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Journal of Neuroscience
Article . 2008 . Peer-reviewed
License: CC BY NC SA
Data sources: Crossref
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Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABAAReceptors Containing α6 and δ Subunits

Authors: Jahanshah Amin; Hartmut Lüddens; Wulf Hevers; Stephen H. Hadley;

Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABAAReceptors Containing α6 and δ Subunits

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 GABAAreceptors, the primary target of most anesthetics. α6β2/3δ receptors are subtypes of the GABAAreceptor 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 α6β2δ and α6β3δ receptors. Additionally, at higher concentrations, ketamine directly activates these GABAAreceptors. 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 α6β2δ receptors. Of the recombinant GABAAreceptor subtypes examined (α1β2, α1β2γ2, α1β2δ, α4β2γ2, α4β2δ, α6β2γ2, α6β2δ, and α6β3δ), the actions of ketamine were unique to α6β2δ and α6β3δ receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from α6-containing GABAAreceptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally nullα6−/−and δ−/−mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on α6β2/3δ receptors.

Related Organizations
Keywords

Mice, Knockout, Neurons, Anesthetics, Dissociative, Patch-Clamp Techniques, Dose-Response Relationship, Drug, Phencyclidine, Neural Inhibition, Membrane Potentials, Rats, Mice, Inbred C57BL, Rats, Sprague-Dawley, Cerebellar Cortex, Mice, Organ Culture Techniques, Oocytes, Animals, Female, Ketamine, Excitatory Amino Acid Antagonists, Cells, Cultured

  • BIP!
    Impact byBIP!
    citations
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    119
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Top 10%
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
119
Top 10%
Top 10%
Top 10%
hybrid