NEUROBIOLOGICAL MECHANISMS OF ALCOHOL DRINKING

在过去的二十年里，酒精滥用和酒精中毒的神经生物学底物一直在进行重大的研究。研究表明，酒精可以通过特定的神经递质受体影响中枢神经系统，其中包括谷氨酸(Glu)、γ-氨基丁酸(GABA)和5-羟色胺(5-HT)神经元系统。最近对饮酒大鼠大脑中局部大脑葡萄糖利用率的研究表明，与食用蔗糖的对照组相比，特定区域被激活。这些数据表明，饮酒涉及不同的大脑区域。然而，目前尚不清楚这些区域的哪些神经递质系统参与其中。这项拨款申请建议通过使用神经递质周转率(TOR)测量来进一步研究这些神经元系统。天冬氨酸、谷氨酸、GABA、多巴胺、去甲肾上腺素和5-羟色胺的周转率将同时在大鼠饮酒前或饮酒后(饮酒后组)和大鼠在蔗糖(蔗糖组)或水(饮水组)之后的小脑区同时测定。这一设计将允许评估饮酒史相似的大鼠饮酒的影响(比较ALC前和ALC后的组)，使用交通工具(比较ALC后的组和水组)，以及口服另一种增强剂的影响(比较ALC后的组和蔗糖组)。第二个实验将评估相同神经递质在相似组大鼠中的TOR，但在酒精的初始阶段，在酒精的任何主要药理作用之前，先摄入蔗糖和水。第二个实验的数据将与第一个实验的数据进行比较，以确定是否有一个子集或独立的神经系统参与了饮酒的启动，以及哪些系统依赖于酒精的药理作用。预计在这两项神经递质TOR研究中将发现一些候选神经系统，这些研究可以通过脑内注射特定受体拮抗剂、烷化剂或神经毒素和微透析程序来进一步表征。拟议中的实验有望为我们理解酒精滥用的过程提供重要的新信息。

The neurobiological substrates of alcohol abuse and alcoholism have been under significant investigation for the last two decades. Research has indicated alcohol can affect the central nervous system through specific neurotransmitter receptors that include glutamate (Glu), gamma-aminobutyric acid (GABA) and Serotonin (5-HT) neuronal systems. Recent investigations of the rates of local cerebral glucose utilization in the brains of rats consuming alcohol suggest specific regions to be activated compared to sucrose consuming controls. These data suggest that different brain regions are involved in alcohol drinking. However, it is not known which neurotransmitter systems in these regions are involved. This grant application proposes to further investigate these neuronal systems by using neurotransmitter turnover rate (TOR) measurements. The turnover rates of aspartate, Glu, GABA, dopamine, norepinephrine and 5-HT will be concurrently determined in small brain regions of rats either prior to (pre-alc group)or following a session of alcohol consumption (post-ale group) and in rats following a session of sucrose (sucrose group) or water (water group consumption. This design will permit assessments of the effects of alcohol consumption in rats with a similar history of alcohol intake (comparing pre-alc group with post-alc group), with vehicle (comparing post-alc group with water group) and the effects of oral consumption of another reinforcer (comparing post-alc group with the sucrose group). A second experiment will assess the TOR of the same neurotransmitters in similar groups of rats, but during the initial phase of alcohol, sucrose and water consumption prior to any major pharmacological actions of alcohol. The data from the second experiment will be compared with the first to determine if a subset of or separate neuronal systems are involved in the initiation of alcohol drinking and what systems are dependent upon the pharmacological actions of alcohol. It is expected that some candidate neuronal systems will be identified in these two neurotransmitter TOR studies that can be further characterized with intracranial injections of specific receptor antagonists, alkylating agents or neurotoxins and microdialysis procedures. The proposed experiments will hopefully add significant new information to our understanding of the processes underlying alcohol abuse.