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PKM？调节与成瘾有关的行为，但对此一无所知 PKM对乙醇摄入量的调节。PKM？是蛋白质mTORC1的重要下游效应因子 调节乙醇消耗的信号复合体，已成为ACTG的中心焦点。PKM？ 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，与酒精相关的PKM增加可能会促进过度 饮酒，这表明抑制PKM？可能是减少酒精消耗的独特策略。PKM？可能 伏核PKM是通过伏核的活动促进药物的自我给药 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PKM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(有条件地敲除显性负性PKM突变体 和一种PKC抑制肽)，以评估NAC PKM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 Pkm？通过mTORC1信令(与研究构成部分4合作)。特指三考 PKM是否通过含有GluA2的AMPA受体促进酗酒 研究表明，PKM？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PKM底物 受体功能。通过了解乙醇摄入和PKM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 PKM¿ regulates addiction-related behavior, but nothing is known about PKM¿ regulation of ethanol intake. PKM¿ is an important downstream effecter of mTORC1, a protein signaling complex that regulates ethanol consumption and has become a central focus of the ACTG. PKM¿ 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 PKM¿ may promote excessive drinking, suggesting PKM¿ inhibition could be a unique strategy to reduce ethanol consumption. PKM¿ may promote drug self-administration through actions in the nucleus accumbens (NAc) since NAc PKM¿ is required conditioned reward for cocaine and morphine The central hypothesis of our proposal is that ethanol activates PKM¿ signaling in the NAc, and that this activation promotes ethanol consumption. Specific Aim 1 uses multiple complementary techniques (conditional knockout of PKM¿, a dominant-negative PKM¿ mutant and a PKC¿ inhibitor peptide) to assess whether NAc PKM¿ promotes binge ethanol consumption, reinstatement, and relapse to drinking. Specific Aim 2 investigates whether ethanol intake activates NAc PKM¿ through mTORC1 signaling (in collaboration with Research Component 4). Specific Aim 3 examines whether PKM¿ promotes binge ethanol intake through GluA2-containing AMPA receptors, based on previous work indicating that PKM¿ increases GluA2 subunits at glutamatergic synapses. Specific Aim 4 uses a new, chemical genetics approach to identify PKM¿ substrates that may regulate ethanol intake and AMPA receptor function. By understanding the interaction between ethanol intake and PKM¿, 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.