Hevers Wulf, Hadley Stephen H, Lüddens Hartmut, Amin Jahanshah
Carl-Ludwig Department of Physiology, University of Leipzig, D-04103 Leipzig, Germany.
J Neurosci. 2008 May 14;28(20):5383-93. doi: 10.1523/JNEUROSCI.5443-07.2008.
Phencyclidine (PCP) and ketamine are dissociative anesthetics capable of inducing analgesia, psychomimetic behavior, and a catatonic state of unconsciousness. Despite broad similarities, there are notable differences between the clinical actions of ketamine and PCP. Ketamine has a lower incidence of adverse effects and generally produces greater CNS depression than PCP. Both noncompetitively inhibit NMDA receptors, yet there is little evidence that these drugs affect GABA(A) receptors, the primary target of most anesthetics. alpha6beta2/3delta receptors are subtypes of the GABA(A) receptor family and are abundantly expressed in granular neurons within the adult cerebellum. Here, using an oocyte expression system, we show that at anesthetically relevant concentrations, ketamine, but not PCP, modulates alpha6beta2delta and alpha6beta3delta receptors. Additionally, at higher concentrations, ketamine directly activates these GABA(A) receptors. Comparatively, dizocilpine (MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]), a potent noncompetitive antagonist of NMDA receptors that is structurally unrelated to PCP, did not produce any effect on alpha6beta2delta receptors. Of the recombinant GABA(A) receptor subtypes examined (alpha1beta2, alpha1beta2gamma2, alpha1beta2delta, alpha4beta2gamma2, alpha4beta2delta, alpha6beta2gamma2, alpha6beta2delta, and alpha6beta3delta), the actions of ketamine were unique to alpha6beta2delta and alpha6beta3delta receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from alpha6-containing GABA(A) receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null alpha6(-/-) and delta(-/-)mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on alpha6beta2/3delta receptors.
苯环己哌啶（PCP）和氯胺酮是解离性麻醉剂，能够诱导镇痛、拟精神病行为和紧张性无意识状态。尽管存在广泛的相似性，但氯胺酮和PCP的临床作用之间存在显著差异。氯胺酮的不良反应发生率较低，并且通常比PCP产生更强的中枢神经系统抑制作用。两者均非竞争性抑制N-甲基-D-天冬氨酸（NMDA）受体，但几乎没有证据表明这些药物会影响γ-氨基丁酸A（GABA(A)）受体，而GABA(A)受体是大多数麻醉剂的主要作用靶点。α6β2/3δ受体是GABA(A)受体家族的亚型，在成年小脑的颗粒神经元中大量表达。在此，我们使用卵母细胞表达系统表明，在麻醉相关浓度下，氯胺酮而非PCP可调节α6β2δ和α6β3δ受体。此外，在较高浓度下，氯胺酮可直接激活这些GABA(A)受体。相比之下，地佐环平（MK-801 [（+）-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸盐]），一种与PCP结构无关的NMDA受体强效非竞争性拮抗剂，对α6β2δ受体没有任何影响。在所检测的重组GABA(A)受体亚型（α1β2、α1β2γ2、α1β2δ、α4β2γ2、α4β2δ、α6β2γ2、α6β2δ和α6β3δ）中，氯胺酮的作用对α6β2δ和α6β3δ受体具有独特性。在解离的颗粒神经元和小脑切片记录中，氯胺酮增强了含α6的GABA(A)受体产生的GABA能电导，而PCP则无作用。此外，在转基因功能缺失的α6(-/-)和δ(-/-)小鼠的小脑颗粒神经元中，氯胺酮的增强作用不存在。这些发现表明，氯胺酮达到的较高中枢神经系统抑制水平可能是其对α6β2/3δ受体的选择性作用的结果。
