ALCOHOL AND NEUROENDOCRINE FUNCTION--OXYTOCIN EXPRESSION

已知酒精给药可抑制 下丘脑神经垂体肽催产素最近的研究表明 这种神经肽可能在耐受性的发展中很重要， 酒精和其他毒品。因此，在酒精中毒中， 酒精会抑制催产素的分泌， 允许建立公差。 本提案的目的是 研究酒精摄入与中枢神经系统的关系， 催产素轴重点研究OT mRNA的变化 和特定下丘脑和下丘脑外区域的肽水平 男性和女性对急性和慢性饮酒反应 大鼠 催产素在特定的下丘脑核团中合成， 大脑的几个不同区域视上核（SON） 催产素主要投射到垂体后叶， 室旁核（PVN）支配垂体和大脑 涉及记忆、情感、动机和自主反射的区域。 下丘脑还有其他辅助核团， 然而，催产素，这些神经元的轴突目的地并不完全是 明白 因此，该系统的解剖学特异性使其成为 理想的神经系统来研究。 待检验的假设是酒精降低稳态 催产素mRNA水平以及特定脑中肽的分泌 与认知和行为相关的区域。这些领域包括： 嗅觉和边缘系统脑干和脊髓催产素mRNA 和肽水平将在显微切割的核区域中测量， 中央投影区。实验旨在：1）确定 急性和慢性酒精消耗对催产素mRNA水平的影响 下丘脑核，以及这种肽在特定 下丘脑外区（脊髓、脑干和边缘区） 雌性和雄性成年大鼠; 2）评价慢性酒精对 催产素系统在生理条件下的反应性 其中其分泌被刺激; 3）评估参与 中枢γ-氨基丁酸（GABA）神经元在 酒精和酒精暴露动物的中央催产素轴;以及4） 为了验证这一假设，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 将利用切除卵巢的雌性大鼠和类固醇替代来检查 乙醇和GABA模拟物对OT mRNA和下丘脑外的作用 OT水平。 这些研究将阐明基本的神经内分泌机制， 与酒精中毒有关，这有望导致 开发新的治疗方法。

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.