Nevo I, Hamon M
INSERM U.288, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Neurochem Int. 1995 Apr;26(4):305-36; discussion 337-42. doi: 10.1016/0197-0186(94)00139-l.
Acute or chronic consumption of alcohol interferes differentially with transmission processes in the CNS, affecting many--if not all--of the known neurotransmitter systems. Conversely, selective pharmacological manipulations of some of these neurotransmitter systems have been shown to reduce ethanol intake and preference as well as the severity of the ethanol withdrawal syndrome in animal models, certain compounds having even been employed successfully in the clinic. This review examines the studies which have attempted to elucidate the roles of these neurotransmitter systems in the mechanisms involved in the various aspects of alcohol abuse and alcoholism, with an emphasis on recent developments. The brain's major amino acid transmitter systems--inhibitory gamma-aminobutyric acid (GABA) and excitatory glutamate--have been widely studied over the past decade, with the general consensus that acute ethanol facilitates GABAergic transmission (by enhancing chloride conductance through the GABAA receptor) and inhibits glutamatergic function (by decreasing cationic conductance through the NMDA receptor). Conversely, the development of tolerance associated with chronic ethanol consumption leads to a reduced GABAergic and increased glutamatergic function. Interactions between ethanol and the monoaminergic transmitter systems are complex. Dopaminergic and noradrenergic mechanisms, along with the endogenous opioid systems of the brain, seem to be implicated in the rewarding effects of ethanol via activation of positive reinforcement pathways, while the serotonergic system mediates negative reinforcement. A number of ligands of the dopaminergic, serotonergic and opioidergic receptors involved in ethanol consumption-related behaviors have been recognized for their effects in reducing ethanol preference and/or alleviating symptoms of the ethanol withdrawal syndrome in various animal models. Several of these substances are being used with success clinically. Studies of the central cholinergic system in alcoholics have provided clues to the mechanisms underlying the deleterious effects of ethanol on learning and memory, and evidence of a reduced central cholinergic activity has been reported in alcohol-dependent patients. Interestingly, acetylcholine-rich grafts and cholinomimetic drugs have been found to ameliorate ethanol-induced behavioral deficits in alcoholized rats. More generally, basic studies on alcohol's effects on central neurotransmission certainly hold the key to the development of new strategies for the treatment of alcoholism.
急性或慢性饮酒对中枢神经系统的传递过程有不同的干扰作用，影响许多（即便不是全部）已知的神经递质系统。相反，在动物模型中，对其中一些神经递质系统进行选择性药理操作已显示可减少乙醇摄入量和偏好，以及减轻乙醇戒断综合征的严重程度，某些化合物甚至已在临床上成功应用。本综述考察了那些试图阐明这些神经递质系统在酒精滥用和酒精中毒各方面所涉及机制中的作用的研究，重点关注近期进展。在过去十年中，大脑主要的氨基酸递质系统——抑制性γ-氨基丁酸（GABA）和兴奋性谷氨酸——受到了广泛研究，普遍的共识是急性乙醇促进GABA能传递（通过增强GABAA受体介导的氯离子电导）并抑制谷氨酸能功能（通过降低NMDA受体介导的阳离子电导）。相反，与慢性乙醇摄入相关的耐受性发展会导致GABA能功能降低和谷氨酸能功能增强。乙醇与单胺能递质系统之间的相互作用很复杂。多巴胺能和去甲肾上腺素能机制，以及大脑的内源性阿片系统，似乎通过激活正性强化途径参与乙醇的奖赏效应，而5-羟色胺能系统介导负性强化。许多参与乙醇消费相关行为的多巴胺能、5-羟色胺能和阿片样物质受体的配体，因其在各种动物模型中减少乙醇偏好和/或减轻乙醇戒断综合征症状的作用而得到认可。其中几种物质正在临床上成功使用。对酗酒者中枢胆碱能系统的研究为乙醇对学习和记忆产生有害影响的潜在机制提供了线索，并且在酒精依赖患者中已报道有中枢胆碱能活性降低的证据。有趣的是，富含乙酰胆碱的移植物和拟胆碱药物已被发现可改善乙醇诱导的酒精化大鼠的行为缺陷。更一般地说，关于酒精对中枢神经传递影响的基础研究肯定是开发治疗酒精中毒新策略的关键。
