Corticostriatal Neuroplasticity and Cognition in Methamphetamine Addiction

甲基苯丙胺成瘾中的皮质纹状体神经可塑性和认知

• 批准号: 8661731
• 负责人: Carmela M Reichel
• 金额: $ 33.19万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661731
• 关键词: Address; Affect; Animal Model; Animals; Behavior assessment; Behavioral; Brain; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Corpus striatum structure; Data; Development; Dose; Electrophysiology (science); Functional disorder; Future; Glutamate Receptor; Glutamates; Goals; Human; In Vitro; Individual; Intake; Link; Measurement; Medial; Memory; Memory impairment; Methamphetamine; Methamphetamine dependence; Modafinil; Modeling; Molecular; N-Methylaspartate; Nature; Neurobiology; Neurocognitive Deficit; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Nootropic Agents; Performance; Pharmaceutical Preparations; Pharmacotherapy; Prefrontal Cortex; Process; Rattus; Recording of previous events; Relapse; Rodent Model; Self Administration; Surface; Synaptic Transmission; Techniques; Testing; Treatment outcome; Withdrawal; addiction; attenuation; base; craving; human subject; improved; innovation; insight; interdisciplinary approach; meetings; memory recognition; metabotropic glutamate receptor 2; metabotropic glutamate receptor 5; neuroadaptation; neurochemistry; neurophysiology; neurotransmission; novel; object recognition; receptor expression; receptor function; relating to nervous system; transmission process

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.

描述（由申请人提供）：大鼠的慢性甲基苯丙胺（METH）自我给药为研究人类中甲基成瘾的认知和动机缺陷提供了转化动物模型。该项目由一种多学科方法组成，用于研究甲基苯丙胺引起的认知和动机功能障碍，确定其在皮质谷氨酸能电路中的关键神经生物学底物，以及通过慢性药物治疗的反向METH诱导的变化。具体而言，我们将首先评估具有慢性甲基甲基化，戒断和重新寻求毒品的大鼠新颖对象和现场识别记忆中的对象识别记忆缺陷。我们假设慢性甲基摄入量会对记忆性能产生负面影响，并且缺陷将与谷氨酸受体（AMPA，NMDA，MGLUR2/3和MGLUR5和MGLUR5）和谷氨酸受体依赖性神经元相关，前额叶和周围皮质中的谷氨酸受体依赖性神经元。我们还将检查潜在的认知增强子通过作用于谷氨酸受体来逆转慢性甲基甲基记忆缺陷的能力。我们预测，慢性莫达非尼或MGLUR5变构调节剂（CDPPB）将通过对上述底物作用，逆转甲基甲基甲基素诱导的认知缺陷并减少寻求药物。最后，我们将使用新型基于操作的注意力设置转移任务来确定慢性甲基SA对前额叶皮层依赖性注意处理的影响。这些研究很重要，因为它们将使用行为，神经化学和神经生理技术的多方面组装在翻译相关的甲基甲基成瘾模型中，为慢性甲基甲基诱导的认知性能和神经塑性变化提供新颖的新颖性。最终，该项目将促进我们对MET成瘾认知缺陷的神经底物的理解，以及神经生物学衍生的MET成瘾治疗方法的发展。