Targeting cell signaling pathways to disrupt drug abuse

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Project Summary Drug abuse is an enormous public health problem. Accordingly, there is an urgent need to improve our understanding of the molecular mechanisms underlying drug abuse, as this information is vital to developing effective strategies to combat this disorder. Therefore, the overall goal of the Johns Hopkins Drug Abuse Research Center is to catalyze progress in defining the signaling pathways that mediate actions of drugs of abuse. To help achieve this goal, the Center will focus on three specific aims: 1) to catalyze synergistic interactions among Center laboratories investigating molecular actions of drug abuse, 2) to encourage application of innovative approaches to this field, and 3) to help train leaders in drug abuse research. Each of the Center laboratories will focus on innovative topics of research that will benefit from synergistic interactions with other Center laboratories. The Worley lab will study mechanisms of mTORC1 activation and its role in mediating the reinforcing properties of cocaine. The Dawson lab will study Thorase, a member of the AAA+ ATPase family, that regulates synaptic plasticity. In particular, recent studies indicate that Thorase plays a key role in regulating disassembly of mTORC1 signaling complexes. Thus, these studies are highly synergistic with those of the Worley lab. The Baraban lab will study the role of the microRNA system in dopamine signaling. They have found that mice lacking the translin/trax RNase complex, a key enzyme that mediates degradation of a subset of microRNAs, produces robust alterations in behavioral responses to cocaine. The Snyder lab will pursue two recent discoveries. One project will focus on defining the role of the Rheb/mTOR signaling pathway in mediating behavioral effects of ketamine, which links directly to studies conducted by the Worley and Dawson labs. Furthermore, nitrosylation plays a major role in regulating both Rheb and Thorase, providing another node of synergistic interaction. The second project is based on the unexpected observation that cocaine, at nanomolar concentrations, triggers autophagy, a process intimately linked to mTOR signaling. As cocaine exerts its classic behavioral effects in the micromolar range, these findings suggest that it also affects cellular function via a novel, high affinity “receptor”. The Snyder lab will build on its identification of a candidate high affinity “receptor” for cocaine to pursue studies aimed at elucidating its function. The Center will establish a Behavioral Core to conduct self-administration assays in mice. As each laboratory uses genetic manipulations in mice to study cell signaling pathways relevant to cocaine action, the Behavioral Core will be an integral, shared facility critical for evaluating the impact of manipulating these pathways on cocaine's reinforcing properties.