Ethanol and Peptidergic Systems in the Central Amygdala

描述(由申请人提供)： 酒精滥用和依赖会在退伍军人中造成严重的发病率和死亡率。为了辨别物质滥用障碍的神经生理学基础，被称为杏仁核的大脑核团的收集已明确地与酒精强化、戒断和渴求有关。特定的杏仁核亚核，特别是杏仁中央核(CEA)被认为是调节包括乙醇在内的许多药物滥用反应所必需的功能系统的一部分。CEA通过向下丘脑和脑干区域的传出投射来调节自主神经和情绪反应，并在戒酒期间被激活。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)。这些递质系统在乙醇的调节作用中也发挥着强大的作用。滥用药物，如乙醇，会增加伏隔核(杏仁核的一部分)中DA的释放；这种影响与幸福感和欣快感有关。相反，酒精戒断往往伴随着高度的焦虑，并与多巴胺功能下降和CEA中CRF水平升高有关。此外，阿片肽受体的操作(药理学或遗传学)也会发生改变。 实验动物的自愿酒精消耗量。最近的解剖学研究有力地表明，DA在调节CEA中的这些肽能系统中发挥了作用。令人惊讶的是，很少有研究集中在CEA中这些递质系统在细胞和突触水平上的直接生理影响。 我们最近的合作工作确定了CRF增强CEA中的GABA能机制。此外，在乙醇对CEA中GABA能传递的影响中，CRF的释放是必需的。使用啮齿动物的体外“脑片”制剂，我们的实验室最近发现了一个新的局部电路CEA途径，似乎主要是由内源性CRF的释放介导的。观察到的突触后效应的大小是非常令人信服的，因为内源性神经肽反应很少被观察到，更不用说完全描述了。此外，我们现在有证据表明，阿片类药物在CEA中具有补药活性。这些行动倾向于反对CRF的行动。通过表征CEA中的这些内源性多肽反应，我们有了一个独特的模型系统来研究施加乙醇对大脑区域的影响，该区域被认为是酒精消耗增强效应的关键。对这些内源性多肽能系统的充分研究，以及DA对它们的调节，可能有助于阐明杏仁核在酒精依赖中的作用。这项关于酒精、CRF、阿片肽和多巴胺在中央杏仁核的直接作用的研究可能为未来药物依赖和药物戒断的神经生物学底物的临床研究提供重要的方向。

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.