ANTIDEPRESSANT PHARMACOLOGY OF THE RODENT CIRCADIAN SYSTEM

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。这一假设正在被 通过测试抗抑郁药和抗精神病药物对 控制日常运动节奏的昼夜节律起搏器的状态 活动、体温和脑电睡眠。 在过去的一年里，该项目侧重于两个主要领域。一个区域 对慢性精神活性药物的影响进行了调查 论调节脑温的治法。这些实验表明 慢性抗抑郁药物与氯吉林、氟西汀或 锂，降低下丘脑温度，特别是在休息期间 昼夜节律周期的阶段。相比之下，慢性治疗与 抗精神病药氯丙嗪或氟哌啶醇增加下丘脑 温度。在过去的一年里，对我们数据的完整分析表明 抗抑郁药物降低下丘脑温度(Th)，但不 设定值。 与C.J.戈登博士进行的合作研究表明药物治疗 仓鼠更喜欢温暖的环境温度，而不是对照组，这表明 药物所致Th下降的负反馈控制下丘脑 降温可能是由于5-羟色胺能特性，实验证明 评估这一假说正在进行中。 抗抑郁药可能通过改变大脑温度来改变下丘脑温度 下丘脑底部的动脉血流或静脉引流。 事实上，每种抗抑郁药物都降低了Th，但有些 未能使Th的昼夜节律延迟，提示前者可能 与抗抑郁机制的关系比 后者。在抑郁症患者中，体温经常升高。 在夜间休息期间，以及药理学和非药理学 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 温度可能对了解它们的治疗机制很重要。 研究的第二个领域是确定 Clorgyline，一种MAOI，慢性降低下丘脑温度 仓鼠和延迟昼夜节律起搏器，在大脑中的单胺 据报道，离散的大脑核团参与了昼夜节律 行为和体温调节。这些研究表明，慢性 氯吉林治疗后大鼠脑内5-羟色胺(5-羟色胺)水平升高 下丘脑的终末区域(视交叉上核)。这一阶段- 5-羟色胺的延迟可能与其对Th的相位延迟效应有关。 离散测量中光照对5-羟色胺水平影响的初步分析 大脑核团表明，终末区域的5-羟色胺水平在 急性光照，而5-羟色胺细胞体中的水平下降。正在进行中 研究人员正在研究光线和5-羟色胺之间的这种关系 新陈代谢。

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.