Corticostriatal Neuroplasticity and Cognition in Methamphetamine Addiction

描述（由申请人提供）：大鼠长期甲基苯丙胺（甲基）自我给药为研究人类甲基苯丙胺成瘾的认知和动机缺陷提供了转化动物模型。该项目包括一个多学科的方法来研究甲基诱导的认知和动机功能障碍，确定其关键的神经生物学底物在皮层神经元能电路，并扭转甲基诱导的变化与慢性药物治疗。具体来说，我们将首先评估对象识别记忆缺陷的新的对象和对象的位置识别记忆的大鼠与历史的慢性甲基自我管理，退出，并重新寻求药物。我们假设，慢性甲基摄入会对记忆表现产生负面影响，并且这种缺陷与前额叶和嗅周皮质中谷氨酸受体（AMPA，NMDA，mGluR 2/3和mGluR 5）和谷氨酸受体依赖性神经元活动的改变有关。我们还将研究潜在的认知增强剂通过作用于谷氨酸受体来逆转慢性甲基诱导的记忆缺陷的能力。我们预测，慢性莫达非尼或mGluR 5变构调节剂（CDPPB）将逆转甲基诱导的认知缺陷，并通过作用于上述底物减少药物寻求。最后，我们将使用一种新的基于操作性的注意定势转移任务来确定慢性甲安非他明对前额叶皮层依赖的注意加工的影响。这些研究是重要的，因为他们将提供新的洞察力慢性甲基诱导的认知性能和神经可塑性的变化，使用多方面的组装行为，神经化学和神经生理学技术在一个与甲基成瘾相关的模型。最终，该项目将促进我们对冰毒成瘾认知缺陷的神经基质的理解，以及冰毒成瘾神经生物学衍生治疗的发展。

DESCRIPTION (provided by applicant): Chronic methamphetamine (meth) self-administration in rats provides a translational animal model for the study of cognitive and motivational deficits of meth addiction in humans. This project consists of a multidisciplinary approach to study meth-induced cognitive and motivational dysfunctions, determine their critical neurobiological substrates in cortical glutamatergic circuitry, and reverse meth-induced changes with chronic pharmacotherapy. Specifically, we will first assess object recognition memory deficits in novel object and object-in-place recognition memory in rats with a history of chronic meth self-administration, withdrawal, and renewed drug-seeking. We hypothesize that chronic meth intake will negatively affect memory performance and that deficits will be related to altered glutamate receptors (AMPA, NMDA, mGluR2/3, and mGluR5) and glutamate receptor dependent neuron activity in the prefrontal and perirhinal cortices. We will also examine the ability of potential cognitive enhancers to reverse chronic meth-induced memory deficits by acting on glutamate receptors. We predict that chronic modafinil or an mGluR5 allosteric modulator (CDPPB) will reverse meth-induced cognitive deficits and reduce drug-seeking by acting on the aforementioned substrates. Finally, we will determine the impact of chronic meth SA on prefrontal cortex dependent attentional processing using a novel operant based attentional set-shifting task. These studies are significant in that they will provide novel insighs on chronic meth-induced changes in cognitive performance and neuroplasticity using a multifaceted assembly of behavioral, neurochemical, and neurophysiological techniques in a translationally relevant model of meth addiction. Ultimately, this project will advance our understanding of the neural substrates of cognitive deficits in meth addiction and the development of neurobiologically derived treatments for meth addiction.