Vitamin D Modulation of Midbrain Dopamine Function: A 11C-PHNO PET Study in Healthy Humans

维生素 D 对中脑多巴胺功能的调节：健康人的 11C-PHNO PET 研究

• 批准号: 10022445
• 负责人: Marc N Potenza
• 金额: $ 82.82万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022445
• 关键词: Acute; Affective; Amphetamines; Animals; Attention; Attention deficit hyperactivity disorder; Basic Science; Behavior; Binding; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain region; Calcitriol; Calcium; Cells; Clinical; Corpus striatum structure; Correlation Studies; Data; Dementia; Development; Disease; Dopamine; Double-Blind Method; Endocrine; Enzymes; Future; Health; Homeostasis; Human; Impaired cognition; Lead; Learning; Literature; Locomotion; Malnutrition; Measures; Mediating; Medical; Memory; Mental Depression; Messenger RNA; Midbrain structure; Mixed Function Oxygenases; Modeling; Nuclear; Nucleus Accumbens; Parkinson Disease; Periodicity; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Placebos; Plasma; Positron-Emission Tomography; Randomized; Research; Resolution; Rewards; Rodent; Role; Scanning; Schizophrenia; Self Administration; Supplementation; Testing; Therapeutic; Tyrosine 3-Monooxygenase; Ventral Striatum; Ventral Tegmental Area; Vitamin D; Vitamin D3 Receptor; Vitamin Deficiency; Vitamins; Work; addiction; autocrine; base; behavior measurement; clinical application; design; dopaminergic neuron; in vivo; information processing; knockout gene; member; mesolimbic system; neurodevelopment; neuroprotection; neuropsychiatric disorder; neurosteroids; neurotransmission; paracrine; performance tests; pre-clinical; receptor; response; synthetic enzyme; vigilance

Project Summary Beyond its well-established role in maintaining systemic calcium homeostasis, a substantial and growing body of research points to the physiological importance of vitamin D as a neuroactive steroid. Despite such data, experimental evidence of vitamin D’s direct effects on brain function in humans is all but lacking. This gap hinders both our understanding of the role of vitamin D in human behavior as well as its therapeutic potential for neuropsychiatric disorders (i.e., including and beyond vitamin deficiency states). Recent preclinical (rodent) research by members of our group demonstrate important modulatory effects of the physiologically active form of vitamin D, calcitriol, on mesolimbic dopamine (DA) systems. These data demonstrate: 1) expression of VDRs in tyrosine hydroxylase (TH) containing DA neurons of the ventral tegmental area (VTA) and dopamine D2/3 receptor-expressing cells in striatum/nucleus accumbens (NAc); and they further show that acute calcitriol administration: 2) increases TH expression in VTA DA neurons; 3) increases dopamine D2/3 receptor mRNA in NAc; 4) increases microdialysate (“tonic”) and cyclic voltammetry (“phasic”) measures of striatal DA release (including in response to amphetamine); 5) increases amphetamine- induced locomotion, and 6) decreases drug (amphetamine) self-administration in animals. If also true of humans, such effects would be of considerable clinical importance, given the number of human behaviors (e.g., learning, memory, reward, affective and information processing, etc.) mediated by mesolimbic/subcortical DA circuits and the number of disorders (e.g., attention deficit hyperactivity disorder, addiction, depression, Parkinson’s disease, etc.) in which mesolimbic/subcortical DA deficits have been implicated. The current exploratory/developmental R01 seeks to test this hypothesis directly in healthy humans. Specifically, we will assess subcortical DA function (in vivo DA release) in 20 medically and psychiatrically healthy (vitamin D sufficient) humans using high-resolution 11C-PHNO PET. Specifically, subjects (N=20) will participate in four 11C-PHNO PET sessions, including two pairs of pre- and post-amphetamine (0.3 mg/kg PO) scans of D2/3 receptor availability (BPND) conducted on two separate days two weeks apart. Scan days will be preceded by placebo/active calcitriol (3.0 µg) pretreatment per a fully randomized, double-blind, counterbalanced, placebo- controlled, within-subject design. We hypothesize that calcitriol will increase amphetamine-stimulated DA release as reflected by greater reductions in ventral striatal D2/3 receptor availability (∆BPND) on active vs. placebo days and that such changes will be accompanied by parallel improvements in DA-mediated behaviors.

项目概要 除了其在维持全身钙稳态方面的既定作用之外，大量且不断增长的身体 研究指出维生素 D 作为神经活性类固醇的生理重要性。 维生素 D 对人类大脑功能有直接影响的实验证据几乎缺乏。 阻碍了我们对维生素 D 在人类行为中的作用及其治疗潜力的理解 用于神经精神疾病（即，包括和超出维生素缺乏状态）。 我们小组成员最近的临床前（啮齿动物）研究表明了重要的调节作用 维生素 D 的生理活性形式，骨化三醇，对中脑边缘多巴胺 (DA) 系统的影响。 证明：1) 腹侧含有 DA 神经元的酪氨酸羟化酶 (TH) 中 VDR 的表达 纹状体/伏核 (NAc) 中的被盖区 (VTA) 和多巴胺 D2/3 受体表达细胞； 他们进一步表明，急性骨化三醇给药：2) 增加 VTA DA 神经元中的 TH 表达；3) 增加 NAc 中的多巴胺 D2/3 受体 mRNA；4) 增加微透析液（“补品”）和循环伏安法 （“阶段性”）纹状体 DA 释放的测量（包括对安非他明的反应）5）增加安非他明- 诱导运动，以及 6) 减少动物的药物（安非他明）自我给药如果也如此。 对于人类来说，考虑到人类行为的数量（例如， 中脑边缘/皮层下 DA 介导的学习、记忆、奖励、情感和信息处理等） 回路和疾病的数量（例如，注意力缺陷多动障碍、成瘾、抑郁症、 帕金森病等），其中涉及中脑边缘/皮质下 DA 缺陷。 当前的探索/开发 R01 试图直接在健康人类中检验这一假设。 具体来说，我们将评估 20 名医学和精神健康的人的皮层下 DA 功能（体内 DA 释放） （维生素 D 充足）使用高分辨率 11C-PHNO PET 的人类具体而言，受试者（N = 20）将参与。 在四次 11C-PHNO PET 疗程中，包括两对 D2/3 的安非他明 (0.3 mg/kg PO) 扫描前和后扫描 受体可用性 (BPND) 在相隔两周的两个单独的日子进行，之后将进行扫描日。 安慰剂/活性骨化三醇 (3.0 µg) 预处理，按照完全随机、双盲、平衡、安慰剂- 我们勇敢地承认骨化三醇会增加安非他明刺激的 DA。 与安慰剂相比，活性药物组腹侧纹状体 D2/3 受体可用性 (ΔBPND) 的更大减少反映了释放 这些变化将伴随着 DA 介导的行为的平行改善。