ETHANOL-NEUROTRANSMITTER INTERACTIONS IN BRAIN NEURONS

大脑神经元中的乙醇-神经递质相互作用

• 批准号: 2045328
• 负责人: MARK S BRODIE
• 金额: $ 14.68万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2045328
• 关键词: ETHANOL; NEUROTRANSMITTER; INTERACTIONS; BRAIN; NEURONS; ETHANOL; NEUROTRANSMITTER; INTERACTIONS; BRAIN; NEURONS

The overall objective of these studies is to understand how ethanol acts on brain areas involved in the mediation of reward, and to determine how specific neurotransmitter systems modify the action of ethanol on brain reward pathways. This knowledge might be exploited to develop drugs which reduce alcohol craving, leading to effective treatments for alcohol abuse. Recent studies have shown that serotonin (5-HT) reuptake inhibitors decrease alcohol abuse in problem drinkers. Although the reason for this is not clear, it is possible that 5-HT reuptake inhibitors act in brain areas involved in reward to reduce alcohol craving. One brain area shown to be important for mediating the rewarding effects of many drugs of abuse is the ventral tegmental area of Tsai (VTA). The VTA is the source of dopaminergic innervation to a number of brain areas (e.g., the nucleus accumbens and the prefrontal cortex) thought to be involved in the rewarding effects of drugs of abuse, and dopamine is an important neurotransmitter in reward. Intracellular and extracellular recording in rat brain slices will be used to assess the action of ethanol and 5-HT on dopaminergic neurons in the VTA. Slices (400 micromoles thick) will be mounted and totally submerged in the recording chamber. Ethanol will be applied in known concentrations in the bath. Ethanol, in concentrations within the behaviorally active range, causes excitation of dopaminergic VTA neurons. Our preliminary data indicates that 5-HT potentiates the excitatory effect of ethanol on some of these VTA neurons. The electrophysiological effects of 5-HT on dopamine-containing neurons of the VTA will be characterized in order to elucidate the mechanism by which 5-HT enhances ethanol-induced excitation in these neurons. Furthermore, the specific 5-HT receptor subtype(s) which mediate this potentiation will be identified. 5-HT reuptake blockers will be examined to determine if they also potentiate the effects of ethanol on VTA neurons, and whether potentiation by these agents is due to their action at serotonergic synapses. In addition, inbred strains of rats (Lewis and Fisher 344) which differ in voluntary EtOH intake will be used to determine whether the sensitivity of VTA neurons to 5-HT potentiation of EtOH excitation is correlated with a genetic predisposition to drink more or less EtOH. Ultimately, these studies may provide a rationale for the efficacy of 5-HT reuptake inhibitors in reducing alcohol abuse, and might also provide a basis for the development of more selective 5-HT-related drugs which would be useful in the treatment of uncontrolled ethanol intake.

这些研究的总体目的是了解乙醇如何作用 在参与奖励中介的大脑领域，并确定如何 特定的神经递质系统修改乙醇对脑的作用 奖励途径。 这些知识可能被利用以开发毒品 减少渴望酒精的渴望，从而有效治疗酒精 虐待。 最近的研究表明，5-羟色胺（5-HT）再摄取 抑制剂减少了饮酒者的酒精滥用。 虽然 原因不清 抑制剂在涉及奖励以减少酒精的大脑区域的作用 渴望。 一个大脑区域显示对中介 许多滥用药物的奖励作用是 Tsai（VTA）。 VTA是多巴胺能神经支配的来源 大脑区域的数量（例如伏隔核和前额叶 认为皮质）被认为参与了药物的奖励作用 滥用和多巴胺是奖励中重要的神经递质。 大鼠脑切片中的细胞内和细胞外记录将是 用于评估乙醇和5-HT对多巴胺能神经元的作用 VTA。 切片（400个微孔厚）将安装并完全 淹没在录音室中。 乙醇将用于已知 浴缸中的浓度。 乙醇，集中度 行为活跃的范围会引起多巴胺能VTA神经元的激发。 我们的初步数据表明5-HT增强了兴奋性 乙醇对其中一些VTA神经元的影响。 电生理学 5-HT对VTA多巴胺神经元的影响将是 为了阐明5-HT增强的机制而被特征 这些神经元中乙醇引起的激发。 此外，具体 介导这种增强的5-HT受体亚型将是 确定。将检查5-ht的再摄取阻滞剂，以确定他们是否是否 还增强乙醇对VTA神经元的影响，以及是否是否 这些代理的增强是由于它们在血清素能的作用 突触。 此外，大鼠的近交菌株（刘易斯和费舍尔344） 自愿摄入的哪些不同，将使用 VTA神经元对ETOH激发的5-HT增强的敏感性是 与遗传易感或多或少地饮用ETOH相关。 最终，这些研究可能为有效性提供理由 5-HT再摄取抑制剂减少酗酒，也可能 为开发更具选择性的5-HT相关药物提供了基础 这将在治疗不受控制的乙醇摄入量中有用。