ALCOHOL AND NEUROENDOCRINE FUNCTION--OXYTOCIN EXPRESSION

众所周知，酒精摄入可以抑制脑脊液中 下丘脑-神经垂体肽，催产素。最近的研究表明 这种神经肽可能在免疫耐受的形成过程中起重要作用 酒精和其他毒品。因此，在酒精中毒中，一个自我延续的循环 可以发展为酒精抑制催产素的分泌，进而 允许建立公差。这项提议的目标是 探讨酒精摄入量与中枢神经系统功能的关系 催产素轴。重点将放在对OT mRNA变化的研究上 和特定下丘脑和下丘脑外区的多肽水平 对男性和女性急性和慢性饮酒的反应 老鼠。 催产素在特定的下丘脑核团中合成，该核团投射到 大脑的几个不同区域。视上核(SON)发出 催产素主要投射到垂体后叶，而 脑室旁核(PVN)既支配脑组织，也支配脑垂体 涉及记忆、情绪、动机和自主反射的区域。 还有其他下丘脑的副核只合成 然而，这些神经元的轴突目的地并不完全是催产素 明白了。因此，该系统的解剖学特性使其成为 理想的神经系统需要研究。 需要检验的假设是酒精降低了稳态 脑内催产素基因表达及其多肽分泌的研究 与认知和行为相关的领域。这些领域包括： 嗅觉和边缘区域，脑干和脊髓。催产素基因 多肽水平将在显微解剖的核区和 中央投影区。设计实验的目的是：1)确定 急、慢性饮酒对大鼠脑内催产素基因表达的影响 下丘脑核团，以及这种多肽在特定情况下的水平 下丘脑外区域(脊髓、脑干和边缘区域) 雌性和雄性成年大鼠；2)评价慢性酒精对大鼠的影响 催产素系统在生理条件下的反应性 它的分泌受到刺激；3)评估参与 中枢伽马-氨基丁酸(GABA)神经元的相互作用 酒精与酒精暴露动物的中枢催产素轴； 为了检验这一假说，在女性中，性腺类固醇改变了 酒精通过GABA受体对OT通路的影响。这些实验 将利用去卵巢的雌性大鼠和类固醇替代来检查 酒精和GABA模拟物对OT基因和下丘脑外周组织的影响 不是很高。 这些研究将阐明基本的神经内分泌机制 与酗酒有关的疾病，这有望导致 开发治疗该病的新方法。

Alcohol administration is known to inhibit the secretion of the hypothalamic-neurohypophysial peptide, oxytocin. Recent studies suggest that this neuropeptide may be important in the development of tolerance to alcohol and other drugs. Thus, in alcoholism, a self-perpetuating cycle could develop in which alcohol inhibits oxytocin secretion which in turn allows for tolerance to be established. The objective of this proposal is to investigate the relation between alcohol intake and the central oxytocin axis. The focus will be on the study of the changes in OT mRNA and peptide levels in specific hypothalamic and extrahypothalamic regions in response to acute and chronic alcohol consumption in male and female rats. Oxytocin is synthesized in specific hypothalamic nuclei that project to several different areas of the brain. The supraoptic nucleus (SON) sends oxytocin projections primarily to the posterior pituitary while the paraventricular nucleus (PVN) innervates the pituitary as well as brain areas involved in memory, emotion, motivation and autonomic reflexes. There are other accessory hypothalamic nuclei that synthesize only oxytocin however, the axon destination of these neurons is not entirely understood. Thus, the anatomical specificity of this system makes it an ideal neuronal system to study. The hypothesis to be tested is that alcohol decreases steady-state oxytocin mRNA levels as well as secretion of the peptide in specific brain areas associated with cognition and behavior. These areas include: the olfactory and limbic areas, the brainstem and spinal cord. Oxytocin mRNA and peptide levels will be measured in microdissected nuclear areas and central projection areas. Experiments are designed to: 1) determine the effect of acute and chronic alcohol consumption on oxytocin mRNA levels in the hypothalamic nuclei, and levels of this peptide in specific extrahypothalamic areas (spinal cord, brain stem and limbic areas) in female and male adult rats; 2) evaluate the effect of chronic alcohol on the responsiveness of the oxytocin system under physiological conditions in which its secretion is stimulated; 3) evaluate the involvement of central gama-aminobutyric acid (GABA) neurons in the interactions between alcohol and the central oxytocin axis in alcohol exposed animals; and 4) To examine the hypothesis that, in the female, gonadal steroids alter the effect of alcohol on OT pathways via a GABA receptor. These experiments will utilize ovariectomized female rats and steroid replacement to examine the efficacy of alcohol and GABA mimetics on OT mRNA and extrahypothalamic OT levels. These studies will elucidate basic neuroendocrine mechanisms that are involved in the disease of alcoholism which hopefully will lead to the development of new methods for its treatment.