EFFECT OF ANTIDEPRESSANT DRUGS ON SENSITIVITY OF THE CIRCADIAN PACEMAKER

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The timing of circadian rhythms is regulated by a circadian clock located in the suprachiasmatic nucleus (SCN). Exposure to a) light and b) serotonergic agonists, resets the timing of the clock and the pattern of behaviors controlled by the clock. The physiological properties and clinical antidepressant drugs effects, on neural pathways that mediate the effects of light and serotonin on circadian and seasonal biological rhythms are being investigated in hamsters. In the first series of experiments, a biobehavioral assay has been used to assess the effect s of antidepressant drugs on the sensitivity of the visual pathway mediating entrainment to light. The MAOI, clorgyline, but not lithium, decreases the sensitivity of the visual pathway mediating phase-resetting by light. This decreased response during clorgyline treatment is consistent with the possibility that serotonergic agents decrease the magnitude of phase-resetting by light. It is unlikely therefore, that a single visual property, i.e. decreased visual sensitivity of the entrainment pathway, underlies the clinical antidepressant property of the two drugs. However, the different effects of the two drugs on visual sensitivity may be related to the different circadian and mood stabilizing effects of the drugs. Chronic treatment with the MAOI, clorgyline, alters phase-resetting by the 5HT agonist 8 OH DPAT, and by the benzodiazepine triazolam. DPAT- induced phase-shifts are smaller in clorgyline-treated than control hamsters suggesting possible desensitization of 5HT receptors. The decreased phase-shifting response following injections by a 5HT 1A agonist and benzodiazepine, indicates that chronic antidepressant drugs may diminish the feedback effects of behavior on the circadian clock. In a second series of experiments, the effect of antidepressant drugs on light induction of the immediate early gene c-fos is being examined. Two questions are being addressed. First, does chronic clorgyline treatment decrease light-induced c=fos expression? Second, is the magnitude of c- fos expression affected similarly by the phase-advancing and phase- delaying effects of light? During subchronic clorgyline treatment there is a decrease in c-fos expression within the SCN cells. The 50% decrease in cells expressing c-fos is consistent with the 50% decrease in the magnitude of the phase-resetting response to light in chronic clorgyline- treated hamsters. Additional data are currently being analyzed. Current experiments are examining the phase-resetting effects of light in hamsters housed in long (summer) and short (winter) photoperiods. Preliminary results indicate that prolonged exposure to a short photoperiod increases the magnitude of light-induced phase-shifts relative to summer photoperiod exposure. We are examining the level of light-induced c-fos induction in short and long photoperiods, as well as the capacity of antidepressant drugs to decrease the magnitude of phase- shifting response.