Regulation of Ethanol Effects on Synaptic Transmission

乙醇对突触传递影响的调节

• 批准号: 8915028
• 负责人: MARISA ROBERTO
• 金额: $ 41.36万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-05 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915028
• 关键词: Abstinence; Acute; Adenylate Cyclase; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcoholism; Alcohols; Amygdaloid structure; Antiepileptic Agents; Anxiety; Behavioral; Biochemical; Brain; Brain region; CRF receptor type 1; Cell Nucleus; Cells; Characteristics; Chronic; Corticotropin-Releasing Hormone; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Down-Regulation; Drug Addiction; Elements; Emotional; Ethanol; Ethanol dependence; Funding; Glutamates; Health; In Vitro; Intake; Isoenzymes; Lead; Measures; Medial; Mediating; Methods; Microdialysis; Molecular; Negative Reinforcements; Neurons; Neurophysiology - biologic function; Norepinephrine; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Predisposition; Presynaptic Receptors; Protein Kinase C; Rattus; Regulation; Relapse; Research; Research Personnel; Role; Second Messenger Systems; Sensory; Shapes; Signal Pathway; Signal Transduction; Slice; Stress; Substance Addiction; Synapses; Synaptic Transmission; System; Techniques; Testing; Therapeutic Agents; Up-Regulation; Whole-Cell Recordings; addiction; alcohol abstinence; alcohol effect; alcohol exposure; alcohol sensitivity; alcoholism therapy; analog; anxiety-like behavior; base; cell type; compulsion; craving; drug withdrawal; dysphoria; gabapentin; gamma-Aminobutyric Acid; glutamatergic signaling; in vivo; negative emotional state; neuroadaptation; norepinephrine system; novel therapeutics; patch clamp; presynaptic; prevent; problem drinker; protein kinase C epsilon; receptor; research study; response; second messenger; synaptic function; transmission process; voltage; withdrawal-induced anxiety

DESCRIPTION (provided by applicant): The central nucleus of the amygdala (CeA) functions as a hub that converts emotionally relevant sensory information into appropriate behavioral and physiological responses, and plays a crucial role in anxiety-like behavior associated with ethanol dependence and withdrawal. Notably, both the corticotropin-releasing factor (CRF) and norepinephrine (NE) systems are critical in behavioral aspects of addiction, including the anxiogenic effects of drug withdrawal. We hypothesize that ethanol dependence induces neuroadaptations in the CeA and that many of these neuroadaptations may persist after cessation of ethanol exposure. Therefore, we propose to investigate whether or not the changes in signal transduction and synaptic functions seen in the CeA persist after prolonged ethanol withdrawal (abstinence) for 1 and 2 weeks. The previous funding period identified critical findings in the understanding of acute alcohol effects and alcohol dependence in the medial subdivision of the CeA. We demonstrated that corticotropin-releasing factor 1 (CRF1) receptors are involved in the ethanol-induced increase in GABA release in CeA and the CRF system is up-regulated after ethanol dependence. Notably, chronic CRF1 antagonist treatment blocked alcohol dependence-induced increases in ethanol consumption. Both the protein kinase C epsilon (PKCepsilon) and adenylate cyclase/protein kinase A (AC/PKA) transduction pathways are involved in mediating the CRF and ethanol effects on GABA release. Ethanol dependence downregulated the GABAB system and gabapentin (a structural analogue of GABA) reversed several behavioral aspects of ethanol dependence. We also identified long-lasting neuroadaptations induced by ethanol dependence in the glutamatergic systems. Based on these combined findings, the research plan of the present competitive renewal will be to continue studying (in vitro and in vivo) the presynaptic mechanisms of ethanol and the neuroadaptations within the CeA during the development of alcohol dependence, with a focus on newly identified intracellular pathways involved in ethanol, CRF and NE effects in the CeA. Since there is no data on the persistence of such neuroadaptive changes after cessation of ethanol exposure, we propose to study neural function during ethanol abstinence and characterize how long those neuroadaptative changes last. The general hypothesis is that chronic ethanol and dependence alter the CRF and NE systems and their effects on CeA GABA and glutamate signaling through common cellular systems to induce a maladaptation in neural function that sensitizes ethanol withdrawal-induced anxiety-like behavior. Given the extreme importance of this observation, it is imperative to provide data that can elucidate the cellular basis of the susceptibility of alcoholics to stress and relapse. A better understanding of the neuroadaptations shaping the synaptic networks involved in ethanol dependence represents a challenge to alcohol researchers and will be useful toward uncovering new therapeutic agents to alleviate alcohol dependence and prevent relapse.

描述（由申请人提供）：杏仁核（CEA）的中央核是将情感相关的感觉信息转化为适当的行为和生理反应的中心，并且在与乙醇依赖和戒断相关的焦虑样行为中起着至关重要的作用。值得注意的是，皮质激素释放因子（CRF）和去甲肾上腺素（NE）系统在成瘾的行为方面至关重要，包括药物戒断的焦虑作用。我们假设乙醇依赖性诱导CEA中的神经适应性，并且在停止乙醇暴露后可能会持续许多这些神经适应。因此，我们建议研究在延长乙醇戒断（节制）1和2周后，CEA中的信号转导和突触功能的变化是否持续存在。上一个资金期确定了在CEA内侧细分中了解急性酒精效应和酒精依赖性的关键发现。我们证明了促肾上腺素释放因子1（CRF1）受体参与乙醇诱导的CEA中GABA释放的增加，并且CRF系统在乙醇依赖性后被上调。值得注意的是，慢性CRF1拮抗剂治疗阻止了酒精依赖性诱导的乙醇消耗量的增加。蛋白激酶C Epsilon（PKCepsilon）和腺苷酸环化酶/蛋白激酶A（AC/PKA）转导途径都参与介导CRF和乙醇对GABA释放的效应。乙醇依赖性下调了GABAB系统和Gabapentin（GABA的结构类似物）逆转了乙醇依赖性的几个行为方面。我们还确定了谷氨酸能系统中乙醇依赖性引起的长期神经适应。基于这些合并的发现，本竞争性更新的研究计划将是继续研究（体外和体内）乙醇的突触前机制以及在酒精依赖发展期间CEA内CEA内的神经适应性，重点是CEA中参与乙醇，CRF和NE效应的细胞内途径。由于没有关于乙醇暴露停止后这种神经适应性变化的持久性的数据，因此我们建议在抗乙醇戒断过程中研究神经功能，并表征这些神经适应性变化的时间。一般的假设是，慢性乙醇和依赖性改变了CRF和NE系统及其对CEA GABA和谷氨酸信号的影响通过常见的细胞系统，以诱导神经功能中的疾病，从而使乙醇戒断诱导的焦虑样行为敏感。考虑到这一观察结果的极为重要，必须提供可以阐明酒精中毒对压力和复发易感性的细胞基础的数据。更好地理解塑造乙醇依赖的突触网络的神经适应性对酒精研究人员的挑战，将有助于发现新的治疗剂以减轻酒精依赖并防止复发。