Newton Philip M, Zeng Lily, Wang Victoria, Connolly Jacklyn, Wallace Melisa J, Kim Chanki, Shin Hee-Sup, Belardetti Francesco, Snutch Terrance P, Messing Robert O
Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608, USA.
J Neurosci. 2008 Nov 5;28(45):11712-9. doi: 10.1523/JNEUROSCI.3621-08.2008.
There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels. These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.
显然需要新的疗法来治疗酒精中毒。在此，基于我们之前使用基因敲除小鼠和细胞培养系统的研究，我们检验了这样一个假设，即神经元钙通道的选择性抑制剂将减少乙醇消耗和中毒。我们证明，用新型N型和T型钙通道混合拮抗剂1-(6,6-双(4-氟苯基)己基)-4-(3,4,5-三甲氧基苄基)哌嗪(NP078585)进行预处理可降低乙醇中毒。NP078585还减弱了乙醇的强化和奖赏特性，这是通过操作性自我给药和乙醇条件性位置偏爱表达来衡量的，并且消除了应激诱导的乙醇寻求行为的恢复。NP078585对缺乏N型钙通道的小鼠的酒精反应没有影响。这些结果表明，选择性钙通道抑制剂可能有助于减少人类酗酒者的急性乙醇中毒和酒精消耗。
