ETHANOL-NEUROTRANSMITTER INTERACTIONS IN BRAIN NEURONS

这些研究的总体目标是了解乙醇的作用 大脑区域参与奖励的调解，并确定如何 特定的神经递质系统改变乙醇对大脑的作用 奖励途径 这些知识可能被用来开发药物 从而减少对酒精的渴望，从而有效治疗酒精 虐待 最近的研究表明，血清素（5-HT）的再摄取 抑制剂减少酗酒者的酒精滥用。 虽然 其原因尚不清楚，5-HT再摄取可能 抑制剂作用于大脑中涉及奖励的区域，以减少酒精 渴望 一个大脑区域被证明是重要的调解 许多滥用药物的奖励作用是腹侧被盖区， Tsai（VTA）. 腹侧被盖区是多巴胺能神经支配的来源， 大脑区域的数量（例如，丘脑前核和前额叶 皮质）被认为与药物的奖赏作用有关， 多巴胺是奖励中重要的神经递质。 将在大鼠脑切片中进行细胞内和细胞外记录。 用于评估乙醇和5-HT对多巴胺能神经元的作用， VTA。 将安装切片（400微摩尔厚）， 淹没在录音室里 乙醇将用于已知的 在浴缸里的浓度。 乙醇，浓度在 行为活动范围，引起多巴胺能腹侧被盖区神经元兴奋。 我们的初步数据表明，5-HT增强兴奋性 乙醇对这些腹侧被盖区神经元的影响。 电生理 5-HT对腹侧被盖区多巴胺能神经元的作用， 其特征在于，以阐明5-HT增强的机制， 乙醇引起的神经元兴奋 此外，具体 介导这种增强作用的5-HT受体亚型将是 鉴定将检查5-HT再摄取阻滞剂，以确定它们是否 也加强了乙醇对腹侧被盖区神经元的影响， 这些药剂的增强作用是由于它们在肾上腺素能神经元上的作用。 突触 此外，近交系大鼠（刘易斯和费舍尔344） 不同的自愿EtOH摄入量将被用来确定是否 VTA神经元对5-HT增强EtOH兴奋的敏感性是 与饮用乙醇的遗传倾向有关。 最终，这些研究可能为以下有效性提供理论依据： 5-羟色胺再摄取抑制剂在减少酒精滥用，也可能 为开发更具选择性的5-HT相关药物提供基础 这将可用于治疗不受控制的乙醇摄入。

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.