Corticostriatal Neuroplasticity and Cognition in Methamphetamine Addiction

描述(申请人提供)：大鼠的慢性甲基苯丙胺(甲基苯丙胺)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一个翻译动物模型。该项目包括一个多学科的方法来研究冰毒引起的认知和动机功能障碍，确定它们在皮质谷氨酸能回路中的关键神经生物学底物，并用慢性药物治疗逆转冰毒引起的改变。具体地说，我们将首先评估有慢性冰毒自我给药、戒断和重新寻求毒品史的大鼠在新物体和物体原地识别记忆中的物体识别记忆缺陷。我们假设，长期摄入冰毒将对记忆表现产生负面影响，这种缺陷将与改变的谷氨酸受体(AMPA、NMDA、mGluR2/3和mGluR5)以及前额叶和周围皮质中谷氨酸受体依赖的神经元活动有关。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冰毒诱导的慢性记忆缺陷的能力。我们预测，慢性莫达非尼或mGluR5变构调节剂(CDPPB)将通过作用于上述底物逆转冰毒诱导的认知障碍和减少药物寻找。最后，我们将使用一种新的基于操作者的注意集转移任务来确定慢性冰毒对前额叶皮质依赖的注意加工的影响。这些研究具有重要意义，因为它们将为慢性冰毒引起的认知表现和神经可塑性的变化提供新的迹象，使用行为、神经化学和神经生理学技术在翻译相关的冰毒成瘾模型中的多方面组合。最终，这个项目将促进我们对冰毒成瘾认知缺陷的神经基础的理解，并开发神经生物学衍生的冰毒成瘾治疗方法。

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.