Effects of chronic cocaine on cognition and glutamate levels in nonhuman primates

 描述(由申请人提供)：可卡因滥用和依赖是长期存在的重大公共卫生问题。然而，目前还没有针对这些疾病的药物治疗被批准。有慢性可卡因使用史的人表现出认知缺陷，包括冲动和执行功能受损。在那些试图戒烟的人中，认知缺陷会增加复发的可能性，并降低行为干预的有效性。因此，更好地了解慢性可卡因暴露的认知后遗症及其与神经化学异常的关系可能会带来新的治疗方法和新的方法，以优化现有的行为干预。在非人类灵长类动物中进行的受控前瞻性研究将在这一努力中发挥关键作用，因为它们能够进行基线(前可卡因)认知评估，并且因为确定了可卡因暴露的数量和持续时间。此外，这类研究没有人类研究中存在的许多混淆，包括多药滥用和病前/共病的精神和医学障碍。通过这个R21探索/开发项目，我们的目标是建立一个翻译平台，分别使用触摸屏技术和体内超高磁场(9.4特斯拉)质子磁共振波谱(MRS)来评估慢性可卡因自我给药对认知和神经化学的影响。这两种方法都已在我们的实验室中实施，并分别用于评估慢性可卡因对松鼠猴子的认知或MRS影响。我们先前的MRS研究表明，长期服用可卡因后，松鼠猴纹状体细胞内谷氨酸含量增加，这可能与谷氨酸异常导致行为不灵活(例如，冲动)有关。我们将前瞻性地评估慢性可卡因自我管理对习得和逆转学习的影响，对作为复发易感性指标的恢复的影响，以及对大脑谷氨酸水平的影响。然后，我们将检查N-乙酰半胱氨酸(NAC)的短期治疗效果，N-乙酰半胱氨酸已在人类可卡因使用者中显示出减少可卡因使用和纠正大脑谷氨酸异常的前景。我们将评估NAC对认知、谷氨酸水平、恢复以及这些变量之间关系的影响。我们假设，慢性可卡因将损害习得和逆转学习，将促进恢复，并将 增加细胞内谷氨酸水平，NAC治疗将使认知正常化，减少恢复，并降低谷氨酸水平。这些实验将为未来的研究建立一个平台，评估慢性可卡因或其他慢性药物暴露对一些认知领域的认知功能、神经化学的影响，以及评估旨在改善认知、神经化学和可卡因/其他药物治疗结果的新干预措施。

 DESCRIPTION (provided by applicant): Cocaine abuse and dependence are long-standing, significant public health issues. Yet, no drug treatments have been approved for these disorders. People with chronic cocaine use histories exhibit cognitive deficits including impulsivity and impaired executive function. Among those attempting to quit, cognitive deficits increase relapse vulnerability and reduce effectiveness of behavioral interventions. Accordingly, developing a better understanding of the cognitive sequelae of chronic cocaine exposure and their relationships to neurochemical abnormalities may lead to new treatments and new ways to optimize existing behavioral interventions. Controlled prospective studies in nonhuman primates will play a key role in this endeavor because they enable baseline (pre-cocaine) cognitive assessment and because amounts and durations of cocaine exposure are defined. Further, such studies are absent the many confounds present in human studies, including polydrug abuse and pre-/co-morbid psychiatric and medical disorders. With this R21 Exploratory/Developmental project, we aim to establish a translational platform to assess, within individual subjects, effects of chronic cocaine self-administration on cognition and on neurochemistry, using touch screen technology and ultra high magnetic field (9.4 Tesla) in vivo proton magnetic resonance spectroscopy (MRS), respectively. Both methodologies have been implemented in our laboratories and used separately to assess cognition or MRS effects of chronic cocaine in squirrel monkeys. Our prior MRS studies have revealed striatal intracellular glutamate increases after chronic cocaine administration to squirrel monkeys, which may be relevant as glutamate abnormalities contribute to behavioral inflexibility (e.g., impulsivity). We will prospectively assess effects of chronic cocaine self-administration on acquisition and reversal learning, on reinstatement as a measure of relapse vulnerability, and on brain glutamate levels. Then, we will examine effects of short-term treatment with N-acetylcysteine (NAC), which has shown promise in human cocaine users for reducing cocaine use and for correcting brain glutamate abnormalities. We will assess NAC effects on cognition, glutamate levels, reinstatement, and on relationships between these variables. We hypothesize that chronic cocaine will impair acquisition and reversal learning, will enhance reinstatement, and will increase intracellular glutamate levels, and that NAC treatment will normalize cognition, reduce reinstatement, and reduce glutamate levels. These experiments will establish a platform for future studies evaluating effects of chronic cocaine or other chronic drug exposures on cognitive function across a number of cognitive domains, on neurochemistry, and for evaluating novel interventions designed to improve cognition, neurochemistry, and cocaine/other drug treatment outcomes.