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

慢性可卡因对非人灵长类动物认知和谷氨酸水平的影响

• 批准号: 8979920
• 负责人: Marc J Kaufman
• 金额: $ 23.7万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8979920
• 关键词: Abstinence; Acetylcysteine; Anterior; Attenuated; Behavior; Behavior Therapy; Behavioral; Brain; Ceftriaxone; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine Users; Cognition; Cognitive; Cognitive deficits; Cognitive remediation; Corpus striatum structure; Development; Discrimination; Discrimination Learning; Disease; Drug Exposure; Economics; Effectiveness; Ethics; Evaluation; Exhibits; Extinction (Psychology); Foundations; Funding; Future; Glutamates; Human; Impulsivity; Individual; Intervention; Laboratories; Lead; Learning; Long-Term Effects; Longitudinal Studies; Magnetic Resonance Spectroscopy; Measures; Medical; Methodology; Nature; Neurotransmitters; Performance; Pharmaceutical Preparations; Placebos; Play; Procedures; Prospective Studies; Protons; Public Health; Reaction Time; Recording of previous events; Relapse; Research; Reversal Learning; Saimiri; Saline; Sampling; Scanning; Self Administration; Staging; Stimulus; Task Performances; Technology; Testing; Time; Training; Treatment outcome; addiction; behavior measurement; cingulate cortex; cocaine exposure; cocaine use; cognitive function; cognitive testing; drug seeking behavior; executive function; improved; in vivo; magnetic field; multidrug abuse; neurochemistry; nonhuman primate; novel; paired stimuli; programs; public health relevance; research study; therapy design; topiramate; touchscreen; vigilance

 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.

 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，但尚未批准针对这些疾病的药物治疗，有长期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。对于那些试图戒烟的人来说，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，更好地了解长期接触可卡因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优化现有行为的新方法。对非人类灵长类动物的对照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，并且因为可卡因暴露的量和持续时间已被确定。此外，此类研究缺乏人类中存在的许多混杂因素。研究，包括多种药物滥用以及发病前/合并的精神和医学疾病。通过这个 R21 探索/发展项目，我们的目标是建立一个转化平台，以评估个体受试者长期自我服用可卡因对认知的影响。在神经化学方面，分别使用触摸屏技术和超高磁场（9.4特斯拉）体内质子磁共振波谱（MRS），这两种方法已在我们的实验室中实施，并分别用于评估慢性可卡因的认知或MRS影响。我们之前的 MRS 研究表明，长期给松鼠猴注射可卡因后，纹状体细胞内谷氨酸会增加，这可能与谷氨酸异常导致行为不灵活有关。 （例如，冲动）。我们将前瞻性地评估长期可卡因自我给药对获得和逆转学习的影响，对作为复发脆弱性衡量标准的恢复以及对大脑谷氨酸水平的影响。 N-乙酰半胱氨酸（NAC），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、谷氨酸的影响。我们发现，长期可卡因会损害习得和逆转学习，会增强恢复能力，并且会影响这些变量之间的关系。 增加细胞内谷氨酸水平，并且 NAC 治疗将使认知正常化，减少恢复并降低谷氨酸水平。这些实验将为未来研究评估长期可卡因或其他慢性药物暴露对多个认知领域认知功能的影响建立一个平台，神经化学，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型干预措施。