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

项目总结 甲基苯丙胺(MA)使用障碍观察到多巴胺信号和认知功能的缺陷 在甲基苯丙胺(MA)中使用障碍，这与多巴胺D2型受体减少有关 (DRD2/3)纹状体的可用性(结合潜力：BPND)。MA的使用也与异常相关 多巴胺能回路中静止的功能连接，这反过来又与决策受损有关 制作。与长期使用MA有关的共同神经异常以及自我控制和自我控制能力的损害 决策表明，治疗的重点是修复DRD2/3信号，以及连接和活动 在中皮质边缘回路可能会减少不适应的决策并改善抑制控制 减少后续MA的使用。鉴于较高的BPND与人类对成瘾的适应能力有关， 为了更成功地对兴奋剂依赖进行行为治疗，增强纹状体DRD2/3信号可能 是治疗兴奋剂成瘾的有效方法。 该项目的目标是测试伐伦克林作为治疗靶点修复脑功能缺陷的潜力。 在MA使用障碍中观察到的多巴胺信号和认知表现。瓦伦尼克林给药 在药物幼稚的大鼠中产生纹状体DRD2/3上调，但在 人类不为人所知。Varenicline还可以改善人类受试者的认知表现，因为 认知障碍可以破坏行为治疗，通过DRD2/3改善varenicline 上调或另一种机制，可能为成瘾的行为治疗提供有用的辅助手段，如 以及其他以DRD2/3缺陷为特征的疾病。 将在健康受试者中评估varenicline治疗的潜在疗效。 甲基苯丙胺使用障碍，采用安慰剂对照双盲设计。因变量将 纹状体Be DRD2/3BPND的正电子发射断层扫描、中皮质边缘功能 通过功能磁共振成像测量的静态连接性和认知表现 测试基于奖励的决策以及认知控制和灵活性。这项研究的结果是 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。

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.