Article

Ketamine, but not phencyclidine, selectively modulates cerebellar GABA(A) receptors containing alpha6 and delta subunits.

Carl-Ludwig Department of Physiology, University of Leipzig, D-04103 Leipzig, Germany.
Journal of Neuroscience (impact factor: 7.11). 06/2008; 28(20):5383-93. DOI:10.1523/JNEUROSCI.5443-07.2008 pp.5383-93
Source: PubMed

ABSTRACT 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.

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Keywords

adverse effects
 
alpha6-containing GABA(A)
 
alpha6beta2/3delta receptors
 
alpha6beta2delta receptors
 
alpha6beta3delta receptors
 
anesthetically relevant concentrations
 
cerebellar granule neurons
 
cerebellar slice recordings
 
dissociated granule neurons
 
granular neurons
 
greater CNS depression
 
higher concentrations
 
ketamine potentiation
 
lower incidence
 
modulates alpha6beta2delta
 
NMDA receptors
 
oocyte expression system
 
potent noncompetitive antagonist
 
recombinant GABA(A)
 
transgenic functionally null alpha6(-/-)