Glycine regulates ethanol intake

描述（由申请人提供）：酒精成瘾的机制仍然不清楚，尽管有充分的文献证明起源于腹侧叶区（VTA）并投射到伏隔核（NAc）的中边缘多巴胺（DA）系统起着关键作用。VTA - DA神经元的输出通常受到强大的gaba介导的突触抑制的限制。然而，对于控制这种重要gaba能突触的因素知之甚少。我们的长期目标是阐明控制gaba能突触的调节机制，作为开发新的酒精疗法的先决条件。本研究提出的具体假设是，中边缘系统中的甘氨酸受体（GlyRs）在控制VTA DA神经元上的gaba能突触和乙醇摄入方面起着主要的调节作用。我们实验室的初步电生理证据表明，GlyRs存在于gaba能末端，它在VTA - DA神经元上形成突触。这些GlyRs的激活减少gaba能传递并增加VTA - DA细胞放电。此外，最近的体内研究表明，将甘氨酸微量注射到NAc或系统给药ORG 25935（甘氨酸转运蛋白1的抑制剂）可减少乙醇摄入量。在这个项目中，我们将在大鼠身上进行实验，大鼠接受了两瓶方案的自我给药训练。具体目标#1将评估VTA GlyRs对自愿乙醇摄入的影响。我们将确定在vta内注射glrs的激动剂和/或拮抗剂对乙醇摄入量和NAc - DA水平的影响。特异性目标#2将描述甘氨酸作用的细胞机制。我们将评估长期饮酒大鼠脑切片VTA - DA神经元记录的电生理信号（如gaba能抑制性突触电流和动作电位）。这项多学科研究的结果可能会为甘氨酸对大脑奖赏通路的影响提供新的见解，并可能引领酗酒者新疗法的发展。

DESCRIPTION (provided by applicant): The mechanism underlying alcohol addiction remains obscure, although it is well documented that the mesolimbic dopamine (DA) system, originating from the ventraltegmental area (VTA) and projecting to the nucleus accumbens (NAc), plays a critical role. The output of VTA DA neurons is normally constrained by powerful GABA-mediated synaptic inhibition. However, little is known about the factors that may govern this important GABAergic synapses. Our long-term goal is to elucidate the regulatory mechanisms controlling the GABAergic synapses as a prerequisite for the development of new therapy of alcoholics. The specific hypothesis behind the proposed research is that the glycine receptors (GlyRs) in the mesolimbic system play a major regulatory role that controls the GABAergic synapses on VTA DA neurons and ethanol intake. Preliminary electrophysiological evidence from our laboratory indicates that GlyRs exist on the GABAergic terminals, which make synapses on VTA DA neurons. Activation of these GlyRs reduces GABAergic transmission and increases VTA DA cell firing. In addition, recent in vivo studies indicate that microinjection of glycine into NAc, or system administration of ORG 25935, an inhibitor of glycine transporter 1, decreases ethanol intake. In this project, we will conduct experiments on rats which are trained for self-administration of ethanol with two-bottle protocol. Specific Aim #1 will assess the effects of VTA GlyRs on voluntary ethanol intake. We will determine the effects of intra-VTA injection of the agonist and/or antagonist of GlyRs on ethanol intake and on NAc DA levels. Specific Aim #2 will characterize the cellular mechanisms of glycine's action. We will assess the electrophysiological signals (e.g. GABAergic inhibitory synaptic currents and action potentials) recorded from VTA DA neurons in brain slices of rats with a long history of ethanol drinking. The result of this multiple disciplinary study may gain new insight into glycine's effects on the brain reward pathways and could lead the development of new therapies of alcoholics. PUBLIC HEALTH RELEVANCE: The mechanism of alcohol addiction remains obscure. Our preliminary studies found that glycine in the mesolimbic system plays an important role in regulating ethanol drinking. This project will investigate the cellular mechanism by which glycine regulates voluntary ethanol drinking. This proposal will bring important information to design rational pharmacotherapeutic interventions in alcoholism.