Abolition of zolpidem sensitivity in mice with a point mutation in the GABAA receptor gamma2 subunit.

D. Cope, Peer Wulff, A. Oberto, M. I. Aller, M. Capogna, F. Ferraguti, C. Halbsguth, H. Hoeger, H. E. Jolin, A. Jones, A. N. J. McKenzie, W. Ogris, A. Poeltl, S. T. Sinkkonen, O. Y. Vekovischeva, E. R. Korpi, W. Sieghart, E. Sigel, P. Somogyi, William Wisden

Research output: Contribution to journalArticle

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Abstract

Agonists of the allosteric benzodiazepine site of GABA(A) receptors bind at the interface of the alpha and gamma subunits. Here, we tested the in vivo contribution of the gamma2 subunit to the actions of zolpidem, an alpha1 Subunit selective benzodiazepine agonist, by generating mice with a phenylalanine (F) to isoleucine (I) substitution at position 77 in the gamma2 subunit. The gamma2F77I mutation has no major effect oil the expression of GABA(A) receptor Subunits ill the cerebellum. The potency of zolpidem, but not that of flurazepam. for the inhibition of [H-3]flunitrazepam binding to cerebellar membranes is greatly reduced in gamma2I77/I77 mice. Zolpidem (1 muM) increased both the amplitude and decay of miniature inhibitory postsynaptic currents (mIPSCs) in Purkinje cells of control C57BL/6 (34% and 92%, respectively) and gamma2F77/F77 (20%, and 84%) mice, but not in those of gamma2F77I mice. Zolpidem tartrate had no effect oil exploratory activity (staircase test) or motor performance (rotarod test) in gamma2I77/I77 mice at doses up to 30 mg/kg (i.p.) that strongly sedated or impaired the control mice. Flurazepam was equally effective in enhancing mIPSCs and disrupting performance in the rotarod test in control and gamma2I77/I77 mice. These results show that the effect of zolpidem. but not flurazepam, is selectively eliminated in the brain by the gamma2F77I point mutation. (C) 2004 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)17-34
Number of pages17
JournalNeuropharmacology
Volume47
DOIs
Publication statusPublished - 2004

Keywords

  • GABA(A) receptor
  • gamma 2 subunit
  • mIPSC
  • zolpidem
  • benzodiazepine
  • cerebellum
  • AMINOBUTYRIC ACID(A) RECEPTOR
  • INHIBITORY SYNAPTIC-TRANSMISSION
  • ADULT-RAT BRAIN
  • GABA(A) RECEPTORS
  • SUBUNIT COMPOSITION
  • QUANTITATIVE IMPORTANCE
  • MINIATURE IPSCS
  • GAMMA-SUBUNIT
  • SUBTYPES
  • MOUSE

Cite this

Abolition of zolpidem sensitivity in mice with a point mutation in the GABAA receptor gamma2 subunit. / Cope, D.; Wulff, Peer; Oberto, A.; Aller, M. I.; Capogna, M.; Ferraguti, F.; Halbsguth, C.; Hoeger, H.; Jolin, H. E.; Jones, A.; McKenzie, A. N. J.; Ogris, W.; Poeltl, A.; Sinkkonen, S. T.; Vekovischeva, O. Y.; Korpi, E. R.; Sieghart, W.; Sigel, E.; Somogyi, P.; Wisden, William.

In: Neuropharmacology, Vol. 47, 2004, p. 17-34.

Research output: Contribution to journalArticle

Cope, D, Wulff, P, Oberto, A, Aller, MI, Capogna, M, Ferraguti, F, Halbsguth, C, Hoeger, H, Jolin, HE, Jones, A, McKenzie, ANJ, Ogris, W, Poeltl, A, Sinkkonen, ST, Vekovischeva, OY, Korpi, ER, Sieghart, W, Sigel, E, Somogyi, P & Wisden, W 2004, 'Abolition of zolpidem sensitivity in mice with a point mutation in the GABAA receptor gamma2 subunit.', Neuropharmacology, vol. 47, pp. 17-34. https://doi.org/10.1016/j.neuropharm.2004.03.007
Cope, D. ; Wulff, Peer ; Oberto, A. ; Aller, M. I. ; Capogna, M. ; Ferraguti, F. ; Halbsguth, C. ; Hoeger, H. ; Jolin, H. E. ; Jones, A. ; McKenzie, A. N. J. ; Ogris, W. ; Poeltl, A. ; Sinkkonen, S. T. ; Vekovischeva, O. Y. ; Korpi, E. R. ; Sieghart, W. ; Sigel, E. ; Somogyi, P. ; Wisden, William. / Abolition of zolpidem sensitivity in mice with a point mutation in the GABAA receptor gamma2 subunit. In: Neuropharmacology. 2004 ; Vol. 47. pp. 17-34.
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T1 - Abolition of zolpidem sensitivity in mice with a point mutation in the GABAA receptor gamma2 subunit.

AU - Cope, D.

AU - Wulff, Peer

AU - Oberto, A.

AU - Aller, M. I.

AU - Capogna, M.

AU - Ferraguti, F.

AU - Halbsguth, C.

AU - Hoeger, H.

AU - Jolin, H. E.

AU - Jones, A.

AU - McKenzie, A. N. J.

AU - Ogris, W.

AU - Poeltl, A.

AU - Sinkkonen, S. T.

AU - Vekovischeva, O. Y.

AU - Korpi, E. R.

AU - Sieghart, W.

AU - Sigel, E.

AU - Somogyi, P.

AU - Wisden, William

PY - 2004

Y1 - 2004

N2 - Agonists of the allosteric benzodiazepine site of GABA(A) receptors bind at the interface of the alpha and gamma subunits. Here, we tested the in vivo contribution of the gamma2 subunit to the actions of zolpidem, an alpha1 Subunit selective benzodiazepine agonist, by generating mice with a phenylalanine (F) to isoleucine (I) substitution at position 77 in the gamma2 subunit. The gamma2F77I mutation has no major effect oil the expression of GABA(A) receptor Subunits ill the cerebellum. The potency of zolpidem, but not that of flurazepam. for the inhibition of [H-3]flunitrazepam binding to cerebellar membranes is greatly reduced in gamma2I77/I77 mice. Zolpidem (1 muM) increased both the amplitude and decay of miniature inhibitory postsynaptic currents (mIPSCs) in Purkinje cells of control C57BL/6 (34% and 92%, respectively) and gamma2F77/F77 (20%, and 84%) mice, but not in those of gamma2F77I mice. Zolpidem tartrate had no effect oil exploratory activity (staircase test) or motor performance (rotarod test) in gamma2I77/I77 mice at doses up to 30 mg/kg (i.p.) that strongly sedated or impaired the control mice. Flurazepam was equally effective in enhancing mIPSCs and disrupting performance in the rotarod test in control and gamma2I77/I77 mice. These results show that the effect of zolpidem. but not flurazepam, is selectively eliminated in the brain by the gamma2F77I point mutation. (C) 2004 Elsevier Ltd. All rights reserved.

AB - Agonists of the allosteric benzodiazepine site of GABA(A) receptors bind at the interface of the alpha and gamma subunits. Here, we tested the in vivo contribution of the gamma2 subunit to the actions of zolpidem, an alpha1 Subunit selective benzodiazepine agonist, by generating mice with a phenylalanine (F) to isoleucine (I) substitution at position 77 in the gamma2 subunit. The gamma2F77I mutation has no major effect oil the expression of GABA(A) receptor Subunits ill the cerebellum. The potency of zolpidem, but not that of flurazepam. for the inhibition of [H-3]flunitrazepam binding to cerebellar membranes is greatly reduced in gamma2I77/I77 mice. Zolpidem (1 muM) increased both the amplitude and decay of miniature inhibitory postsynaptic currents (mIPSCs) in Purkinje cells of control C57BL/6 (34% and 92%, respectively) and gamma2F77/F77 (20%, and 84%) mice, but not in those of gamma2F77I mice. Zolpidem tartrate had no effect oil exploratory activity (staircase test) or motor performance (rotarod test) in gamma2I77/I77 mice at doses up to 30 mg/kg (i.p.) that strongly sedated or impaired the control mice. Flurazepam was equally effective in enhancing mIPSCs and disrupting performance in the rotarod test in control and gamma2I77/I77 mice. These results show that the effect of zolpidem. but not flurazepam, is selectively eliminated in the brain by the gamma2F77I point mutation. (C) 2004 Elsevier Ltd. All rights reserved.

KW - GABA(A) receptor

KW - gamma 2 subunit

KW - mIPSC

KW - zolpidem

KW - benzodiazepine

KW - cerebellum

KW - AMINOBUTYRIC ACID(A) RECEPTOR

KW - INHIBITORY SYNAPTIC-TRANSMISSION

KW - ADULT-RAT BRAIN

KW - GABA(A) RECEPTORS

KW - SUBUNIT COMPOSITION

KW - QUANTITATIVE IMPORTANCE

KW - MINIATURE IPSCS

KW - GAMMA-SUBUNIT

KW - SUBTYPES

KW - MOUSE

U2 - 10.1016/j.neuropharm.2004.03.007

DO - 10.1016/j.neuropharm.2004.03.007

M3 - Article

VL - 47

SP - 17

EP - 34

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -