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

Agonists of the allosteric benzodiazepine site of GABAA 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 on the expression of GABAA receptor subunits in the cerebellum. The potency of zolpidem, but not that of flurazepam, for the inhibition of [3H]flunitrazepam binding to cerebellar membranes is greatly reduced in gamma2I77/I77 mice. Zolpidem (1 microM) 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 on 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

Abolition of zolpidem sensitivity in mice with a point mutation in the GABAA receptor γ2 subunit

Agonists of the allosteric benzodiazepine site of GABAA receptors bind at the interface of the α and γ subunits. Here, we tested the in vivo contribution of the γ2 subunit to the actions of zolpidem, an α1 subunit selective benzodiazepine agonist, by generating mice with a phenylalanine (F) to isoleucine (I) substitution at position 77 in the γ2 subunit. The γ2F77I mutation has no major effect on the expression of GABAA receptor subunits in the cerebellum. The potency of zolpidem, but not that of flurazepam, for the inhibition of [ 3H]flunitrazepam binding to cerebellar membranes is greatly reduced in γ2I77/I77 mice. Zolpidem (1 μM) increased both the amplitude and decay of miniature inhibitory postsynaptic currents (mIPSCs) in Purkinje cells of control C57BL/6 (34% and 92%, respectively) and γ2F77/F77 (20% and 84%) mice, but not in those of γ2F77I mice. Zolpidem tartrate had no effect on exploratory activity (staircase test) or motor performance (rotarod test) in γ2I77/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 γ2I77/I77 mice. These results show that the effect of zolpidem, but not flurazepam, is selectively eliminated in the brain by the γ2F77I point mutation. © 2004 Elsevier Ltd. All rights reserved

Sicherheit in der Nachbetriebsphase von Endlagern fuer radioaktive Abfaelle

Im Auftrag des Bundesministeriums fuer Umwelt, Naturschutz und Reaktorsicherheit (BMU) hat die GRS im Vorhaben SR 2220/INT 9037 'Sicherheit in der Nachbetriebsphase von Endlagern fuer radioaktive Abfaelle' (1995-1998) auf der Basis der Weiterentwicklung von Wissenschaft und Technik im nationalen und internationalen Rahmen das BMU in seiner Aufsichtstaetigkeit auf dem Gebiet der Langzeitsicherheit fuer Endlager radioaktiver Abfaelle unterstuetzt und beraten, ad-hoc-Aufgaben fuer das BMU wahrgenommen sowie das BMU in den entsprechenden internationalen Gremien unterstuetzt. Der vorliegende Abschlussbericht fasst die wichtigsten von der GRS im Rahmen dieses Vorhabens erzielten Ergebnisse zusammen und verweist zur Klaerung von Details auf GRS-Arbeitsberichte und die einschlaegigen Veroeffentlichungen der GRS. (orig.)On behalf of the Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU), GRS supported and advised the BMU in its supervising activities in the area of long-term safety of final repositories for radioactive waste, solved ad hoc problems for the BMU, and supported the BMU in the corresponding international boards in the project SR 2220/INT 9037 'Safety in the post-closure phase of final repositories for radioactive waste' (1995-1998). The final report presented here summarises the most important results obtained by GRS in the frame of this project and refers for details to GRS working reports and to corresponding GRS publications. (orig.)98 refs.Available from TIB Hannover: RO 3190(1999-535) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman