ANTIDEPRESSANT PHARMACOLOGY OF THE RODENT CIRCADIAN SYSTEM

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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.