GSK3beta signaling in cocaine reward and memory

强迫性寻毒和吸毒行为是成瘾的标志，而这些行为 尽管对个人造成了强烈的负面后果，但仍在继续。不适应的条件学习过程， 与分子和细胞的可塑性一起，在这种强迫行为的发展中起着主要作用。 包括可卡因在内的成瘾药物参与了分子信号通路，这些信号通路参与了 学习过程。一旦学习，接触以前与可卡因有关的线索可能会导致 伴随着强烈的药物渴求而产生的条件性生理反应，这可能会引发复发。 因此，成瘾治疗的一个目标是打破以前学到的积极知识之间的联系 可卡因的主观影响和标志可卡因可获得性的环境线索。为了实现这一目标 目标是，需要关于该电路内的电路和分子信号的详细信息 为了强化和强化可卡因奖励背景记忆。糖原合成酶-3β(GSK3b)是 独一无二地定位于调节神经元功能和可塑性。它在多巴胺介导的行为中很重要。 在记忆过程中，GSK3的活性是可卡因诱导的条件奖赏、多动、 和运动敏感化。与复发相关的是，GSK3b通过暴露在环境中而激活 以前与可卡因配对，重要的是，在可卡因重新激活后抑制GSK3b活性 记忆可以消除先前确定的可卡因地点偏好。该项目将全面解决 假设GSK3b信号对可卡因诱导的奖赏、神经可塑性和 可卡因相关背景记忆的重新巩固。使用有条件的遗传缺失小鼠 模型中，GSK3b介导可卡因诱导的条件奖赏的解剖和细胞底物将 将被澄清。可卡因奖赏所必需的GSK3b信号通路的组成部分 可卡因记忆的重新巩固将被研究，包括GSK3b的下游效应，即 MTORC1复合体。维持可卡因记忆的重要解剖底物将是 重点研究由背侧海马体到杏仁基底外侧核再到核团的环路 伏伏草。另一个目标是将研究扩展到可卡因静脉注射自我给药模型，以 研究可卡因召回后抑制GSK3能否消除寻找可卡因的行为 回忆。关于维持可卡因记忆的过程可能会有什么不同，我们知之甚少 因此，对性别差异的调查是该项目的另一个目标。vbl.使用 这些多学科的方法，我们定位于揭示分子机制和途径 潜在的可卡因奖励、情景记忆、渴望和复发，具有建立GSK3b的潜力 作为治疗学防止寻求可卡因复发的新靶点。

Compulsive drug-seeking and drug-taking behaviors are the hallmark of addiction, and these behaviors continue despite intense negative consequences to the individual. Maladaptive conditioned learning processes, together with molecular and cellular plasticity, play major roles in the development of this compulsive behavior. Addictive drugs including cocaine engage molecular signaling pathways that are involved in associative learning processes. Once learned, exposure to cues previously associated with cocaine can lead to conditioned physiological responses that are accompanied by intense drug craving which can trigger relapse. Hence, a goal of addiction treatment is to break the associations between previously learned positive subjective effects of cocaine and environmental cues that signal cocaine availability. In order to achieve this goal, detailed information is needed about the circuitry and molecular signaling within that circuitry that serves to reinforce and strengthen cocaine reward contextual memories. Glycogen synthase kinase-3beta (GSK3b) is uniquely positioned to regulate neuronal function and plasticity. It is important in dopamine-mediated behaviors and in memory processes, and GSK3 activity is required for cocaine-induced conditioned reward, hyperactivity, and locomotor sensitization. Relevant to relapse, GSK3b is activated by exposure to an environment previously paired with cocaine and, importantly, inhibition of GSK3b activity after reactivation of cocaine memories can abolish a previously established cocaine place preference. This project will address the overall hypothesis that GSK3b signaling is necessary for cocaine-induced reward, neuroplasticity and the reconsolidation of cocaine-associated contextual memories. Using a conditional genetic deletion mouse model, the anatomical and cellular substrates where GSK3b mediates cocaine-induced conditioned reward will be elucidated. Components of the GSK3b signaling pathway that are necessary for cocaine reward and reconsolidation of cocaine memories will be investigated including the downstream effector of GSK3b, the mTORC1 complex. The anatomic substrates of importance for maintenance of cocaine memories will be studied with the focus on a circuit consisting of the dorsal hippocampus to basolateral amygdala to nucleus accumbens. An additional aim will be to extend the studies into a cocaine iv self-administration model in order to investigate if cocaine seeking behaviors can be abolished by inhibition of GSK3 after recall of cocaine memories. Little is known about how the processes governing maintenance of cocaine memories may differ between males and females and hence, investigation of sex differences is another goal of the project. Using these multidisciplinary approaches, we are positioned to reveal molecular mechanisms and pathways underlying cocaine reward, contextual memories, craving and relapse, with the potential of establishing GSK3b as a novel target for therapeutics to prevent relapse to cocaine seeking.