Ethanol-Neurotransmitter Interactions in Brain Neurons

脑神经元中的乙醇-神经递质相互作用

• 批准号: 6928541
• 负责人: MARK S BRODIE
• 金额: $ 31万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928541
• 关键词: behavioral /social science research tag; brain imaging /visualization /scanning; craving; dopamine; electrophysiology; ethanol; ion channel blocker; kinase inhibitor; laboratory rat; membrane channels; membrane potentials; neurochemistry; neurons; physical chemical interaction; potassium channel; potassium ion; reinforcer; serotonin; tegmentum; voltage /patch clamp

DESCRIPTION (provided by applicant): The overall specific aims of this project are to understand the action of ethanol on brain pathways that mediate reward. The dopaminergic neurons of the ventral tegmental area (DA-VTA neurons) are important for the mediation of the reinforcing properties of ethanol, and the firing rate of these neurons is increased by ethanol. We have shown that serotonin potentiates ethanol excitation of DA-VTA neurons. Our subsequent studies have investigated ionic currents in the membrane of DA-VTA neurons to elucidate the ionic mechanism of this potentiation. In the previous project period, we focused on two membrane currents that may underlie the serotonin potentiation, the calcium-dependent potassium current SK, and the mixed cationic current lh. SK can be reduced by drugs like apamin or by depletion of intracellular calcium. We found that serotonin reduces Ih, and produces changes in the spike afterhyperpolarization similar to those produced by apamin. In our preliminary studies, we found that concurrent reduction of both of these currents produces profound potentiation of ethanol excitation. We have developed a model to explain this observation. In the proposed studies, five specific aims will seek to explore the relationship between ethanol excitation and potentiation of that excitation by serotonin. Specific Aim #1 will establish the concentration-response curve for very low concentrations of ethanol during blockade of SK and Ih. Specific Aim #2 will ascertain whether serotonin potentiation of ethanol excitation is mediated by concurrent reduction of SK and Ih. Specific Aims #3 and #4 will determine how blockade of SK and Ih alter specific membrane properties of DA-VTA neurons, and how ethanol effects on specific membrane properties are altered by SK and Ih blockade. Specific Aim #5 will use imaging of intracellular free calcium to determine whether prolonged administration of serotonin depletes intracellular stores of calcium. These studies directly build on our interesting initial observations of ethanol potentiation by blockade of SK and Ih, and will provide important information on how sensitivity to ethanol excitation may be modulated by neurotransmitter effects on ionic currents in DA-VTA neurons. Ultimately, information generated by this project may help in the development of pharmacotherapies for the amelioration of alcoholism.

描述（由申请人提供）：该项目的总体具体目的是了解乙醇对介导奖励的大脑通路的作用。腹侧盖区（DA-VTA神经元）的多巴胺能神经元对于介导乙醇的增强特性很重要，并且这些神经元的发射速率被乙醇提高。我们已经证明5-羟色胺增强了DA-VTA神经元的乙醇激发。我们随后的研究研究了DA-VTA神经元膜中的离子电流，以阐明这种增强的离子机理。在上一个项目期间，我们专注于两种膜电流，这些膜电流可能是5-羟色胺增强的基础，依赖钙的钾电流SK和混合阳离子电流LH。 Apamin等药物可以减少SK或通过细胞内钙的耗竭。我们发现5-羟色胺会降低IH，并产生类似于阿瓜蛋白产生的峰值的无质量升高后峰值的变化。在我们的初步研究中，我们发现这两种电流的同时减少都会产生乙醇激发的深刻增强。我们已经开发了一个模型来解释这一观察结果。在拟议的研究中，五个具体的目标将寻求探索乙醇激发与5-羟色胺激发的增强之间的关系。特定的目标＃1将在SK和IH封锁期间建立非常低浓度的乙醇的浓度响应曲线。具体的目标＃2将确定乙醇激发的5-羟色胺增强是通过同时减少SK和IH介导的。具体目的＃3和＃4将决定SK和IH的封锁改变DA-VTA神经元的特定膜特性，以及SK和IH阻滞改变了乙醇对特定膜特性的影响。具体目标＃5将使用细胞内无钙的成像来确定钙延长钙蛋白耗竭的钙的细胞内储存。这些研究直接建立在我们对SK和IH封锁乙醇增强的有趣初步观察结果上，并将提供有关神经递质对DA-VTA神经元离子电流的影响如何调节对乙醇激发的敏感性的重要信息。最终，该项目产生的信息可能有助于开发酗酒的药物治疗。