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The Journal of Neuroscience, May 14, 2008, 28(20):5383-5393; doi:10.1523/JNEUROSCI.5443-07.2008

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Cellular/Molecular
Ketamine, But Not Phencyclidine, Selectively Modulates Cerebellar GABA_A Receptors Containing 6 and Subunits

Wulf Hevers,^1,3 Stephen H. Hadley,² Hartmut Lüddens,¹ and Jahanshah Amin²

¹Carl-Ludwig Department of Physiology, University of Leipzig, D-04103 Leipzig, Germany, ²Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida 33612, and ³Laboratory of Molecular Biology at the Department of Psychiatry, University of Mainz, D-55131 Mainz, Germany

Correspondence should be addressed to Jahanshah Amin, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612. Email: Jamin{at}health.usf.edu

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. 6β2/3 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 6β2 and 6β3 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 6β2 receptors. Of the recombinant GABA_A receptor subtypes examined (1β2, 1β22, 1β2, 4β22, 4β2, 6β22, 6β2, and 6β3), the actions of ketamine were unique to 6β2 and 6β3 receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from 6-containing GABA_A receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null 6^–/– and ^–/–mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on 6β2/3 receptors.

Key words: ketamine; 6β2/3 GABA_A receptors; granule neurons; slice recording; cerebellum; transgenic mice; tonic conductance

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Received Dec. 10, 2007; revised April 10, 2008; accepted April 10, 2008.

Correspondence should be addressed to Jahanshah Amin, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612. Email: Jamin{at}health.usf.edu

This article has been cited by other articles:

				X. Chen, S. Shu, and D. A. Bayliss HCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine J. Neurosci., January 21, 2009; 29(3): 600 - 609. [Abstract] [Full Text] [PDF]

				D.-S. Choi, W. Wei, J. K. Deitchman, V. N. Kharazia, H. M. B. Lesscher, T. McMahon, D. Wang, Z.-H. Qi, W. Sieghart, C. Zhang, et al. Protein Kinase C{delta} Regulates Ethanol Intoxication and Enhancement of GABA-Stimulated Tonic Current J. Neurosci., November 12, 2008; 28(46): 11890 - 11899. [Abstract] [Full Text] [PDF]

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