Ketamine Potentiates AMPA Receptor-mediated Activity in the Somatosensory Cortex

氯胺酮 NMDA受体 AMPA受体 麻醉剂 医学 拟精神病 神经科学 药理学 麻醉 背景(考古学) 谷氨酸受体 受体 生物 内科学 古生物学
作者
Bushra Yasin,Damian J. Williams,Carla Troyas,Neil L. Harrison,Christopher D. Makinson,Paul S. García
出处
期刊:Anesthesiology [Ovid Technologies (Wolters Kluwer)]
卷期号:141 (3): 611-614
标识
DOI:10.1097/aln.0000000000005108
摘要

Despite nearly five decades of clinical use, a mechanistic description of ketamine's ability to reliably produce anesthesia for surgery has been elusive. Ketamine is classified as a "dissociative anesthetic" because it produces a markedly distinct anesthetized state compared to other anesthetic drugs. Furthermore, ketamine acts by increasing the high-frequency oscillations in the beta-gamma range, which is distinct from γ-aminobutyric acid–mediated (GABAergic) anesthetics.1 Ketamine was thought to exert its anesthetic effect by acting as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors.2,3 However, the lack of anesthetic effects with MK-801, a non-competitive NMDA receptor antagonist structurally similar to ketamine, suggests that NMDAR antagonism may not be the primary mechanism for ketamine anesthesia. Ketamine also affects α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) which is thought to contribute to its antidepressant effects,4,5 but its interaction with AMPARs in the context of general anesthesia mechanisms remains unexplored.Several studies have reported the role of AMPARs in the antidepressant effect of sub-anesthetic doses of ketamine (concentrations estimated to range 30 to 50 µM) in rodents.6–8 However, the involvement of AMPARs in ketamine-induced unconsciousness at higher doses (100 µM) has yet to be fully addressed. In this study, we used whole cell recordings to explore the effect of ketamine on the postsynaptic AMPARs in pyramidal cells at layer 5 of the somatosensory cortex. First, we investigated how ketamine alters AMPAR kinetics by measuring the decay time constant (tau) of AMPAR spontaneous excitatory postsynaptic currents (sEPSCs) before and after ketamine administration. We utilized this approach to show that ketamine 100 µM, which is a clinically relevant concentration for surgical anesthesia (see below), significantly prolonged the AMPAR-mediated decay time constant by about 34% in sEPSCs at -70 mV. However, at ketamine 30 µM, the impact was less pronounced, showing an increase of roughly 11%, albeit still statistically significant (fig. 1). Altogether, these results raise the possibility that the observed increase in decay time constant, may have clinical or physiologic relevance for anesthesia.We compared NMDA and AMPA evoked EPSCs (eEPSCs) within cells by calculating their current ratio. In these conditions, both NMDAR and AMPAR are exposed equally to synaptically released glutamate, independent of the electrode positioning or number of presynaptic afferents, and thus provide a more reliable comparison of the effect of ketamine on NMDA and AMPA currents. Ketamine significantly increased the AMPA/NMDA ratio, suggesting that ketamine alters glutamatergic neurotransmission, by disrupting the balance between AMPAR and NMDAR activity (fig. 2). When ketamine was administered at 30 µM, its influence on AMPA current amplitude was less pronounced. This outcome aligns with the effect of ketamine 30 µM on the decay tau of this receptor.Because there was no consistent increase in AMPA eEPSCs amplitude at 30 uM (P = 0.53), this suggests that the increase in AMPA:NMDA at the lower ketamine concentration was driven by the observed reduction in NMDA eEPSCs amplitude. To further confirm the previous observation, we measured the components of eEPSCs related to AMPA and NMDA receptors. AMPAR currents were isolated by using APV and picrotoxin to block NMDA and GABAergic activity, respectively, while NMDA currents were obtained by blocking AMPAR activity with CNQX. Ketamine significantly increased AMPAR current amplitudes and reduced NMDAR current amplitudes (Supplemental Digital Content 1, https://links.lww.com/ALN/D608: ketamine increased the AMPAR current from 121.9 ± 25.1 pA to 322.5 ± 16.7, **P = 0.004, n = 4, paired t test).Given that any change in the properties of presynaptic release of glutamate would be expected to similarly impact AMPA and NMDA currents, the observed divergent effects of ketamine application on these currents indicates that the effect of ketamine on AMPAR EPSCs is likely postsynaptic. These findings reveal that AMPAR sEPSC potentiation by ketamine occurs with anesthetic concentrations and therefore may play a role in ketamine-induced unconsciousness.It may seem paradoxical that an anesthetic agent which acts as an antagonist of the glutamatergic NMDAR could generate excitation. To our knowledge, this study is the first to indicate that ketamine might render patients unconscious by increasing synaptic activity of the brain rather than by decreasing it. This view is supported by human imaging studies, which demonstrate, contrary to volatile gases and propofol, that there is no decrease in brain metabolism when sub-anesthetic or anesthetic doses of ketamine are administered, compared to awake, conscious states.9In summary, based on our findings, we conclude that ketamine anesthesia can be better understood as disrupting essential networks for consciousness rather than simply an inhibition of cortical activity, like the unconsciousness present during seizures. Our results demonstrate that a disruption in the balance of AMPAR and NMDAR by ketamine in the somatosensory cortex may contribute to its mechanism of inducing unconsciousness. The simultaneous blockade of NMDAR and potentiation of AMPAR postsynaptic currents can create an imbalance in synaptic strength that ultimately results in the lowering of the threshold for action potential firing and consequently increased synaptic "noise" leading to disruption of network activity that is vital for consciousness.10A limitation in our study arises from the specific ketamine concentrations used in our ex vivo preparation, which fails to completely replicate the plasma binding and diffusion kinetics of an in vivo brain.11,12 Our estimated brain concentrations were determined based on existing literature for subanesthetic and anesthetic doses.13 In mice, the recommended intraperitoneal injection dose of ketamine for surgical anesthesia is 50 to 100 mg/kg.14,15 This corresponds to a brain level of approximately 90 to 180 µM16–20 after 10 min of administration. Therefore, we focused on the effect of 100 µM ketamine which falls within the anesthetic range, but also a concentration of ketamine (30 µM) representative of a subanesthetic dose. However, one should also bear in mind that working with coronal brain slices poses challenges, such as uneven drug distribution, a variability in AMPAR and NMDAR expression, and truncation of afferents that could ultimately impact the recorded activity and introduce a response-dose mismatch.Dr. García is supported by the James S. McDonnell Foundation (St. Louis, Missouri) grant number: 220023046. Dr. Makinson has support from the National Institutes of Health, National Institute of Neurologic Disorders and Stroke R00NS104215, and National Institute of Mental Health DP2MH132944 (Bethesda, Maryland). Dr. Harrison has support from National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism AA030604.Dr. García has provided clinical consultation and expert witness testimony regarding ketamine and other anesthetics. He is also a named inventor on several patents owned by Columbia University (New York, New York) related to human electroencephalogram. Dr. García is also a co-founder of Lantern Laboratory, Inc. (Cortlandt Manor, New York), a company that develops electroencephalogram technology. None of these disclosures have any financial relevancy to the work presented. The other authors declare no competing interests.Supplemental Digital Content 1: Ketamine potentiates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) and suppresses NMDAR-mediated currents in pharmacologic isolated receptors, https://links.lww.com/ALN/D608

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
刚刚
calmxp发布了新的文献求助10
刚刚
刚刚
退休退休早日退休完成签到,获得积分10
2秒前
母广明完成签到,获得积分10
3秒前
3秒前
Sene发布了新的文献求助10
3秒前
啊哈哈发布了新的文献求助30
4秒前
kiminonawa发布了新的文献求助100
4秒前
5秒前
23完成签到,获得积分10
6秒前
agape111完成签到,获得积分20
6秒前
nn完成签到 ,获得积分10
6秒前
Oscar应助科研通管家采纳,获得10
6秒前
Akim应助科研通管家采纳,获得10
6秒前
小二郎应助科研通管家采纳,获得10
7秒前
小蘑菇应助科研通管家采纳,获得10
7秒前
慕青应助科研通管家采纳,获得10
7秒前
科研通AI2S应助科研通管家采纳,获得10
7秒前
7秒前
酷波er应助nyf凡采纳,获得10
7秒前
陈曦发布了新的文献求助10
7秒前
无花果应助superspace采纳,获得10
8秒前
calmxp完成签到,获得积分10
8秒前
隐形曼青应助认真的新筠采纳,获得10
8秒前
乐乐应助有热心愿意采纳,获得10
8秒前
百分之五完成签到,获得积分10
9秒前
9秒前
mingkle发布了新的文献求助30
9秒前
寻道图强应助木耳采纳,获得30
10秒前
10秒前
10秒前
务实紫真完成签到,获得积分10
11秒前
12秒前
leowin关注了科研通微信公众号
12秒前
顺利毕业发布了新的文献求助30
12秒前
13秒前
小蘑菇应助星空采纳,获得10
14秒前
15秒前
高分求助中
Evolution 10000
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
юрские динозавры восточного забайкалья 800
A new approach of magnetic circular dichroism to the electronic state analysis of intact photosynthetic pigments 500
Diagnostic immunohistochemistry : theranostic and genomic applications 6th Edition 500
Chen Hansheng: China’s Last Romantic Revolutionary 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3148527
求助须知:如何正确求助?哪些是违规求助? 2799622
关于积分的说明 7836197
捐赠科研通 2457012
什么是DOI,文献DOI怎么找? 1307684
科研通“疑难数据库(出版商)”最低求助积分说明 628247
版权声明 601655