Atypical PKMe in Models of Binge Drinking and Relapse

尽管酒精使用障碍的成本很高，而且普遍存在，但治疗选择有限。 因此，人们对开发新的治疗酒精使用障碍的药物很感兴趣。 新的证据表明，非典型的PKMζ调节与成瘾相关的行为，但对此一无所知 PKMζ对乙醇摄入量的调节。PKMζ是一种重要的mTORc1下游效应蛋白 调节乙醇消耗的信号复合体，已成为ACTG的中心焦点。PKMζ 由Prkcz基因编码，对记忆维持至关重要。脑内Prkcz的表达在 近交系和精选的高酒精饮酒系小鼠，以及C57BL/6小鼠的纹状体 在喝了一轮酒精之后。因此，与乙醇相关的PKMζ的增加可能会促进过度 这表明抑制PKMζ可能是减少酒精消耗的独特策略。Pkmζ可以 通过伏核的作用促进药物的自我给药，因为伏核PKMζ是 可卡因和吗啡的条件奖赏我们提案的中心假设是乙醇 激活NAC中的PKMζ信号，这种激活促进了乙醇的消耗。具体目标1 使用多种互补技术(条件基因敲除PKMζ，显性负性PKMζ突变体 和PKCζ抑制肽)来评估NAC PKMζ是否促进酗酒， 复职，并重新酗酒。特定目标2调查酒精摄入是否激活NAC Pkmζ通过mTORc1信令(与研究构成部分4合作)。特指三考 PKMζ是否通过含有GluA2的AMPA受体促进酗酒 研究表明，PKMζ增加了谷氨酸能突触上的GluA2亚单位。《特定目标4》使用一种新的、 用化学遗传学方法鉴定可能调节乙醇摄入和AMPA的PKMζ底物 受体功能。通过了解乙醇摄入和PKMζ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，作为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.