EFFECT OF ANTIDEPRESSANT DRUGS ON SENSITIVITY OF THE CIRCADIAN PACEMAKER

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In this project we investigate the physiological properties of the neural pathways that mediate the effect of light on the timing of daily and seasonal biological rhythms. The timing of these rhythms is regulated by a circadian clock located in the suprachiasmatic nucleus. Exposure to fight resets the timing of the clock and the pattern of behaviors controlled by the clock. There are two aspects of this research. First, we examine the clock phase-resetting properties of light-pulses of different intensities and durations in drug-free animals. Second, we examine the effects of chronic, antidepressant drug treatments on clock phase-resetting properties of light. There are three major findings of these recent investigations. First, we confirmed that in drug-free hamsters, the photic sensitivity of this pathway is constant throughout the circadian cycle. That is, equivalent quantities of light delivered at different circadian phases produce phase-shifts that are 50% of the maximum response at each phase. Second, these experiments demonstrate that chronic treatment with the antidepressant drug, clorgyline, decreases sensitivity to light, and that the magnitude of this effect is dependent upon the phase of the circadian cycle at which light is delivered. Thus, more light is required to produce a 50% phase-shift response to evening light than to produce a 50% response to morning light. The shift in the daily pattern of sensitivity to light may contribute to the antidepressant properties of this drug. The mechanism of this shift in sensitivity is currently being examined. The drug may alter the integration of light over time. Third, although previously published reports indicate that lithium alters visual responses as measured by electrooculographic and neurophysiological techniques, our recent data suggests that lithium fails to alter the sensitivity or responsiveness of the photic entrainment pathway. These results underscore the view that this photic system, which is responsible for the entrainment of circadian rhythms, is separate from other visual systems. For example, the photic system mediating entrainment has a high response threshold (about 6 log units above the threshold for vision) and integrates light stimuli for up to 45 minutes (in contrast to 1-3 seconds for some rod photoreceptors). The fact that lithium alters visual responses, but not entrainment responses to light underscores the need to conduct further research on this specific and distinct photic system.