H. Lundbeck A/S, Translational Biology, Valby, Denmark; University of Copenhagen, Faculty of Health and Medical Sciences, Department of Drug Design and Pharmacology, Copenhagen, Denmark; Institut d'Investigacions Biomèdiques de Barcelona IIBB-CSIC, Department of Neurochemistry and Neuropharmacology, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, IDIBAPS, Barcelona, Spain.
Institut d'Investigacions Biomèdiques de Barcelona IIBB-CSIC, Department of Neurochemistry and Neuropharmacology, Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, IDIBAPS, Barcelona, Spain.
Neuropharmacology. 2019 Nov 1;158:107745. doi: 10.1016/j.neuropharm.2019.107745. Epub 2019 Aug 21.
Non-competitive N-methyl-d-aspartate receptor antagonists mimic schizophrenia symptoms and produce immediate and persistent antidepressant effects. We investigated the effects of ketamine and phencyclidine (PCP) on thalamo-cortical network activity in awake, freely-moving male Wistar rats to gain new insight into the neuronal populations and brain circuits involved in the effects of NMDA-R antagonists. Single unit and local field potential (LFP) recordings were conducted in mediodorsal/centromedial thalamus and in medial prefrontal cortex (mPFC) using microelectrode arrays. Ketamine and PCP moderately increased the discharge rates of principal neurons in both areas while not attenuating the discharge of mPFC GABAergic interneurons. They also strongly affected LFP activity, reducing beta power and increasing that of gamma and high-frequency oscillation bands. These effects were short-lasting following the rapid pharmacokinetic profile of the drugs, and consequently were not present at 24 h after ketamine administration. The temporal profile of both drugs was remarkably different, with ketamine effects peaking earlier than PCP effects. Although this study is compatible with the glutamate hypothesis for fast-acting antidepressant action, it does not support a local disinhibition mechanism as the source for the increased pyramidal neuron activity in mPFC. The short-lasting increase in thalamo-cortical activity is likely associated with the rapid psychotomimetic action of both agents but could also be part of a cascade of events ultimately leading to the persistent antidepressant effects of ketamine. Changes in spectral contents of high-frequency bands by the drugs show potential as translational biomarkers for target engagement of NMDA-R modulators.
非竞争性 N-甲基-D-天冬氨酸受体拮抗剂模拟精神分裂症症状并产生即时和持久的抗抑郁作用。我们研究了氯胺酮和苯环利定（PCP）对清醒、自由活动的雄性 Wistar 大鼠丘脑-皮质网络活动的影响，以深入了解参与 NMDA-R 拮抗剂作用的神经元群体和脑回路。使用微电极阵列在中背/中央丘脑和内侧前额叶皮层（mPFC）中进行单个单元和局部场电位（LFP）记录。氯胺酮和 PCP 适度增加了两个区域的主要神经元的放电率，而不减弱 mPFC GABA 能中间神经元的放电。它们还强烈影响 LFP 活动，降低β功率并增加γ和高频振荡带的功率。这些作用在药物快速药代动力学特征后持续时间很短，因此在氯胺酮给药后 24 小时内不存在。两种药物的时间分布非常不同，氯胺酮的作用早于 PCP 的作用。尽管这项研究与快速作用抗抑郁作用的谷氨酸假说一致，但它不支持局部去抑制机制是 mPFC 中锥体神经元活动增加的来源。丘脑-皮质活动的短暂增加可能与两种药物的快速致幻作用有关，但也可能是导致氯胺酮持续抗抑郁作用的一系列事件的一部分。药物对高频带光谱含量的改变显示出作为 NMDA-R 调节剂的靶标结合的转化生物标志物的潜力。
