Varenicline-associated alterations in dopamine D2-type receptors, self-control, and decision making in methamphetamine users

甲基苯丙胺使用者中与伐尼克兰相关的多巴胺 D2 型受体、自我控制和决策的改变

• 批准号: 9816563
• 负责人: Megan N McClintick
• 金额: $ 6.16万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816563
• 关键词: Aftercare; Age; Agonist; Animals; Behavior Therapy; Behavioral Assay; Binding; Brain; Centers for Disease Control and Prevention (U.S.); Chantix; Characteristics; Chronic; Clinical Trials; Cognitive deficits; Corpus striatum structure; DRD2 gene; DSM-V; Decision Making; Disease; Dopamine; Double-Blind Method; Dropout; Enrollment; FDA approved; Functional Imaging; Functional Magnetic Resonance Imaging; Goals; Grant; Human; Impairment; Individual; Link; London; Measures; Methamphetamine; Midbrain structure; Multimodal Imaging; Neurophysiology - biologic function; Nicotinic Receptors; Participant; Performance; Pharmaceutical Preparations; Placebos; Positron-Emission Tomography; Prefrontal Cortex; Process; Psychostimulant dependence; Public Health; Rattus; Reaction Time; Reporting; Research; Residential Treatment; Rest; Reversal Learning; Rewards; Risk; Risk-Taking; Role; Seeds; Self Administration; Self-control as a personality trait; Sex Differences; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Time; Treatment outcome; Up-Regulation; Ventral Tegmental Area; Work; acetylcholine receptor agonist; addiction; analog; base; behavior measurement; behavior test; cognitive control; cognitive function; cognitive performance; cognitive task; design; discount; discounting; effective therapy; exercise training; flexibility; human subject; improved; indexing; meetings; methamphetamine use; methamphetamine user; molecular imaging; neurochemistry; neuropsychiatry; overdose death; receptor; recruit; relating to nervous system; repaired; resilience; sex; smoking cessation; stimulant abuse; stimulant use; stimulant use disorder; success; therapeutic development; therapeutic target; treatment group; varenicline

PROJECT SUMMARY Methamphetamine (MA) Use Disorder Deficits in dopamine signaling and cognitive function are observed in Methamphetamine (MA) Use Disorder, which have been linked to reduced dopamine D2-type receptor (DRD2/3) availability (binding potential: BPND) in the striatum. MA use is also associated with abnormal functional connectivity at rest within dopaminergic circuitry, which in turn is associated with impaired decision making. The shared neural abnormalities linked with chronic MA use and impairments in self-control and decision-making suggest that treatments focused on repairing DRD2/3 signaling, and connectivity and activity within mesocorticolimbic circuitry may decrease maladaptive decision-making and improve inhibitory control to reduce subsequent MA use. Given that higher BPND has been linked to resilience to addiction in humans and to greater success of behavioral treatments for stimulant dependence, enhancing striatal DRD2/3 signaling may be a useful therapeutic approach for stimulant addiction. The goal of this project is to test the potential of varenicline as a therapeutic target to repair deficits in dopamine signaling and cognitive performance observed in MA Use Disorder. Varenicline administration produces striatal DRD2/3 upregulation in drug-naïve rats, but whether varenicline has the same effect in humans is not known. Varenicline also improves cognitive performance in human subjects, and because cognitive deficits can undermine behavioral treatments, improvement with varenicline, either through DRD2/3 upregulation or another mechanism, may provide a useful adjunct to behavioral treatments for addictions as well as other disorders which feature deficits in DRD2/3. The potential therapeutic effects of varenicline treatment will be assessed in healthy human subjects with methamphetamine-use disorder, using a placebo-controlled double-blind design. The dependent variables will be DRD2/3 BPND in striatum, measured using positron emission tomography, mesocorticolimbic functional connectivity at rest, measured using functional magnetic resonance imaging, and cognitive performance in tests of reward-based decision making and cognitive control and flexibility. The results of this research have the potential to advance the design and development of therapeutic targets for treating stimulant use disorders and other neuropsychiatric problems featuring DRD2/3 deficits.

项目概要 甲基苯丙胺 (MA) 使用障碍 观察到多巴胺信号传导和认知功能缺陷 甲基苯丙胺 (MA) 使用障碍，与多巴胺 D2 型受体减少有关 (DRD2/3) 在纹状体中的可用性（结合潜力：BPND）也与异常相关。 多巴胺能回路内静止的功能连接，这反过来又与决策受损有关 共同的神经异常与长期使用 MA 和自我控制能力受损有关。 决策表明治疗重点是修复 DRD2/3 信号传导、连接性和活性 中皮质边缘回路内的神经元可能会减少适应不良决策并改善抑制控制 鉴于较高的 BPND 与人类对成瘾的恢复能力有关，因此可以减少后续的 MA 使用。 为了使兴奋剂依赖性行为治疗取得更大成功，增强纹状体 DRD2/3 信号传导可能 是一种有效的治疗兴奋剂成瘾的方法。 该项目的目标是测试伐尼克兰作为修复缺陷的治疗靶点的潜力 在 MA 使用障碍中观察到的多巴胺信号传导和认知表现。 在未接受药物治疗的大鼠中产生纹状体 DRD2/3 上调，但伐尼克兰是否在 瓦尼克兰还能改善人类受试者的认知表现，这一点尚不清楚。 认知缺陷可能会破坏行为治疗，伐尼克兰可以通过 DRD2/3 进行改善 上调或其他机制，可能为成瘾行为治疗提供有用的辅助手段，例如 以及其他以 DRD2/3 缺陷为特征的疾病。 伐尼克兰治疗的潜在治疗效果将在健康人类受试者中进行评估 甲基苯丙胺使用障碍，使用安慰剂对照双盲设计。 纹状体中的 DRD2/3 BPND，使用正电子发射断层扫描测量，中皮质边缘功能 使用功能性磁共振成像测量静息时的连接性以及认知表现 这项研究的结果是基于奖励的决策以及认知控制和灵活性的测试。 促进兴奋剂使用障碍治疗靶点设计和开发的潜力 以及其他以 DRD2/3 缺陷为特征的神经精神问题。