Pehrson Alan L, Hillhouse Todd M, Haddjeri Nasser, Rovera Renaud, Porter Joseph H, Mørk Arne, Smagin Gennady, Song Dekun, Budac David, Cajina Manuel, Sanchez Connie
Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.).
Lundbeck Research USA, Paramus, New Jersey (A.L.P., G.S., D.S., D.B., M.C., C.S.); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark (C.S.); Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (T.M.H.); Psychology Department, Virginia Commonwealth University, Richmond, Virginia (T.M.H., J.H.P.); Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France (R.R., N.H.); and H. Lundbeck A/S, Copenhagen-Valby, Denmark (A.M.)
J Pharmacol Exp Ther. 2016 Sep;358(3):472-82. doi: 10.1124/jpet.116.233924. Epub 2016 Jul 11.
Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processing speed, executive function, and memory. However, the cause of these effects is unclear, and there are several competing theories on the underlying mechanism, notably including regionally-selective downstream enhancement of glutamate neurotransmission and increased acetylcholine (ACh) neurotransmission. The current work sought to evaluate the ACh hypothesis by examining vortioxetine's ability to reverse scopolamine-induced impairments in rodent tests of memory and attention. Additionally, vortioxetine's effects on hippocampal extracellular ACh levels were examined alongside studies of vortioxetine's pharmacokinetic profile. We found that acute vortioxetine reversed scopolamine-induced impairments in social and object recognition memory, but did not alter scopolamine-induced impairments in attention. Acute vortioxetine also induced a modest and short-lived increase in hippocampal ACh levels. However, this short-term effect is at variance with vortioxetine's moderately long brain half life (5.1 hours). Interestingly, subchronic vortioxetine treatment failed to reverse scopolamine-induced social recognition memory deficits and had no effects on basal hippocampal ACh levels. These data suggest that vortioxetine has some effects on memory that could be mediated through cholinergic neurotransmission, however these effects are modest and only seen under acute dosing conditions. These limitations may argue against cholinergic mechanisms being the primary mediator of vortioxetine's cognitive effects, which are observed under chronic dosing conditions in patients with MDD.
重度抑郁症（MDD）是一种常见的精神疾病，通常伴有认知功能受损，而这些认知症状可能是功能能力的重要决定因素。伏硫西汀是一种多模式抗抑郁药，可能改善MDD患者认知功能的某些方面，包括注意力、处理速度、执行功能和记忆力。然而，这些作用的原因尚不清楚，关于潜在机制有几种相互竞争的理论，特别是包括谷氨酸神经传递的区域选择性下游增强和乙酰胆碱（ACh）神经传递增加。目前的研究旨在通过检测伏硫西汀在啮齿动物记忆和注意力测试中逆转东莨菪碱诱导的损伤的能力来评估ACh假说。此外，在研究伏硫西汀的药代动力学特征的同时，还检测了其对海马细胞外ACh水平的影响。我们发现，急性给予伏硫西汀可逆转东莨菪碱诱导的社交和物体识别记忆损伤，但并未改变东莨菪碱诱导的注意力损伤。急性给予伏硫西汀还可使海马ACh水平适度且短暂升高。然而，这种短期效应与伏硫西汀适度较长的脑半衰期（5.1小时）不一致。有趣的是，亚慢性给予伏硫西汀未能逆转东莨菪碱诱导的社交识别记忆缺陷，且对基础海马ACh水平无影响。这些数据表明，伏硫西汀对记忆有一些可通过胆碱能神经传递介导的作用，然而这些作用较小，且仅在急性给药条件下可见。这些局限性可能表明胆碱能机制并非伏硫西汀认知作用的主要介导因素，而伏硫西汀的认知作用是在MDD患者的慢性给药条件下观察到的。
