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 除了其在维持全身性钙稳态方面的作用之外 研究表明，维生素D作为神经活性类固醇的身体重要性。尽管有这样的数据， 维生素D对人类脑功能的直接影响的实验证据几乎缺乏。这个差距 阻碍我们对维生素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（即包括维生素缺乏状态）。 我们小组成员的最新临床前（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，钙化三醇，在中断多巴胺（DA）系统上。这些数据 演示：1）含有腹侧神经元的酪氨酸羟化酶中VDR的表达 纹状体/伏隔核中表达受体的细胞（NAC）中表达受体的细胞（VTA）和多巴胺D2/3。和 他们进一步表明，急性钙化剂给药：2）增加了VTA DA神经元中的TH表达； 3） 在NAC中增加多巴胺D2/3受体mRNA； 4）增加微透析（“补品”）和循环伏安法 （“阶段”）纹状体DA释放的度量（包括对苯丙胺的响应）； 5）增加苯丙胺 - 诱导的运动和6）减少动物中的药物（苯丙胺）自我给药。如果也是正确的 鉴于人类行为的数量，人类将考虑临床重要性（例如， 学习，记忆，奖励，情感和信息处理等）由中唇/皮层DA介导 圈子和疾病的数量（例如，注意力缺陷多动障碍，成瘾，抑郁症， 帕金森氏病等）涉及中间/皮质下DA的定义。 当前的探索性/发育R01试图直接在健康的人类中检验这一假设。 特别是，我们将在医学和精神上健康中评估皮层下DA功能（体内DA释放） （维生素D足够）使用高分辨率11C-Phno PET的人。具体而言，受试者（n = 20）将参加 在四个11c-phno PET会议中，包括两对d2/3的前和后苯丙胺（0.3 mg/kg PO）扫描 接收器的可用性（BPND）在相隔两周的两天内进行。扫描日将在 安慰剂/主动钙三醇（3.0 µg）每一个完全随机的，双盲，平衡，安慰剂 - 受控的主体内设计。我们假设钙三醇将增加苯丙胺刺激的DA 在活动与安慰剂上的腹侧纹状体D2/3受体可用性（∆BPND）中的较大减少反映的释放反映 几天，这种变化将伴随着DA介导的行为的平行改善。