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

α1 Subunit-Containing GABA Type A Receptors in Forebrain Contribute to the Effect of Inhaled Anesthetics on Conditioned Fear

“…The gene knock-in approach has recently been used to determine the contribution of GABA A -R subunits to the behavioral effects of benzodiazepines and intravenous anesthetics (Rudolph et al, 1999;Low et al, 2000;Jurd et al, 2002;Reynolds et al, 2003;Cope et al, 2004). These studies created individual mouse lines with point mutations that reduced/eliminated sensitivity to these drugs.…”

Remote Control of Neuronal Signaling

“…The AlstR ligand allatostatin is a short peptide that is a selective and highly potent agonist for the D. melanogaster receptor; in addition, the cognate ligands of related mammalian receptors (e.g., somatostatin and opioid receptors) are inactive at AlstR. System relies on expression of a modified glutamate-and ivermectin-gated chloride channel from C. elegans, GluCl␣␤; point mutations reduce sensitivity to glutamate; slow onset (4-6 h) and time to peak (12 h) of silencing and prolonged recovery (4 days) with systemic administration; cells must express both ␣ and ␤ subunits (which allows for additional spatial resolution through intersectional expression strategies) GABA A -Zolpidem Positive allosteric GABA A agonists bind benzodiazepine site at interface of ␣ and ␥ 2 subunits; an F77I mutation of ␥ 2 abolishes zolpidem binding; conditional expression of wild-type ␥ 2 on a ␥ 2 F77I background enables selective neuronal silencing with zolpidem; the F77I mutation also abolishes binding of an inverse allosteric agonist, suggesting this same method could be used for neuronal activation Cope et al, 2004Cope et al, , 2005Ogris et al, 2004;Wulff et al, 2007;Wisden et al, 2009 8-OH-DPAT, 8-hydroxy-2-dipropylaminotetralin.…”

The effects of zolpidem treatment on GABAA receptors in cultured cerebellar granule cells: Changes in functional coupling

“…Cope et al (2004) demonstrated in vivo that the γ2 subunit is important for the action of zolpidem as well. Therefore, altered expression of this subunit would affect the binding of [ 3 H]flunitrazepam to its binding sites located at the interface of an α and a γ2 subunit (Sieghart, 1995;Buhr and Sigel, 1997).…”

“…Using a knock-in approach, Crestani et al (2000) confirmed the preferential affinity of zolpidem for the α1 subtype of GABA A receptors, and Cope et al (2004) demonstrated the contribution of the γ2 subunit to its action in vivo. In addition to its pronounced sedative properties and mild anxiolytic and myorelaxant effects (Depoortere et al, 1986;Sanger et al, 1996), several published papers have suggested that zolpidem might have better anticonvulsant activity than previously thought (Crestani et al, 2000;Peričić et al, 2008;.…”