Novel Molecular Mechanisms of Abusable Drugs

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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.