University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, ON, K1Z 7K4, Canada.
University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, ON, K1Z 7K4, Canada.
Neuropharmacology. 2019 Mar 1;146:12-18. doi: 10.1016/j.neuropharm.2018.11.006. Epub 2018 Nov 8.
In addition to schizophrenia and bipolar disorder, aripiprazole is approved as an adjunct for major depressive disorder (MDD). Adding aripiprazole to the 5-HT reuptake inhibitor escitalopram reverses the inhibitory action of escitalopram on firing activity of rat 5-HT, norepinephrine (NE) and DA neurons. This study investigated how aripiprazole, escitalopram and their combination affect the net effect of 5-HT and NE neurotransmission in the rat hippocampus. Electrophysiological recordings of hippocampus CA pyramidal neurons were conducted in anesthetized Sprague-Dawley rats after 2- and 14-day administration regimens. Aripiprazole and escitalopram (2 and 5 mg/kg/day, respectively) were delivered alone or in combination through subcutaneous injections and implanted osmotic minipumps, respectively. Overall neurotransmission of 5-HT and NE were assessed by determining possible enhancements in tonic activation of 5-HT receptors and α- and α-adrenoceptors. This was achieved by assessing increases of firing rate of pyramidal neurons due to disinhibition induced by injections of antagonists for these three types of receptors. While neither 2- and 14-day administration of escitalopram nor aripiprazole significantly altered firing rate of pyramidal neurons following injection of 5-HT antagonist WAY100635, their combination for 14 days significantly increased this parameter. Fourteen days of the same drug regimens did not change firing following injection of the α- and α-adrenoceptor antagonists prazosin and idazoxan, respectively. A synergy between aripiprazole and escitalopram was thus documented by an increase in the tonic activation of 5-HT receptors after 14 days of administration that may account, at least in part, for the benefits of this strategy in MDD.
除了精神分裂症和双相情感障碍，阿立哌唑也被批准作为一种辅助药物，用于治疗重度抑郁症（MDD）。阿立哌唑与 5-羟色胺再摄取抑制剂艾司西酞普兰联合使用，可以逆转艾司西酞普兰对大鼠 5-羟色胺、去甲肾上腺素（NE）和多巴胺神经元放电活动的抑制作用。本研究旨在探讨阿立哌唑、艾司西酞普兰及其联合应用如何影响大鼠海马 5-羟色胺和 NE 神经传递的净效应。在麻醉的 Sprague-Dawley 大鼠中，通过电生理记录海马 CA 锥体神经元，在 2 天和 14 天给药方案后进行。阿立哌唑和艾司西酞普兰（分别为 2 和 5mg/kg/天）分别通过皮下注射和植入渗透微型泵单独或联合给药。通过确定 5-羟色胺受体和 α-和 α-肾上腺素受体的紧张性激活是否增强，来评估 5-HT 和 NE 的整体神经传递。这是通过评估由于这些三种类型受体的拮抗剂注射引起的锥体神经元放电率的增加来实现的。虽然 2 天和 14 天的艾司西酞普兰给药或阿立哌唑给药均未显著改变 5-HT 拮抗剂 WAY100635 注射后锥体神经元的放电率，但它们联合给药 14 天可显著增加该参数。相同药物方案的 14 天不会改变注射 α-和 α-肾上腺素受体拮抗剂普萘洛尔和伊达唑胺后的放电率。因此，14 天的阿立哌唑和艾司西酞普兰联合用药可增强 5-羟色胺受体的紧张性激活，这可能至少部分解释了这种策略在 MDD 中的益处。
