HORMONE RHYTHMS: METABOLIC SIGNIFICANCE IN PSYCHIATRY

这是NIMH研究科学家奖的修改后的续签申请， 在21-25年的研究科学家计划中。焦点是HPA轴 成人和青少年重度抑郁症的多动症。在工作中 假设这种过度活动是中枢神经系统(CNS)- 作为CNS胆碱能神经传递增加的结果， 轴本身的正常适应性生理(无质的缺陷)。至 为了阐明这一点，正在HPA的几个层面上进行研究 在抑郁症患者和个别匹配的正常对照组中， 包括开发一种低剂量中枢胆碱能刺激试验 没有混杂的副作用，使用绵羊促肾上腺皮质激素(OCRH) 刺激评估促肾上腺皮质激素下调，小剂量ACTH1.24 刺激以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， 和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，以检验中枢胆碱能增加的假说 重度抑郁症患者HPA轴过度活动的神经传递。 在脑垂体水平，oCRH挑战使用和不使用甲替拉奉的研究 预先抑制皮质醇，阐明皮质醇的作用 对促肾上腺皮质激素下调的反馈。在肾上腺水平，额外的 低剂量ACTH1.24挑战研究寻找治疗的最佳剂量 抑郁症和抑郁症患者肾上腺敏感度的区别 并对肾上腺进行磁共振成像以确定体积。 另一种假设是抑郁症患者的HPA轴多动 依赖于国家，在治疗之后，激素措施将 以始终如一的方式回归正常。因此，正在对患者进行研究 第二次是在病情缓解和停药至少一次的时候 一个月。 计划进行研究开发的是功能神经成像研究。 特别是SPECT。这种神经成像技术对于确定 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，可能还有细胞膜， 渗透性。这个假说是抑郁症患者的 RCBF和HMPAO摄取，尤其是在眼眶额叶皮质。使用 用于SPECT和PET的特异性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.