Corticostriatal Neuroplasticity and Cognition in Methamphetamine Addiction

描述（由申请人提供）：大鼠慢性自我给药甲基苯丙胺（冰毒）为研究人类冰毒成瘾的认知和动机缺陷提供了一个可翻译的动物模型。本项目采用多学科方法研究冰毒诱导的认知和动机功能障碍，确定其在皮质谷氨酸能回路中的关键神经生物学底物，并通过慢性药物治疗逆转冰毒诱导的变化。具体来说，我们将首先评估具有慢性冰毒自我服用史、戒断史和重新寻求药物史的大鼠在新物体和物体就地识别记忆中的物体识别记忆缺陷。我们假设慢性冰毒摄入会对记忆表现产生负面影响，并且记忆缺陷与谷氨酸受体（AMPA、NMDA、mGluR2/3和mGluR5）的改变以及前额叶和周围皮层中谷氨酸受体依赖的神经元活性有关。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冰毒诱导的记忆缺陷的能力。我们预测慢性莫达非尼或mGluR5变速调节剂（CDPPB）将通过作用于上述底物来逆转甲基苯丙胺诱导的认知缺陷并减少药物寻找。最后，我们将使用一种新的基于操作的注意设置转移任务来确定慢性冰毒SA对前额叶皮层依赖的注意加工的影响。这些研究具有重要意义，因为它们将在冰毒成瘾的翻译相关模型中使用行为，神经化学和神经生理学技术的多方面组合，为慢性冰毒诱导的认知表现和神经可塑性变化提供新的见解。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，以及对冰毒成瘾的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.