Understanding the Neurobiological Correlates of Ethanol's Aversive Actions

了解乙醇厌恶行为的神经生物学相关性

• 批准号: 8649445
• 负责人: Elizabeth J Glover
• 金额: $ 4.92万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649445
• 关键词: Abstinence; Acute; Address; Alcohol consumption; Alcohol dependence; Alcohols; Aversive Stimulus; Behavior; Behavioral; Behavioral Paradigm; Brain region; Cell Nucleus; Cells; Cessation of life; Chronic; Cocaine; Cues; Data; Dependence; Development; Electrophysiology (science); Environment; Equilibrium; Ethanol; Ethanol dependence; Exposure to; Extinction (Psychology); Functional disorder; Future; Heavy Drinking; Immunohistochemistry; Individual; Knowledge; Label; Lesion; Measures; Mediating; Methods; Midbrain structure; Nature; Neurobiology; Neurons; Opiates; Outcome; Pathway interactions; Pharmaceutical Preparations; Play; Population; Prefrontal Cortex; Procedures; Process; Property; Rattus; Relapse; Reporting; Research; Research Personnel; Rewards; Rodent; Rodent Model; Role; Shock; Signal Pathway; Signal Transduction; Slice; Stimulus; Substantia nigra structure; Synapses; Taste Perception; Testing; Tracer; Training; Ventral Tegmental Area; Work; addiction; alcohol effect; alcohol exposure; alcohol reward; alcohol seeking behavior; alcohol use disorder; base; classical conditioning; design; dopaminergic neuron; drinking; drinking behavior; drug of abuse; experience; hippocampal pyramidal neuron; in vivo; information processing; innovation; insight; interest; neurobiological mechanism; novel; optogenetics; patch clamp; public health relevance; research study; response

DESCRIPTION (provided by applicant): The propensity to drink alcohol can be thought of as a balance between ethanol's rewarding (use-promoting) and aversive (use-limiting) properties. Accordingly, individuals who experience fewer negative effects of alcohol are more likely to drink heavily and develop alcohol use disorders. In addition, alcohol dependence is associated with increased tolerance to the aversive properties of alcohol, which is likely to facilitate continued drinking in addicts and relapse during abstinence. While a significant body of research has focused on the use- promoting properties of alcohol and their involvement in addiction, much less has been done to investigate the neurobiological correlates of alcohol's use-limiting properties and their role in the progression to dependence. Recently, however, a midbrain region known as the rostromedial tegmental nucleus (RMTg) was identified and characterized for its involvement in negative reward prediction error and the behavioral response to aversive stimuli through its prominent inhibitory control over dopamine neurons. Interestingly, the prelimbic (PrL) cortex, which is involved in signaling the salience of environmental stimuli, sends a very dense projection to the RMTg. The present proposal will test a novel hypothesis that the PrL cortex relays information about the aversive properties of conditioned environmental stimuli --- including information related to the aversive actions of alcohol --- via its projection to the RMTg. It is further hypothesized that modulation of aversive signals by the RMTg plays an important role in modulating alcohol drinking, and that the normal processing of aversive properties of alcohol by the RMTg is altered by chronic alcohol exposure. An innovative set of studies is proposed to examine the role of the role of the RMTg in mediating the aversive properties of alcohol. Aim 1 will examine Fos induction following ethanol-induced conditioned taste aversion (CTA) using retrograde tract tracing in combination with immunohistochemistry to confirm the involvement of the PrL-RMTg pathway in signaling alcohol's aversive actions. These studies will also examine the effect of inhibition of this pathway on the development of ethanol-induced CTA using in vivo optogenetics to inhibit RMTg-projecting PrL neurons. Aim 2 will investigate the effect of inhibition of the PrL-RMTg pathway on ethanol-seeking and drinking behavior using in vivo optogenetics procedures in combination with operant behavior. Aim 3 will determine the effect of alcohol dependence on the synaptic response of RMTg neurons to input from PrL cortex. The results of these studies will provide new insights into the role of the RMTg in alcohol drinking and dependence and will help to address the gap in our understanding of the neurobiological mechanisms that contribute to the addictive process.

描述（由申请人提供）：饮酒倾向可以被认为是乙醇的奖励（促进使用）和厌恶（限制使用）特性之间的平衡。因此，经历酒精负面影响较少的人更有可能大量饮酒并患上酒精使用障碍。此外，酒精依赖与对酒精厌恶特性的耐受性增加有关，这可能会促进成瘾者继续饮酒并在戒酒期间复发。虽然大量研究集中在酒精的促进使用特性及其与成瘾的关系上，但对酒精的使用限制特性及其在成瘾过程中的作用的神经生物学相关性的研究却少之又少。然而，最近，一个被称为嘴内侧被盖核（RMTg）的中脑区域被识别和表征，因为它通过对多巴胺神经元的显着抑制控制参与负奖励预测错误和对厌恶刺激的行为反应。有趣的是，前边缘 (PrL) 皮层负责发出环境刺激的显着性信号，它向 RMTg 发送非常密集的投射。目前的提议将测试一个新的假设，即 PrL 皮层通过向 RMTg 的投射来传递有关条件环境刺激的厌恶特性的信息，包括与酒精的厌恶行为相关的信息。进一步假设，RMTg 对厌恶信号的调节在调节饮酒中起着重要作用，并且 RMTg 对酒精厌恶特性的正常处理会因长期酒精暴露而改变。提出了一组创新的研究来检验 RMTg 在调节酒精厌恶特性中的作用。目标 1 将使用逆行道追踪结合免疫组织化学检查乙醇诱导的条件性味觉厌恶 (CTA) 后 Fos 的诱导，以确认 PrL-RMTg 通路参与信号酒精厌恶行为。这些研究还将利用体内光遗传学抑制 RMTg 投射的 PrL 神经元，研究抑制该通路对乙醇诱导的 CTA 发育的影响。目标 2 将利用体内光遗传学程序与操作行为相结合，研究抑制 PrL-RMTg 通路对乙醇寻求和饮酒行为的影响。目标 3 将确定酒精依赖对 RMTg 神经元对 PrL 皮层输入的突触反应的影响。这些研究的结果将为 RMTg 在饮酒和酒精依赖中的作用提供新的见解，并将有助于弥补我们对导致成瘾过程的神经生物学机制的理解上的差距。