ANTIDEPRESSANT PHARMACOLOGY OF THE RODENT CIRCADIAN SYSTEM

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The therapeutic mechanism of antidepressant drugs is likely to include a circadian component. This possibly is being examined by testing in hamsters the effects of antidepressant and neuroleptic drugs on the sate of the circadian pacemaker that controls daily rhythms of motor activity, temperature and EEG sleep. Different classes of psychoactive drugs differentially alter the circadian pattern of temperature within the hypothalamus, the brain region containing the circadian pacemaker as well as central thermostat which regulates body temperature. Chronic antidepressant drug treatments decrease hypothalamic temperature during the rest (light) phase. The neuroleptic drugs (chlorpromazine and haloperidol) increases hypothalamic temperature during the rest phase. Antidepressant drugs and neuroleptic drugs increase and decrease respectively, the circadian amplitude of hypothalamic temperature. In depressed patients, elevated body temperature is often observed during nocturnal rest. Pharmacological and non-pharmacological treatments of depression have been reported to lower body temperature. We hypothesize that decreased hypothalamic temperature, particularly during the nocturnal rest phase, is an important component of the therapeutic response to pharmacological and non-pharmacological treatments for depression. A recent line of investigation has explored the role of serotonin in modulating the circadian system response to light. VIP cells within the SCN are of interest for two reasons. First, the visual pathway for circadian entrainment, and a serotonergic pathway originating in the raphe nucleus, both project of these VIP cells. Second, VIP levels within the SCN exhibit seasonal variation as a result of changes in daylength. VIP cells may therefore be part of a seasonal mechanism that controls circadian variation in light responsiveness and behavior. The relationship between vasoactive intestinal peptide (VIP) containing cells, and serotonin levels within the suprachiasmatic nucleus (SCN) is being examined using immunohistochemical and image analysis techniques. We have found that chronic treatment with the antidepressant drug clorgyline elevates immunoreactivity to vasoactive intestinal peptide (VIP) throughout the rostral caudal extent of the SCN. This is the first description of a chronic antidepressant drug affecting VIP within the SCN. The increase in VIP immunoreactivity is likely to be related to chronic elevation of serotonin within the SCN since serotonergic fibers project to VIP cells within the SCN. It is hypothesized that in seasonal depression, the behavioral effect on circadian rhythms (e.g. sleep- wakefulness) of serotonergic antidepressant drugs, is mediated by the drug effect on VIP cells within the SCN.