Novel Molecular Mechanisms of Abusable Drugs

项目摘要-Snyder项目 我们的实验室长期以来一直专注于大脑中的分子信号系统，这些系统是脑部运动的基础 精神药物，尤指可滥用药物。本提案涉及当前感兴趣的两个领域。 长期以来，人们都知道可卡因会以适度的效力损害单胺的运输。我们最近发现了一种 非常高亲和力的可卡因‘受体’。仅0.1毫微米的可卡因就能在皮质培养物中诱导自噬， 比药物的其他作用强几千倍。我们鉴定出BASP-1蛋白是明显的 可卡因目标。我们建议进行研究，以阐明可卡因-BASP-1联系及其与精神活动的相关性。 可卡因。 在第二个项目中，我们将探索氯胺酮是如何通过mTOR产生抗抑郁作用的。我们最近 建立了NMDA信号触发NO生成亚硝酸甘油醛的相关途径 磷酸脱氢酶(GAPDH)与泛素E3连接酶Siah1的复合体。在这个建筑群中，Siah1 降解小G蛋白Rheb，这是mTOR的生理刺激，从而导致mTOR降低 活动。通过阻断NMDA受体，氯胺酮引发了相反的过程，mTOR增强。利用一种 不同的代理人，我们建议解释这个信号系统，以努力理解 氯胺酮的精神分裂/抗抑郁作用，并有望导致更有效/更安全的治疗。

Project Summary – Snyder Project Our laboratory has long focused on molecular signaling systems in the brain that underlie actions of psychotropic drugs, especially abusable agents. The present proposal addresses two areas of current interest. Cocaine has long been known to impair monoamine transport with modest potency. We recently discovered a very high affinity cocaine `receptor.' As little as 0.1 nM cocaine induces autophagy in cortical cultures, thousands of times more potent than other actions of the drug. We identified BASP-1 protein as the apparent cocaine target. We propose studies to elucidate cocaine-BASP-1 links and their relevance to psychoactivity of cocaine. In a second project, we will explore how ketamine elicits its antidepressant actions via mTOR. We recently established a relevant pathway wherein NMDA signaling triggers NO generation to nitrosylate glyceraldehyde phosphate dehydrogenase (GAPDH) in a complex with the ubiquitin E3-ligase Siah1. In this complex, Siah1 degrades the small G protein Rheb, a physiologic stimulus for mTOR, thereby leading to diminished mTOR activity. By blocking NMDA receptors, ketamine elicits the reverse process, mTOR enhancement. Utilizing a variety of agents, we propose to explicate this signaling system in an effort to understand psychotomimetic/antidepressant actions of ketamine and, hopefully, lead to more effective/safer therapies.