Palachick Benjamin, Chen Yi-Chyan, Enoch Abigail J, Karlsson Rose-Marie, Mishina Masayoshi, Holmes Andrew
Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane Room 2N09, Rockville, MD 20852-9411, USA.
Alcohol Clin Exp Res. 2008 Aug;32(8):1479-92. doi: 10.1111/j.1530-0277.2008.00715.x. Epub 2008 Jun 28.
The glutamate system plays a major role in mediating EtOH's effects on brain and behavior, and is implicated in the pathophysiology of alcohol-related disorders. N-methyl-D-aspartate receptor (NMDAR) antagonists such as MK-801 (dizocilpine) interact with EtOH at the behavioral level, but the molecular basis of this interaction is unclear.
We first characterized the effects of MK-801 treatment on responses to the ataxic (accelerating rotarod), hypothermic and sedative/hypnotic effects of acute EtOH administration in C57BL/6J and 129/SvImJ inbred mice. Effects of another NMDAR antagonist, phencyclidine, on EtOH-induced sedation/hypnosis were also assessed. Gene knockout of the NMDAR subunit NR2A or l-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate GluR1 or pharmacological antagonism of the NMDAR subunit NR2B (via Ro 25-6981) was employed to examine whether inactivating any one of these glutamate signaling molecules modified MK-801's effect on EtOH-related behaviors.
MK-801 markedly potentiated the ataxic effects of 1.75 g/kg EtOH and the sedative/hypnotic effects of 3.0 g/kg EtOH, but not the hypothermic effects of 3.0 g/kg EtOH, in C57BL/6J and 129/SvImJ mice. Phencyclidine potentiated EtOH-induced sedation/hypnosis in both inbred strains. Neither NR2A nor GluR1 KO significantly altered basal EtOH-induced ataxia, hypothermia, or sedation/hypnosis. Ro 25-6981 modestly increased EtOH-induced sedation/hypnosis. The ability of MK-801 to potentiate EtOH-induced ataxia and sedation/hypnosis was unaffected by GluR1 KO or NR2B antagonism. NR2A KO partially reduced MK-801 + EtOH-induced sedation/hypnosis, but not ataxia or hypothermia.
Data confirm a robust and response-specific potentiating effect of MK-801 on sensitivity to EtOH's intoxicating effects. Inactivation of three major components of glutamate signaling had no or only partial impact on the ability of MK-801 to potentiate behavioral sensitivity to EtOH. Further work to elucidate the mechanisms underlying NMDAR x EtOH interactions could ultimately provide novel insight into the role of NMDARs in alcoholism and its treatment.
谷氨酸系统在介导乙醇对大脑和行为的影响中起主要作用，并与酒精相关障碍的病理生理学有关。N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂如MK-801（地佐环平）在行为水平上与乙醇相互作用，但其相互作用的分子基础尚不清楚。
我们首先在C57BL/6J和129/SvImJ近交系小鼠中，研究了MK-801处理对急性给予乙醇后共济失调（加速转棒试验）、体温过低及镇静/催眠作用反应的影响。还评估了另一种NMDAR拮抗剂苯环利定对乙醇诱导的镇静/催眠作用的影响。采用NMDAR亚基NR2A或α-氨基-3-羟基-5-甲基异恶唑-4-丙酸受体GluR1基因敲除，或NMDAR亚基NR2B的药理学拮抗（通过Ro 25-6981），以研究这些谷氨酸信号分子中的任何一种失活是否会改变MK-801对乙醇相关行为的影响。
在C57BL/6J和129/SvImJ小鼠中，MK-801显著增强了1.75 g/kg乙醇的共济失调作用以及3.0 g/kg乙醇的镇静/催眠作用，但未增强3.0 g/kg乙醇的体温过低作用。苯环利定增强了两个近交系中乙醇诱导的镇静/催眠作用。NR2A和GluR1基因敲除均未显著改变基础乙醇诱导的共济失调、体温过低或镇静/催眠作用。Ro 25-6981适度增加了乙醇诱导的镇静/催眠作用。MK-801增强乙醇诱导的共济失调和镇静/催眠作用的能力不受GluR1基因敲除或NR2B拮抗的影响。NR2A基因敲除部分降低了MK-801 +乙醇诱导的镇静/催眠作用，但未降低共济失调或体温过低作用。
数据证实MK-801对乙醇中毒作用的敏感性具有强大且反应特异性的增强作用。谷氨酸信号传导的三个主要成分失活对MK-801增强对乙醇行为敏感性的能力没有或只有部分影响。进一步阐明NMDAR与乙醇相互作用机制的工作最终可能为NMDAR在酒精中毒及其治疗中的作用提供新的见解。
