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.

项目摘要 除了在维持全身钙稳态方面的既定作用外， 研究指出维生素D作为神经活性类固醇的生理重要性。尽管有这些数据， 维生素D对人类大脑功能的直接影响的实验证据几乎是缺乏的。这一差距 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 对于神经精神障碍（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， 维生素D的生理活性形式骨化三醇对中脑边缘多巴胺（DA）系统的作用。这些数据 证明：1）VDRs在腹侧含酪氨酸羟化酶（TH）的DA神经元中的表达 被盖区（VTA）和纹状体/伏隔核（NAc）中表达多巴胺D2/3受体的细胞;和 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中多巴胺D2/3受体mRNA; 4）增加微透析液（“滋补”）和循环伏安法 （“阶段性”）纹状体DA释放的措施（包括对安非他明的反应）; 5）增加安非他明- 诱导的运动，和6）减少动物中的药物（安非他明）自我给药。如果也是真的 对于人类来说，这样的效果将具有相当大的临床重要性，考虑到人类行为的数量（例如， 学习、记忆、奖赏、情感和信息处理等）中脑边缘/皮质下DA介导 回路和紊乱的数量（例如，注意力缺陷多动障碍，成瘾，抑郁， 帕金森氏症等）其中涉及中脑边缘/皮质下DA缺陷。 目前的探索性/开发性R 01旨在直接在健康人群中测试这一假设。 具体来说，我们将评估20名医学和精神病学健康的皮质下DA功能（体内DA释放）， （维生素D充足）人类使用高分辨率11 C-PHNO PET。具体而言，受试者（N=20）将参与 在四次11 C-PHNO PET检查中，包括两对安非他明（0.3 mg/kg PO）前和后D2/3扫描 受体可用性（BPND）在两周内的两个不同的日子进行。扫描日之前， 安慰剂/活性骨化三醇（3.0 µg）预处理，根据一项完全随机化、双盲、平衡、安慰剂- 受试者内对照设计。我们假设骨化三醇会增加安非他明刺激的DA 通过活性药物组腹侧纹状体D2/3受体可用性（CARBPND）较安慰剂组降低更大反映了释放 这些变化将伴随着DA介导的行为的平行改善。