakage from ethanol-exposed neurons more strongly than that from intact neurons. In conclusion, acamprosate showed effective reduction of drinking behavior in rats and protected ethanol-exposed neurons by multiple blocking of glutamate signaling.
阿坎酸，即双（3-乙酰氨基丙烷-1-磺酸盐）的钙盐，有助于维持酒精依赖患者的戒酒状态，但其在中枢神经系统中的作用机制尚不清楚。在此，我们报告了阿坎酸对标准实验室Wistar大鼠乙醇饮用行为的影响，包括自愿乙醇消耗和乙醇剥夺效应。在通过仅提供一个装有10%乙醇的饮水瓶来安排强迫乙醇消耗后，给大鼠提供两个饮水瓶供其选择，一个装有水，另一个装有10%乙醇。在选择了高乙醇偏好的大鼠中，重复口服阿坎酸可减少自愿乙醇饮用。在连续三个月可以接触两个饮水瓶后，将大鼠剥夺乙醇三天，然后再次提供两个饮水瓶。乙醇剥夺后，乙醇偏好增加，而阿坎酸在很大程度上消除了这种增加。将大鼠大脑皮层的原代神经元培养物暴露于乙醇四天后，通过乳酸脱氢酶（LDH）的细胞外泄漏来测量的神经毒性，是在与谷氨酸孵育1小时后，然后在无乙醇的情况下孵育24小时诱导产生的。N-甲基-D-天冬氨酸受体阻滞剂5-甲基-10,11-二氢-5H-二苯并[a,d]-环庚烯-5,10-亚胺、代谢型谷氨酸受体亚型5拮抗剂6-甲基-2-（苯乙炔基）吡啶和电压门控钙通道阻滞剂硝苯地平均抑制了谷氨酸诱导的乙醇暴露神经元的LDH泄漏。阿坎酸比完整神经元更强烈地抑制谷氨酸诱导的乙醇暴露神经元的LDH泄漏。总之，阿坎酸在大鼠中显示出有效减少饮酒行为，并通过对谷氨酸信号的多重阻断保护乙醇暴露的神经元。
