Orosensory Contributions to Alcohol Ingestion

描述（由申请人提供）：本提案代表了酒精药理学和味觉神经生物学领域的研究人员之间的合作努力，以系统地检查味觉受体和处理食欲口服酒精信息的中枢神经回路对遗传介导的酒精偏好的贡献。虽然在确定介导酒精强化并促进其消耗的生物学机制方面取得了重大进展，但我们对控制口服酒精摄入的启动和维持的复杂神经解剖学回路的理解远未完成。在过去的十年中，来自动物和人类研究的大量证据支持酒精摄入和天然强化甜味物质消费之间存在强大的遗传影响关系，但酒精和甜味摄入遗传共变的机制目前尚不清楚。我们实验室的最新研究结果表明，口服酒精刺激有效地激活孤束核中的甜味反应味觉回路，并且口服甜味受体的药理学阻断直接抑制了这些通路中酒精诱导的活性。新的初步行为数据表明，小鼠T1 r3甜味受体的基因缺失在长期摄入测试中对通常高度偏好的浓度的酒精产生了冷漠。特定目标1下的实验将测量多个选择性繁殖的酒精偏好/非偏好大鼠品系及其非选择性祖系的NST中乙醇味觉信息的神经生理学处理，以检验增强的酒精诱导的中枢甜味回路激活是与遗传介导的酒精偏好相关的一致生物表型的假设。具体目标2下的实验将检查味觉甜味受体阻断对酒精和甜味偏好P、HAD 1、HAD 2和C57 BL品系/品系及其各自的非偏好/非选择品系中对乙醇的心理物理口腔感觉反应的影响，以检验减少甜味途径的口腔酒精刺激将降低口腔感觉介导的乙醇偏好的假设。在这个项目的结论，我们将产生一个有价值的数据解决味觉受体和中枢神经通路的具体贡献传递食欲口服酒精信息的遗传影响的乙醇偏好。更一般地说，这些研究将增强我们对酒精感觉信息的中枢神经系统处理的理解，这是一个目前还不太清楚的领域。

DESCRIPTION (provided by applicant): The present proposal represents a collaborative effort between investigators in the fields of alcohol pharmacology and gustatory neurobiology to systematically examine the contribution of gustatory receptor and central neural circuits processing appetitive oral alcohol information to genetically-mediated alcohol preference. Although significant progress has been made in identifying the biological mechanisms that mediate alcohol reinforcement and contribute to its consumption, our understanding of the complex neuroanatomical circuits that control initiation and maintenance of oral alcohol ingestion is far from complete. A substantial body of evidence from animal and human studies over the last decade has supported a robust genetically-influenced relationship between the ingestion of alcohol and consumption of naturally-reinforcing sweet substances, but the mechanisms underlying inherited co-variation in alcohol and sweet intake are presently unknown. Recent findings from our laboratory have shown that oral alcohol stimulation potently activates sweet-responsive gustatory circuits in the nucleus of the solitary tract and that alcohol-induced activity in these pathways is directly inhibited by pharmacological blockade of oral sweet receptors. New preliminary behavioral data indicate that genetic deletion of the T1r3 sweet taste receptor in mice produces indifference to alcohol in long-term intake tests at concentrations that are normally highly preferred. Experiments under Specific Aim 1 will measure the neurophysiological processing of ethanol gustatory information in the NST across multiple selectively bred alcohol-preferring/-nonpreferring rat lines and their nonselected progenitor lines to test the hypothesis that enhanced alcohol-induced activation of central sweet taste circuits is a consistent biological phenotype associated with genetically-mediated alcohol preference. Experiments under Specific Aim 2 will examine the effects of gustatory sweet receptor blockade on psychophysical orosensory responses to ethanol in alcohol- and sweet-preferring P, HAD1, HAD2, and C57BL lines/strains and their respective nonpreferring/nonselected lines to test the hypothesis that reduction of oral alcohol stimulation of sweet taste pathways will decrease orosensory-mediated ethanol preference. At the conclusion of this project, we will have produced a body of valuable data addressing the specific contribution of gustatory receptor and central neural pathways conveying appetitive oral alcohol information to genetically-influenced ethanol preference. More generally, these studies will enhance our understanding of the central nervous system processing of alcohol sensory information, an area that is currently not well understood.