EFFECT OF ANTIDEPRESSANT DRUGS ON SENSITIVITY OF THE CIRCADIAN PACEMAKER

在这个项目中，我们研究了神经系统的生理特性， 介导光和5-羟色胺（5-HT）激动剂作用的途径 每日和季节性生物节律的时间。 的时机 这些节奏是由位于大脑中的生物钟调节的。 视交叉上核（SCN）。 暴露于a）光和B）能维生素E 激动剂，重置时钟的时间和行为模式， 由时钟控制。 这两个因素的能力，以重置 生物钟在这个项目中被评估。 我们发现 抗抑郁药物治疗改变了 光 这种行为反应伴随着c-fos的减少 在SCN细胞内表达。 第二，我们发现相位重置 5-HT激动剂和苯二氮卓类药物降低 抗抑郁药物治疗。 相位重置响应对光的灵敏度在整个时间内是恒定的。 24小时，但是长期服用抗抑郁药， 氯吉林，差异改变敏感性，以光在不同的 24小时循环的各个阶段。 因此，需要更多的光来 产生50%的相移响应，而不是产生50%的相移响应。 对夜晚光线的反应。 我们的数据表明锂不能改变 光夹带路径的灵敏度或响应性， 尽管其他研究小组发现锂可以改变视觉反应， 通过眼电图和神经生理学技术测量。 的 事实上，锂改变视觉反应，但不是夹带反应 光强调有必要对此进行进一步的研究 特殊和独特的光系统。 我们最近发现氯吉林治疗可以减少c-fos 在SCN细胞内的表达，所述SCN细胞接收来自所述细胞的投影。 视网膜下丘脑束 表达c-fos的细胞减少50%， 这与相位复位幅度的50%减小相一致 对光的反应，但不是对光敏感性的较小降低。 这一分子标记将为进一步评价该疾病提供一种有用的技术 抗抑郁药物对光暗周期的影响。 去年完成的实验表明， 抗抑郁药物治疗改变了5 HT的相位重置 激动剂8 OH DPAT和苯二氮卓类三唑仑。 DPAT诱导 氯吉林处理仓鼠的相移比对照组小 提示可能的5 HT受体脱敏。 减少 注射5 HT 1A激动剂和 苯二氮卓类药物，表明慢性抗抑郁药物可能会减少 行为对生物钟的反馈作用。

In this project we investigate the physiological properties of the neural pathways that mediate the effect of light and serotonin (5HT) agonists 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 (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 capacity of these two factors to reset the circadian clock is being evaluated in this project. We have found that antidepressant drug treatments alter the phase-resetting effects of light. This behavioral response is accompanied by a decrease in c-fos expression within SCN cells. Second, we have found that phase-resetting by 5HT agonists and benzodiazepines in decreased by chronic antidepressant drug treatment. The sensitivity of the phase-resetting response to light is constant over twenty-four hours, but chronic treatment with the antidepressant drug, clorgyline, differentially alters sensitivity to light at different phases of the twenty-four hour cycle. Thus, more light is required to produce a 50% phase-shift response to morning light than to produce a 50% response to evening light. Our data suggests that lithium fails to alter the sensitivity or responsiveness of the photic entrainment pathway, although lithium was found by other groups to alter visual responses as measured by electrooculographic and neurophysiological techniques. 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. We have recently found that clorgyline treatment decreases c-fos expression within SCN cells that receive a projection from the retinohypothalamic tract. The 50% decrease in cells expressing c-fos is consistent with the 50% decrease in the magnitude of the phase-resetting response to light, but not to the smaller decrease in photic sensitivity. This molecular marker will be a useful technique for further evaluating antidepressant drug effects on entrainment to the light-dark cycle. Experiments completed during the past year indicate that chronic treatment with antidepressant drugs alter phase-resetting by the 5HT agonist 8 OH DPAT, and by the benzodiazepine triazolam. DPAT-induced phase-shifts are smaller in clorgyline-treated hamsters than controls suggesting a possible desensitization of 5HT receptors. The decreased phase-shifting response following injections by a 5HT 1A agonist and a benzodiazepine, indicates that chronic antidepressant drugs may diminish the feedback effects of behavior on the circadian clock.