EFFECT OF ANTIDEPRESSANT DRUGS ON SENSITIVITY OF THE CIRCADIAN PACEMAKER

抗抑郁药物对昼夜节律起搏器敏感性的影响

• 批准号: 6162879
• 负责人: W C DUNCAN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162879
• 关键词: MAO inhibitors; antidepressants; brain regulatory center; circadian rhythms; gene induction /repression; hamsters; lithium; neuropharmacology; photostimulus; protooncogene; psychopharmacology; serotonin; suprachiasmatic nucleus; visual pathways

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 effects of antidepressant drugs on the sensitivity of the visual pathway mediating entrainment to light. The MAOI, clorgyline, and 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. 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 a 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 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.

昼夜节律的时间是由位于 视交叉上核（SCN）。 暴露于a）光和B） 肾上腺素能激动剂，重置时钟的时间和模式， 由时钟控制的行为。生理特性和 临床抗抑郁药物的影响，对神经通路，介导 光和5-羟色胺对昼夜节律和季节生物学的影响 在仓鼠中研究节律。 在第一系列实验中，生物行为测定被用于 评估抗抑郁药物对敏感性的影响， 视觉通路介导对光的夹带。MAOI，氯吉林，和 锂，降低视觉通路介导的敏感性 通过光进行相位复位。氯吉林治疗期间， 治疗与肾上腺素能药物 降低了光的相位复位幅度。 用MAOI，氯吉兰进行慢性治疗，改变了 5 HT激动剂8 OH DPAT和苯二氮卓类三唑仑。 DPAT诱导 在氯吉林处理的仓鼠中相移比对照仓鼠小 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。 在第二个系列的实验中，抗抑郁药物对 正在研究立即早期基因c-fos的光诱导。 两 问题正在得到解决。 首先，慢性氯吉林治疗 降低光诱导的c-fos表达？ 第二， c-fos的表达也受到相位提前的影响， 光的相位延迟效应 亚慢性氯吉兰治疗期间 SCN细胞内c-fos表达减少。 这50% 表达c-fos的细胞的减少与表达c-fos的细胞减少50%一致。 慢性视网膜病变患者对光的相位重置反应的幅度 氯吉林处理的仓鼠。