Thorase Regulation of the Actions of Cocaine

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Thorase Regulation of the Actions of Cocaine Addiction to drugs of abuse such as cocaine is a world-wide health crisis. In the USA there are an estimated 1.5 million current cocaine users, a number that has been relatively stable. Extensive studies have revealed that cocaine, induces plastic changes in the brain that underlie the behavioral changes including changes in expression of AMPA receptors as well as activation of the mechanistic target of rapamycin complex 1 (mTORC1) in the onset and maintenance of cocaine addiction. We discovered Thorase, an AAA+ ATPases that serves to facilitate the disassembly AMPA receptors and recently discovered it also disassembles mTORC1. Our hypothesis is that Thorase is poised to play a pivotal and critical role in the behavioral and cellular responses to cocaine by directing both AMPA receptor expression and mTORC1 activity and thus underlies important changes in dopaminergic neuroplasticity which we will explore in the following Aims. Aim 1: In order to fully comprehend the actions of cocaine on Thorase and mTOR signaling the functional and biochemical interactions of Thorase with mTOR and components of mTORC1 will be explored and defined. Aim 2: The role of Thorase activity on cocaine’s reinforcing properties will be studied. Self-administration and reinstatement to cocaine seeking behavior will be monitored in wild type, Thorase KO and Thorase TG mice. Aim 3: As Rapamycin blocks cocaine induced behaviors in rodents, it is reasonable to predict that cocaine is hyperactivating mTORC1. Since inhibition or genetic deletion of nNOS, and thus NO, has similar effects on cocaine behaviors as rapamycin, and S-nitrosylation inhibits Thorase activity, we hypothesize that cocaine is inhibiting Thorase through S-nitrosylation resulting in hyperactivation of mTORC1 and altering expression of AMPA receptors. Aim 4: Will address whether mTORC1 and Thorase are largely responsible for the proteomic and translational changes following exposure to cocaine. Changes to the transcriptome, translatome and proteome in response to cocaine exposure will be explored. The overarching goal of this project is to define the role of Thorase in the regulation of neuroplastic responses that underlie the addictive behaviors to cocaine.