Experimental 7T MRI Unit , Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) , Barcelona 08036 , Spain.
Department of Neurochemistry and Neuropharmacology , Instituto de Investigaciones Biomédicas de Barcelona, CSIC, IDIBAPS , Barcelona 08036 , Spain.
ACS Chem Neurosci. 2019 Jul 17;10(7):3318-3326. doi: 10.1021/acschemneuro.9b00288. Epub 2019 Jun 18.
Depression is a chronic and debilitating illness that interferes severely with many human behaviors, and is the leading cause of disability in the world. There is data suggesting that deficits in serotonin neurotransmission can contribute to the development of depression. Indeed, >90% of prescribed antidepressant drugs act by increasing serotonergic transmission at the synapse. However, this increase is offset by a negative feedback operating at the level of the cell body of the serotonin neurons in the raphe nuclei. In the present work, we demonstrate: , the intracortical infusion of ketamine induced an antidepressant-like effect in the forced swim test, comparable to that produced by systemic ketamine; , systemic and intracortical ketamine increased serotonin and noradrenaline efflux in the prefrontal cortex, but not in the dorsal raphe nucleus; , systemic and intracortical administration of ketamine increased the efflux of glutamate in the prefrontal cortex and dorsal raphe nucleus; , systemic ketamine did not alter the functionality of 5-HT receptors in the dorsal raphe nucleus. Taken together, these findings suggest that the antidepressant-like effects of ketamine are caused by the stimulation of the prefrontal projection to the dorsal raphe nucleus and locus coeruleus caused by an elevated glutamate in the medial prefrontal cortex, which would stimulate release of serotonin and noradrenaline in the same area. The impact of both monoamines in the antidepressant response to ketamine seems to have different time frames.
抑郁症是一种慢性且使人虚弱的疾病，严重干扰了人类的许多行为，是世界上导致残疾的主要原因。有数据表明，血清素神经传递的缺陷可能导致抑郁症的发展。事实上，超过 90%的处方抗抑郁药物通过增加突触处的血清素传递而起作用。然而，这种增加被在中缝核的 5-羟色胺神经元细胞体水平起作用的负反馈所抵消。在本工作中，我们证明：（1）内侧前额叶皮质内注射氯胺酮可在强迫游泳试验中诱导出抗抑郁样效应，与全身氯胺酮产生的效应相当；（2）全身和皮质内注射氯胺酮可增加前额叶皮质和背缝核的 5-羟色胺和去甲肾上腺素的外排，但不增加背缝核；（3）全身和皮质内给予氯胺酮可增加前额叶皮质和背缝核的谷氨酸外排；（4）全身氯胺酮不会改变背缝核中 5-HT 受体的功能。综上所述，这些发现表明，氯胺酮的抗抑郁样作用是由内侧前额叶皮质中谷氨酸升高引起的对背缝核和蓝斑核的前额叶投射的刺激引起的，这将刺激同一区域中 5-羟色胺和去甲肾上腺素的释放。两种单胺类物质在氯胺酮抗抑郁反应中的作用似乎具有不同的时间框架。
