Recent evidence suggests that a novel serotonin receptor 5-HT 7 localized in the hypothalamus downregulates in response to treatment with the antidepressant fluoxetine (Sleight et al. 1995). This receptor has also been implicated in the regulation of circadian rhythms (Lovenberg et al. 1993). Here Depression may involve many possible abnormalities corresponding to multiple biological correlates of dysfunction or dysregulation in either one or several brain neurotransmitter systems (Cooper et al. 1996;Nair and Sharma 1989), a property that may contribute to the apparent disparity in symptomology and response to antidepressant therapy. The strict classical notions of neurotransmitter dysregulation hypotheses that associate depression with a deficiency of a vailable neurotransmitter or subresponsivity of mainly noradrenergic and/ or serotonergic receptor systems are recently being expanded to include disturbances in biological rhythm regulation. Impairment of the efficiency of rhythm maintenance or rhythm desynchronization has been suggested by many to lead to mental fatigue and depression (Goodwin et al. 1982;Hallonquist et al. 1986;Healy 1987;Partonen 1994;Schwartz 1993;Wirz-Justice and Campbell 1982;Wirz-Justice et al. 1995). Clinically, it has been extensively documented that the timing and structure of rhythms in physiological, behavioral, and endocrinological functions seem to be abnormal in depression (Coiro et al. 1993;Duncan 1996;File 1990;Kupfer 1995;Nair and Sharma 1989;Wehr et al. 1979). Furthermore, studies investigating the patterns of circadian rhythms of patients diagnosed with depression have been undertaken with the premise of disturbed rhythmicity as a central theme underlying the etiology of some affective disorders (Duncan 1996;Goodwin et al. 1982;Healy 1987;Siever and Davis, 1985;Souetre et al. 1988).Although melatonin is generally thought to be a primary modulator of circadian function through the suprachiasmatic nucleus (SCN) of the hypothalamus (Armstrong and Redman 1993;Binkley 1993;Cassone et al. 1993;Dubocovich 1991;Ibata et al. 1997;Reiter 1993; From the Bristol-Myers Squibb Company (ULM, ASE), Neuroscience Drug Discovery, Wallingford, Connecticut; and University of Connecticut, Department of Pharmaceutical Sciences (GG), Storrs, Connecticut, USA.Address correspondence to: U. Lena Mullins, Ph.D., BristolMyers Squibb Company, Neuroscience Drug Discovery, Department 408, 5 Research Parkway, Wallingford, Connecticut 06492, USA.Received January 1, 1999; revised March 23, 1999; accepted March 26, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 3 Effects of Antidepressants 353 Stankov et al. 1993), the serotonergic system also plays a critical role in circadian modulation. The SCN receives dense projections from the raphe serotonergic neurons originating in the brainstem (Jacobs and Azmitia 1992;Meyer-Bornstein and Morin 1996;Van De Kar and Lorens 1979). Lesions of the median raphe serotonergic system using the neurotoxic agent 5,7-dihydroxytryptamine (5,7-DHT) produce a sever...

The hypothalamic suprachiasmatic nucleus (SCN) is primarily responsible for the regulation of circadian rhythmicity. Melatonin, the pineal-derived neurohormone, modulates the rhythmic output of the SCN. Property timed exposure to melatonin is able to induce changes in rhythmic function and thereby entrain circadian rhythms of activity. c-fos is an immediate early gene that is transiently expressed in neurons in response to receptor activation. The ventrolateral portion of the SCN (vSCN) is activated in response to phase-shifting stimuli, an event which is marked by an increase in the expression of c-fos.