HORMONE RHYTHMS: METABOLIC SIGNIFICANCE IN PSYCHIATRY

这是 NIMH 研究科学家奖的修订续展申请， 21-25 岁的研究科学家计划。重点是HPA轴 成人和青少年重度抑郁症的多动症。工作中 假设这种过度活跃是中枢神经系统（CNS）- 由于中枢神经系统胆碱能神经传递增加而驱动 轴本身的正常适应性生理学（无质量缺陷）。至 为了阐明这一点，HPA 的多个级别正在进行研究 重度抑郁症和单独匹配的正常对照的轴， 包括开发低剂量中枢神经系统胆碱能刺激试验 没有混杂的副作用，并且使用绵羊 CRH (OCRH) 刺激评估促肾上腺皮质激素下调，低剂量 ACTH1.24 刺激评估肾上腺敏感性和磁共振 (MR) 肾上腺成像以确定大小。血浆 ACTH、皮质醇、 将测量 oCRH 以及生物活性 ACTH。 未来计划的实验包括： 在中枢神经系统水平上，刺激 药物刺激中枢胆碱能后的 HPA 轴 神经传递，检验中枢胆碱能增加的假设 重度抑郁症中 HPA 轴过度活跃的神经传递。 在垂体水平，使用和不使用美替拉酮的 oCRH 挑战研究 抑制皮质醇的预处理，明确皮质醇的贡献 对促肾上腺皮质激素下调的反馈。在肾上腺水平上，额外 低剂量 ACTH1.24 挑战研究，寻找最佳剂量 区分抑郁症患者和抑郁症患者肾上腺敏感性的差异 控制和肾上腺磁共振成像以确定体积。 进一步的假设是，抑郁症患者的 HPA 轴过度活跃是 取决于状态，并且治疗后，激素措施将 以一致的方式恢复正常。因此，正在研究患者 当他们处于缓解状态并且停止服药至少一段时间时进行第二次 一个月。 计划进行的研究开发是功能性神经影像学研究。 特别是SPECT。这种神经影像技术可用于确定 局部脑血流量 (rCBF) 和 HMPAO 等化合物的摄取， 这也反映了血脑屏障，可能还反映了细胞膜， 渗透性。假设抑郁症患者的抑郁症会表现出下降 rCBF 和 HMPAO 的吸收尤其是在眶额皮质中。与 一起工作 SPECT 和 PET 的特定胆碱能受体配体也在计划中。

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.