Ethanol and Peptidergic Systems in the Central Amygdala

杏仁核中央的乙醇和肽能系统

• 批准号: 8333556
• 负责人: Scott D. Moore
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333556
• 关键词: Accounting; Acute; Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohol-Related Disorders; Alcoholism; Amygdaloid structure; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Area; Behavior; Biological; Biological Models; Brain; Brain Stem; Brain region; Cell Nucleus; Chronic; Clinical Research; Collection; Corticotropin-Releasing Hormone; Data; Development; Diagnosis; Diet; Disease; Dopamine; Dopamine Receptor; Drug Addiction; Dynorphins; Emotional; Enkephalins; Esthesia; Ethanol; Ethanol dependence; Euphoria; Event; Feeling; Future; Hour; Hypothalamic structure; In Vitro; Individual; Intervention; Investigation; Laboratories; Lead; Leucine Enkephalin; Link; Liquid substance; Literature; Measurable; Measures; Mediating; Medical; Methods; Morbidity - disease rate; Neurobiology; Neurons; Neuropeptides; Neurotransmitters; Nucleus Accumbens; Operative Surgical Procedures; Opioid; Opioid Peptide; Opioid Receptor; Pathway interactions; Peptide Receptor; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Physiology; Play; Population; Preparation; Process; Property; Receptor Activation; Recovery; Regulation; Research; Rodent; Role; Services; Slice; Stress; Substance abuse problem; Synapses; Synaptic Transmission; System; Therapeutic; Therapeutic Studies; United States Department of Veterans Affairs; Ventral Tegmental Area; Veterans; Withdrawal; Work; alcohol craving; alcohol effect; alcohol exposure; alcohol reinforcement; base; craving; drug of abuse; drug withdrawal; enhancing factor; feeding; kappa opioid receptors; meetings; mortality; nerve supply; neurophysiology; neurotransmission; novel; postsynaptic; public health relevance; receptor sensitivity; response; transmission process

DESCRIPTION (provided by applicant): Ethanol abuse and dependence causes significant morbidity and mortality within the veteran population. In an attempt to discern the neurophysiological basis of substance abuse disorders, the collection of brain nuclei referred to as the amygdala formation has become unequivocally linked to ethanol reinforcement, withdrawal and craving. Specific amygdaloid subnuclei, particularly the central amygdala nucleus (CeA) have been identified as part of a functional system essential to mediating the response to many drugs of abuse, including ethanol. The CeA modulates autonomic and emotional responses via efferent projections to hypothalamic and brainstem areas, and is activated during withdrawal from ethanol. Behaviors dependent on amygdala activity are strongly affected by several endogenous neurotransmitter systems: Corticotropinreleasing factor (CRF), opioid peptides (including enkephalin and dynorphin) and dopamine (DA). These transmitter systems also play powerful roles in mediating effects of ethanol. Drugs of abuse such as ethanol enhance release of DA in the nucleus accumbens (part of the "extended amygdala"); this effect is associated with feelings of well-being and euphoria. Conversely, ethanol withdrawal is often accompanied by high levels of anxiety and is associated with a decrease in DA function and heightened CRF levels in CeA. In addition, manipulation of opioid peptide receptors (either pharmacologically or genetically) alters the amount of voluntary ethanol consumption in experimental animals. Recent anatomical research strongly suggests a role for DA in modulating these peptidergic systems in CeA. Surprisingly, little research has focused on direct physiological effects of these transmitter systems at the cellular and synaptic level in the CeA. Our recent collaborative work has determined that CRF enhances GABAergic mechanisms in the CeA. Furthermore, release of CRF is necessary for the effects of ethanol on GABAergic transmission in CeA. Using an in vitro rodent "brain slice" preparation, our laboratory has recently uncovered a novel local circuit CeA pathway that appears to be largely mediated by the release of endogenous CRF. The magnitude of the observed postsynaptic effect is extremely compelling because endogenous neuropeptide responses have rarely been observed, much less fully characterized. In addition, we now have evidence of tonic activity of opioids in the CeA. These actions tend to oppose the actions of CRF. By characterizing these endogenous peptidergic responses in CeA, we have a unique model system to study effects of applied ethanol in a brain region considered critical to the reinforcing effects of ethanol consumpion. A full investigation of these endogenous peptidergic systems, and their regulation by DA, could help elucidate role of the amygdala in ethanol dependence. This proposed investigation of direct effects of ethanol, CRF, opioid peptides, and DA in the central amygdala may provide significant direction for future clinical studies of the neurobiological substrates of drug dependence and drug withdrawal.

描述（由申请人提供）： 乙醇滥用和依赖导致退伍军人群体中的显著发病率和死亡率。在试图辨别物质滥用障碍的神经生理学基础时，被称为杏仁核形成的脑核团的集合已经与乙醇强化、戒断和渴望明确相关。特定的杏仁核亚核，特别是中央杏仁核（CeA）已被确定为一个功能系统的一部分，必不可少的调解许多药物的滥用，包括乙醇的反应。CeA通过下丘脑和脑干区域的传出投射调节自主神经和情绪反应，并在酒精戒断期间被激活。依赖杏仁核活动的行为受到几种内源性神经递质系统的强烈影响：促肾上腺皮质激素释放因子（CRF），阿片肽（包括脑啡肽和强啡肽）和多巴胺（DA）。这些递质系统在介导乙醇的作用中也起着重要作用。滥用药物，如乙醇，会增强杏仁核（“延伸杏仁核”的一部分）中DA的释放;这种效应与幸福感和欣快感有关。相反，酒精戒断通常伴随着高水平的焦虑，并与DA功能下降和CeA中CRF水平升高相关。此外，操纵阿片肽受体（无论是神经或遗传）改变了 实验动物自愿摄入乙醇的量。最近的解剖学研究强烈表明DA在CeA中调节这些肽能系统的作用。令人惊讶的是，很少有研究集中在直接的生理效应，这些递质系统在细胞和突触水平的CeA。 我们最近的合作工作已经确定CRF增强CeA中的GABA能机制。此外，CRF的释放是乙醇影响CeA GABA能传递的必要条件。使用体外啮齿动物“脑切片”的准备，我们的实验室最近发现了一种新的本地电路CeA途径，似乎在很大程度上是由内源性CRF的释放介导。观察到的突触后效应的大小是非常引人注目的，因为内源性神经肽反应很少被观察到，更不用说充分表征。此外，我们现在有证据表明阿片类药物在CeA中具有滋补活性。这些行动倾向于反对CRF的行动。通过表征CeA中的这些内源性肽能反应，我们有一个独特的模型系统来研究应用乙醇在被认为对乙醇消耗的强化作用至关重要的脑区中的影响。对这些内源性肽能系统及其受DA调节的全面研究有助于阐明杏仁核在乙醇依赖中的作用。这一建议的调查乙醇，CRF，阿片肽，DA在中央杏仁核的直接影响，可能为未来的临床研究的药物依赖和药物戒断的神经生物学底物提供了重要的方向。