Atypical PKMe in Models of Binge Drinking and Relapse

尽管酒精使用障碍的成本高且普遍存在，但治疗选择有限。 因此，人们对开发新的治疗剂来治疗酒精使用障碍非常感兴趣。 新的证据表明，非典型PKM调节成瘾相关的行为，但没有什么是已知的 PKM可调节乙醇摄入量。PKM β是mTORC 1的重要下游效应子， 信号复合物，调节乙醇的消耗，并已成为ACTG的中心焦点。PKM系列 由Prkcz基因编码，对记忆的维持至关重要。脑Prkcz表达高于 饮用大量乙醇的近交系和选择系小鼠，以及C57 BL/6小鼠的纹状体中 酒精摄入量的影响。因此，乙醇相关的PKM β增加可能促进过度的 这表明PKM抑制可能是减少乙醇消耗的独特策略。PKM 由于NAc PKM是通过在丘脑核（NAc）中的作用促进药物自我给药， 可卡因和吗啡所需的条件奖励我们的建议的中心假设是，乙醇， 激活NAc中的PKM β信号传导，并且这种激活促进乙醇消耗。具体目标1 使用多种互补技术（PKM β的条件性敲除，一种显性阴性PKM β突变体 和PKC β抑制剂肽）来评估NAc PKM β是否促进酒精的过度消耗， 复吸，复饮。具体目标2研究乙醇摄入是否激活NAc PKM通过mTORC 1信号转导（与研究组件4合作）。具体目标3检查 PKM β是否通过含GluA 2的AMPA受体促进酒精的摄入，基于先前的研究， 这项工作表明PKM能增加谷氨酸能突触上的GluA 2亚单位。Specific Aim 4使用了一种新的， 化学遗传学方法来确定PKM的底物，可以调节乙醇的摄入量和AMPA 受体功能通过了解乙醇摄入量和PKM代谢之间的相互作用，我们希望实现 我们的长期目标是确定新的信号通路，这些通路是未来药物开发的目标， 治疗酒精使用障碍。

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.