Ketamine, but not phencyclidine, selectively modulates cerebellar GABAA receptors containing α6 and δ subunits

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.