Ticku M K, Kulkarni S K
Department of Pharmacology, University of Texas Health Science Center, San Antonio 78284-7764.
Pharmacol Biochem Behav. 1988 Jun;30(2):501-10. doi: 10.1016/0091-3057(88)90487-x.
The behavioral and biochemical effects of ethanol in man and animals have been investigated for a long time. A role of catecholamines in the central stimulatory action and during withdrawal has been envisaged, but more recent observations have revealed the involvement of inhibitory synaptic transmitter, GABA, in the actions of ethanol. Ethanol-induced motor incoordination, hypnosedation, antianxiety, and anticonvulsant actions are reported to be GABA-mediated. Involvement of the GABA system has been implicated in ethanol withdrawal-induced seizures in animals. More direct evidences using Cl- influx studies in synaptoneurosomes and spinal neuronal culture studies confirm such a mode of action of ethanol, probably influencing the chloride channel modulation at the GABA-benzodiazepine receptor ionophore complex. RO15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-Oxo-4H-imidazo [1,5-alpha], [1,4] benzodiazepine-3-carboxylate), a novel imidazobenzodiazepine, an analogue of the classical benzodiazepine antagonist is reported to possess alcohol antagonistic properties. RO15-4513 reverses both the behavioral and biochemical effects of ethanol, including the action of GABA-induced Cl- fluxes. But its potential clinical application may be restricted due to its inverse agonistic property. The present review focuses on the GABA-linked behavioral and biochemical actions of ethanol and discusses the potential of RO15-4513 as an alcohol antagonist.
乙醇对人和动物行为及生化方面的影响已被研究了很长时间。人们曾设想儿茶酚胺在中枢刺激作用及戒断过程中发挥作用，但最近的观察结果显示，抑制性突触递质γ-氨基丁酸（GABA）也参与了乙醇的作用。据报道，乙醇诱导的运动不协调、催眠镇静、抗焦虑和抗惊厥作用均由GABA介导。GABA系统的参与被认为与动物乙醇戒断诱发的癫痫发作有关。在突触体神经小体中进行的氯离子内流研究以及脊髓神经元培养研究提供了更直接的证据，证实了乙醇的这种作用模式，乙醇可能影响GABA-苯二氮䓬受体离子载体复合物处的氯离子通道调节。新型咪唑并苯二氮䓬RO15-4513（8-叠氮基-5,6-二氢-5-甲基-6-氧代-4H-咪唑并[1,5-α][1,4]苯二氮䓬-3-羧酸乙酯）是经典苯二氮䓬拮抗剂的类似物，据报道具有酒精拮抗特性。RO15-4513可逆转乙醇的行为和生化效应，包括GABA诱导的氯离子通量的作用。但其潜在的临床应用可能因其反向激动特性而受到限制。本综述重点关注乙醇与GABA相关的行为和生化作用，并讨论RO15-4513作为酒精拮抗剂的潜力。
