Atypical PKMe in Models of Binge Drinking and Relapse

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Despite the high cost and widespread prevalence of alcohol use disorders, treatment options are limited. Thus, there is considerable interest in developing new therapeutic agents to treat alcohol use disorders. New evidence suggests that atypical PKMζ regulates addiction-related behavior, but nothing is known about PKMζ regulation of ethanol intake. PKMζ is an important downstream effecter of mTORC1, a protein signaling complex that regulates ethanol consumption and has become a central focus of the ACTG. PKMζ is encoded by the Prkcz gene and is critical for memory maintenance. Brain Prkcz expression is greater in inbred and selected lines of mice that drink high amounts of ethanol, and in the striatum of C57BL/6 mice after a single bout of ethanol intake. Thus, ethanol-related increases in PKMζ may promote excessive drinking, suggesting PKMζ inhibition could be a unique strategy to reduce ethanol consumption. PKMζ may promote drug self-administration through actions in the nucleus accumbens (NAc) since NAc PKMζ is required conditioned reward for cocaine and morphine The central hypothesis of our proposal is that ethanol activates PKMζ signaling in the NAc, and that this activation promotes ethanol consumption. Specific Aim 1 uses multiple complementary techniques (conditional knockout of PKMζ, a dominant-negative PKMζ mutant and a PKCζ inhibitor peptide) to assess whether NAc PKMζ promotes binge ethanol consumption, reinstatement, and relapse to drinking. Specific Aim 2 investigates whether ethanol intake activates NAc PKMζ through mTORC1 signaling (in collaboration with Research Component 4). Specific Aim 3 examines whether PKMζ promotes binge ethanol intake through GluA2-containing AMPA receptors, based on previous work indicating that PKMζ increases GluA2 subunits at glutamatergic synapses. Specific Aim 4 uses a new, chemical genetics approach to identify PKMζ substrates that may regulate ethanol intake and AMPA receptor function. By understanding the interaction between ethanol intake and PKMζ, we hope to achieve our long-term goal of identifying novel signaling pathways that are targets for future development of drugs to treat alcohol use disorders.