Glycine regulates ethanol intake

描述(由申请人提供)：酒精成瘾的机制仍然不清楚，尽管有很好的证据表明，起源于腹侧被盖区(VTA)并投射到伏隔核(NAC)的中脑边缘多巴胺(DA)系统发挥着关键作用。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，人们对可能控制这种重要的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。这项研究背后的具体假设是，中脑边缘系统中的甘氨酸受体(GlyRs)在控制VTA DA神经元上的GABA能突触和酒精摄入方面发挥着重要的调节作用。我们实验室的初步电生理证据表明，GlyRs存在于GABA能终末，与VTA DA神经元形成突触。这些GlyRs的激活减少了GABA能传递，增加了VTA DA细胞的放电。此外，最近的体内研究表明，向NAc内微量注射甘氨酸，或系统注射甘氨酸转运蛋白1的抑制剂ORG 25935，可以减少乙醇的摄入量。在这个项目中，我们将在大鼠身上进行实验，这些大鼠接受了两瓶乙醇自我给药的训练。具体目标#1将评估VTA GlyRs对自愿酒精摄入的影响。我们将确定VTA内注射GlyRs激动剂和/或拮抗剂对乙醇摄入量和NAC DA水平的影响。具体目标#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片中VTA DA神经元记录的电生理信号(如GABA能抑制突触电流和动作电位)。这项多学科研究的结果可能会对甘氨酸对大脑奖赏通路的影响有新的认识，并可能引导酒精患者新疗法的开发。 与公共健康相关：酒精成瘾的机制仍然不清楚。我们的初步研究发现，中脑边缘系统中的甘氨酸在调节酒精饮酒方面起着重要作用。该项目将研究甘氨酸调节自愿饮酒的细胞机制。这一建议将为设计合理的酒精中毒药物治疗干预措施提供重要信息。

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.