Role of sigma receptors in ethanol reinforcement

该项目将在波士顿丰富的神经科学社区的波士顿大学进行，涉及Sigma受体，这是哺乳动物特有的结合部位，调节其他神经递质系统，在边缘脑结构中大量表达。药理学研究表明，Sigma受体调节可卡因和甲基苯丙胺的作用。最近，西格玛受体也被提出用来调节乙醇的兴奋特性，这与人类酒精中毒的西格玛受体多态的发现是一致的。然而，直到最近，对sigma受体系统的理解一直受到无法获得特定的、亚选择性配体或缺乏sigma受体亚基的突变小鼠模型的阻碍。此外，Sigma受体在乙醇自愿摄入或自我给药中的作用尚不清楚。目前的多学科应用利用行为、药理学和分子技术来确定在不同的酒精过量消耗模型中，Sigma受体对乙醇奖励和强化的调节作用。将研究两种过量酒精摄入的模型，基因选择的偏爱酒精的大鼠和退出的近交系大鼠在慢性、间歇性暴露于乙醇蒸气期间不依赖，分别强调乙醇的积极和消极的强化特性。 乙醇的自我吸收将被药物调节(特定目标1)， 通过给药新的Sigma受体配体，并通过使用Sigma-1受体KO小鼠在分子上(在特定目的2)。在特定的目标3中，将研究慢性酒精暴露和对酒精的先天偏好对离散边缘脑区SIGM受体蛋白表达的影响。 慢性乙醇暴露和对乙醇的先天偏好对大鼠脑内A受体蛋白表达的影响 将在特定目标3中研究离散的边缘脑区。

The project, to be conducted at the Boston University in the rich neuroscience community of Boston, concerns Sigma receptors, unique mammalian binding sites that modulate other neurotransmitter systems and which are richly expressed in limbic brain structures. Pharmacological studies indicate that sigma receptors modulate actions of cocaine and methamphetamine. Recently, sigma receptors also have been proposed to modulate motivating properties of ethanol, consistent with findings of sigma receptor polymorphisms in human alcoholism. Until very recently, however, the understanding of sigma receptor systems had been hampered by the unavailability of specific, subtj^je-selective ligands or of mutant mouse models that lack sigma receptor subt5T)es. Furthermore, the role of sigma receptors in voluntary intake or self-administration of ethanol are unknown. The present multipdisciplinary application uses behavioral, pharmacological, and molecular techniques to determine the modulatory role of sigma receptors on ethanol reward and reinforcement in distinct models of excessive ethanol consumption. Two models of excess ethanol intake will be studied, genetically selected alcohol-preferring rats and withdrawn outbred rats niade dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol, respectively. Ethhanol self-admlnistrartation will be pharmacologically modulated (Specific Aim 1), through the administration of novel sigma receptor ligands, and molecularly (in Specific Aim 2), Through the use of sigma-1 receptor KO mice. The impact of chronic exposure to ethanol and of innate preference for ethanol on sigm receptor protein expression in discrete limbic brains regions wil lbe investigated in Specific Aim 3. impact of chronic exposure to ethanol and of innate preference for ethanol on a receptor protein expression in discrete limbic brain regions will be investigated in Specific Aim 3.