Pehrson Alan L, Pedersen Christian S, Tølbøl Kirstine Sloth, Sanchez Connie
Department of Psychology, Montclair State University, Montclair, NJ, United States.
H. Lundbeck A/S, Copenhagen, Denmark.
Front Pharmacol. 2018 Mar 6;9:162. doi: 10.3389/fphar.2018.00162. eCollection 2018.
Major depressive disorder (MDD) is associated with cognitive impairments that may contribute to poor functional outcomes. Clinical data suggests that the multimodal antidepressant vortioxetine attenuates some cognitive impairments in MDD patients, but the mechanistic basis for these improvements is unclear. One theory suggests that vortioxetine improves cognition by suppressing γ-amino butyric acid (GABA)ergic neurotransmission, thereby increasing glutamatergic activation. Vortioxetine's effects on cognition, GABA and glutamate neurotransmission have been supported in separate experiments, but no empirical work has directly connected vortioxetine's cognitive effects to those on GABA and glutamate neurotransmission. In this paper, we attempt to bridge this gap by evaluating vortioxetine's effects in the subchronic PCP (subPCP) model, which induces impaired cognitive function and altered GABA and glutamate neurotransmission. We demonstrate that acute or subchronic vortioxetine treatment attenuated subPCP-induced deficits in attentional set shifting (AST) performance, and that the selective 5-HT receptor antagonist ondansetron or the 5-HT reuptake inhibitor escitalopram could mimic this effect. Furthermore, acute vortioxetine treatment reversed subPCP-induced object recognition (OR) deficits in rats, while subchronic vortioxetine reversed subPCP-induced Object Recognition and object placement impairments in mice. Finally, subPCP treatment reduced GABA receptor expression in a manner that was insensitive to vortioxetine treatment, and subchronic vortioxetine treatment alone, but not in combination with subPCP, significantly increased GABA's affinity for the GABA receptor. These data suggest that vortioxetine reverses cognitive impairments in a model associated with altered GABA and glutamate neurotransmission, further supporting the hypothesis that vortioxetine's GABAergic and glutamatergic effects are relevant for cognitive function.
重度抑郁症（MDD）与认知障碍有关，这些认知障碍可能导致不良的功能结局。临床数据表明，多模式抗抑郁药伏硫西汀可减轻MDD患者的一些认知障碍，但这些改善的机制尚不清楚。一种理论认为，伏硫西汀通过抑制γ-氨基丁酸（GABA）能神经传递来改善认知，从而增加谷氨酸能激活。伏硫西汀对认知、GABA和谷氨酸神经传递的影响在单独的实验中得到了支持，但尚无实证研究直接将伏硫西汀的认知作用与对GABA和谷氨酸神经传递的作用联系起来。在本文中，我们试图通过评估伏硫西汀在亚慢性苯环己哌啶（subPCP）模型中的作用来填补这一空白，该模型可导致认知功能受损以及GABA和谷氨酸神经传递改变。我们证明，急性或亚慢性伏硫西汀治疗可减轻subPCP诱导的注意力转换（AST）性能缺陷，并且选择性5-羟色胺受体拮抗剂昂丹司琼或5-羟色胺再摄取抑制剂艾司西酞普兰可模拟这种效果。此外，急性伏硫西汀治疗可逆转subPCP诱导的大鼠物体识别（OR）缺陷，而亚慢性伏硫西汀可逆转subPCP诱导的小鼠物体识别和物体放置障碍。最后，subPCP治疗以对伏硫西汀治疗不敏感的方式降低了GABA受体表达，单独的亚慢性伏硫西汀治疗可显著增加GABA对GABA受体的亲和力，但与subPCP联合使用时则不然。这些数据表明，伏硫西汀可逆转与GABA和谷氨酸神经传递改变相关模型中的认知障碍，进一步支持了伏硫西汀的GABA能和谷氨酸能作用与认知功能相关的假说。
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