ANTIDEPRESSANT PHARMACOLOGY OF THE RODENT CIRCADIAN SYSTEM

啮齿动物昼夜节律系统的抗抑郁药理学

• 批准号: 3759410
• 负责人: W C DUNCAN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3759410
• 关键词: antidepressants; antipsychotic agents; body physical activity; body temperature; body temperature regulation; brain metabolism; chordate locomotion; circadian rhythms; cortisol; drug administration rate /duration; hamsters; hypothalamus; lighting; neurochemistry; neurotransmitter metabolism; oxygen consumption; photobiology; psychobiology; psychopharmacology; serotonin

We have hypothesized that the therapeutic mechanism of antidepressant drugs depends on their effects on the circadian system. This hypothesis is being examined by testing the effects of antidepressant and neuroleptic drugs on the state of the circadian pacemaker that controls daily rhythms of motor activity, temperature and EEG sleep. During the past year this project has focused on two major areas. One area of investigation has been on the effects of chronic psychoactive drug treatment on regulation of brain temperature. These experiments indicate that chronic antidepressant drug treatment with clorgyline, fluoxetine or lithium, lowers hypothalamic temperature, particularly during the rest phase of the circadian cycle. In contrast, chronic treatment with the neuroleptic drugs chlorpromazine or haloperidol increase hypothalamic temperature. During the past year, complete analysis of our data indicates that antidepressant drugs decrease hypothalamic temperature (Th), but not set-point. Collaborative studies conducted with Dr. C.J. Gordon indicate drug-treated hamsters prefer warmer ambient temperatures than controls, indicating negative feedback control of the drug-induced decrease in Th. Hypothalamic cooling is possibly due to serotonergic properties, and experiments to evaluate this hypothesis are in progress. Antidepressant may alter hypothalamic temperature by changing cerebral arterial blood flow or venous drainage at the base of the hypothalamus. The fact that each of the antidepressant drugs decreased Th, but some failed to phase-delay the daily rhythm in Th, suggests that the former may be more closely associated with the antidepressant mechanism than the latter. In depressed patients, elevated body temperature is often observed during nocturnal rest, and pharmacological and non-pharmacological treatments of depression have been reported to lower body temperature. Therefore, the findings that antidepressant drugs decrease hypothalamic temperature may be important in understanding their therapeutic mechanism. A second area of research has been to determine the chronic effects of clorgyline, an MAOI which chronically decreases hypothalamic temperature in hamsters and delays the circadian pacemaker, on brain monoamines in discrete brain nuclei reported to be involved in circadian regulation of behavior and thermoregulation. These studies indicate that chronic clorgyline treatment elevates and phase-delays serotonin (5HT) levels in terminal regions of the hypothalamus (suprachiasmatic nucleus). The phase- delay of 5HT may be related to its phase-delaying effects on Th. Preliminary analysis of light effects on 5HT levels measured in discrete brain nuclei suggests that 5HT levels in terminal regions increase during acute light exposure, whereas levels in 5HT cell bodies decrease. Ongoing investigations are examining this relationship between light and serotonin metabolism.

我们假设抗抑郁药物的治疗机制 取决于它们对昼夜节律系统的影响。 这一假设被 通过测试抗抑郁药和神经安定药对 昼夜节律起搏器的状态，控制运动的日常节奏， 活动、体温和脑电图睡眠。 在过去的一年里，该项目侧重于两个主要领域。 一个领域 的研究一直是关于慢性精神活性药物的影响 调节脑温治疗。 这些实验表明 慢性抗抑郁药物治疗与氯吉林，氟西汀或 锂，降低下丘脑温度，特别是在休息期间 生理周期的一个阶段。 与此相反， 精神安定药氯丙嗪或氟哌啶醇增加下丘脑 温度 在过去的一年里，对我们数据的全面分析表明， 抗抑郁药物降低下丘脑温度（Th），但不 设定点 与C.J.戈登博士进行的合作研究表明， 仓鼠比对照组更喜欢温暖的环境温度，表明 负反馈控制药物诱导的Th减少。 下丘脑 冷却可能是由于电子能的性质， 评估这个假设正在进行中。 抗抑郁药可能通过改变大脑皮层的温度来改变下丘脑的温度 下丘脑底部的动脉血流或静脉引流。 事实上，每种抗抑郁药物都能降低Th，但有些药物能降低Th。 未能相位延迟Th的日节律，表明前者可能 与抗抑郁机制的关系比 后者 在抑郁症患者中，经常观察到体温升高 在夜间休息期间，以及药物和非药物 据报道，抑郁症的治疗可以降低体温。 因此，抗抑郁药物降低下丘脑的研究结果 温度可能对理解其治疗机制很重要。 第二个研究领域是确定 氯吉林，一种MAOI，长期降低下丘脑温度， 仓鼠和延迟昼夜节律起搏器，对大脑单胺， 据报道，离散的脑核团参与昼夜节律调节， 行为和体温调节。 这些研究表明，慢性 氯吉兰治疗提高和阶段延迟血清素（5 HT）水平， 下丘脑的末端区域（视交叉上核）。 阶段- 5 HT的延迟可能与其对Th的时相延迟作用有关。 光对5HT浓度影响的初步分析 脑核团表明，5 HT水平在终端地区增加， 急性光暴露，而5HT细胞体中的水平降低。 正在进行 研究人员正在研究光和血清素之间的关系 新陈代谢.