Ketamine, but not phencyclidine, selectively modulates cerebellar GABAA receptors containing α6 and δ subunits
Ketamine, but not phencyclidine, selectively modulates cerebellar GABAA receptors containing α6 and δ subunits
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DOI：
10.1523/jneurosci.5443-07.2008
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发表时间：
2008-05-14
影响因子：
5.3
通讯作者：
Amin, Jahanshah
中科院分区：
文献类型：
--
作者：
Hevers, Wulf;Hadley, Stephen H.;Amin, Jahanshah
苯环利定（PCP）和氯胺酮是分离性麻醉药，能够诱导镇痛、拟精神行为和无意识的紧张性状态。尽管有广泛的相似之处，但氯胺酮和五氯苯酚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，通常比PCP产生更大的CNS抑制。这两种药物都非竞争性抑制NMDA受体，但几乎没有证据表明这些药物会影响大多数麻醉剂的主要靶点GABA（A）受体。α 6 β 2/3 δ受体是GABA（A）受体家族的亚型，并且在成人小脑内的颗粒神经元中大量表达。在这里，使用卵母细胞表达系统，我们表明，在麻醉相关浓度，氯胺酮，但不是PCP，调制α 6 β 2 δ和α 6 β 3 δ受体。此外，在较高浓度下，氯胺酮直接激活这些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]）是一种结构上与PCP无关的NMDA受体的强效非竞争性拮抗剂，对α 6 β 2 δ受体无任何影响。在检查的重组GABA（A）受体亚型（α 1 β 2、α 1 β 2 γ 2、α 1 β 2 δ、α 4 β 2 γ 2、α 4 β 2 δ、α 6 β 2 γ 2、α 6 β 2 δ和α 6 β 3 δ）中，氯胺酮的作用仅限于α 6 β 2 δ和α 6 β 3 δ受体。在分离的颗粒神经元和小脑切片记录中，氯胺酮增强了由含α 6的GABA（A）受体引起的GABA能电导，而PCP没有显示出影响。此外，在转基因功能无效α 6（-/-）和δ（-/-）小鼠的小脑颗粒神经元中不存在氯胺酮增强作用。这些结果表明，氯胺酮达到的较高CNS β 2受体水平可能是其对α 6 β 2/3 δ受体的选择性作用的结果。
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. alpha 6 beta 2/3 delta 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 alpha 6 beta 2 delta and alpha 6 beta 3 delta 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 alpha 6 beta 2 delta receptors. Of the recombinantGABA(A) receptor subtypes examined (alpha 1 beta 2, alpha 1 beta 2 gamma 2, alpha 1 beta 2 delta, alpha 4 beta 2 gamma 2, alpha 4 beta 2 delta, alpha 6 beta 2 gamma 2, alpha 6 beta 2 delta, and alpha 6 beta 3 delta), the actions of ketamine were unique to alpha 6 beta 2 delta and alpha 6 beta 3 delta receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from alpha 6- containing GABA(A) receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null alpha 6(-/-) and delta(-/-) mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on alpha 6 beta 2/3 delta receptors.