HORMONE RHYTHMS: METABOLIC SIGNIFICANCE IN PSYCHIATRY

这是NIMH研究科学家奖的更新申请， 21-25年，在研究科学家计划。重点是HPA轴 成人和青少年重性抑郁症多动障碍工作 假设这种过度活跃是中枢神经系统（CNS）- 由于CNS胆碱能神经传递增加， 轴本身的正常适应性生理学（无质量缺陷）。到 为了阐明这一点，正在HPA的几个级别进行研究 在重度抑郁症患者和个体匹配的正常对照中， 包括开发低剂量CNS胆碱能刺激试验 没有混杂的副作用，并使用绵羊CRH（OCRH） 刺激以评估促肾上腺皮质激素下调，低剂量ACTH 1.24 刺激以评估肾上腺敏感性，以及磁共振 (MR)肾上腺成像以确定大小。血浆促肾上腺皮质激素，皮质醇， 和oCRH以及生物活性ACTH将被测量。 未来计划的实验包括：在中枢神经系统水平，刺激中枢神经系统， 药物刺激中枢胆碱能神经后HPA轴的变化 神经传递，以检验中枢胆碱能增加的假设 抑郁症下丘脑-垂体-肾上腺轴过度活跃的神经传递机制 在垂体水平，有和无甲吡酮的oCRH激发研究 预处理以抑制皮质醇，以阐明皮质醇的贡献 反馈到促肾上腺皮质激素下调。在肾上腺水平， 低剂量ACTH 1.24激发研究，以找到最佳剂量 抑郁症患者和 对照组和肾上腺的MR成像用于体积测定。 进一步的假设是，抑郁症的HPA轴过度活跃， 状态依赖性，以及随后治疗，激素措施将 以一种始终如一的方式恢复正常。因此，患者正在研究 第二次，当他们处于缓解期并停止服药至少 一个月 计划进行的研究开发是功能性神经成像研究。 特别是SPECT。这种神经成像技术有助于确定 局部脑血流量（rCBF）和化合物如HMPAO的摄取， 它也反映了血脑屏障，可能还有细胞膜， 磁导率假设抑郁症患者会表现出 rCBF和HMPAO摄取，尤其是在眶额皮质。工作与 还计划用于SPECT和PET的特异性胆碱能受体配体。

This is a revised renewal application for a NIMH Research Scientist Award, for years 21-25 in the Research Scientist Program. The focus is HPA axis hyperactivity in adult and adolescent major depression. The working hypothesis is that this hyperactivity is central nervous system (CNS)- driven, as a result of increased CNS cholinergic neurotransmission, with normal adaptive physiology of the axis itself (no qualitative defects). To elucidate this, studies are being undertaken at several levels of the HPA axis in major depressives and individually matched normal controls, including development of a low-dose CNS cholinergic stimulation test devoid of confounding side effects, and use of ovine CRH (OCRH) stimulation to assess corticotroph downregulation, low-dose ACTH1.24 stimulation to assess adrenal gland sensitivity, and magnetic resonance (MR) imaging of the adrenal for size determination. Plasma ACTH, cortisol, and oCRH will be measured, as well as bioactive ACTH. Future planned experiments include: At the CNS level, stimulation of the HPA axis following pharmacologic stimulation of central cholinergic neurotransmission, to test the hypothesis of increased central cholinergic neurotransmission underlying HPA axis hyperactivity in major depression. At the pituitary level, oCRH challenge studies with and without metyrapone pretreatment to suppress cortisol, to clarify the contribution of cortisol feedback to corticotroph downregulation. At the adrenal level, additional low-dose ACTH1.24 challenge studies to find the optimal dose for discriminating differences in adrenal sensitivity between depressives and controls, and MR imaging of the adrenals for volume determination. A further hypothesis is that HPA axis hyperactivity in depression is state-dependent, and that following treatment, the hormone measures will return to normal in a consistent manner. Thus, patients are being studied a second time when they are in remission and off medication for at least one month. Planned for research development are studies with functional neuroimaging. specifically SPECT. This neuroimaging technique is useful for determining regional cerebral blood flow (rCBF) and uptake of compounds like HMPAO, which also reflects blood-brain barrier, and possibly cell membrane, permeability. The hypothesis is that depressives will show decreases in rCBF and HMPAO uptake especially in the orbital frontal cortex. Work with specific cholinergic receptor ligands for SPECT and PET also is planned.