Loss of zolpidem efficacy in the hippocampus of mice with the GABAA receptor gamma2 F77I point mutation.

Zolpidem is a hypnotic benzodiazepine site agonist with some c-aminobutyric acid (GABA)A receptor subtype selectivity. Here, we have tested the effects of zolpidem on the hippocampus of c2 subunit (c2F77I) point mutant mice. Analysis of forebrain GABAA receptor expression with immunocytochemistry, quantitative [ 3 H]muscimol and [ 35 S] t-butylbicyclophosphorothionate (TBPS) autoradiography, membrane binding with [ 3 H]flunitrazepam and [ 3 H]muscimol, and comparison of miniature inhibitory postsynaptic current (mIPSC) parameters did not reveal any differences between homozygous c2I77 ⁄I77 and c2F77 ⁄F77 mice. However, quantitative immunoblot analysis of c2I77 ⁄I77 hippocampi showed some increased levels of c2, a1, a4 and d subunits, suggesting that differences between strains may exist in unassembled subunit levels, but not in assembled receptors. Zolpidem (1 lm) enhanced the decay of mIPSCs in CA1 pyramidal cells of control (C57BL ⁄6J, c2F77 ⁄F77) mice by � 60%, and peak amplitude by � 20% at 33‐ 34 � C in vitro. The actions of zolpidem (100 nm or 1 lm) were substantially reduced in c2I77 ⁄I77 mice, although residual effects included a 9% increase in decay and 5% decrease in peak amplitude. Similar results were observed in CA1 stratum oriens ⁄alveus interneurons. At network level, the effect of zolpidem (10 lm) on carbachol-induced oscillations in the CA3 area of c2I77 ⁄I77 mice was significantly different compared with controls. Thus, the c2F77I point mutation virtually abolished the actions of zolpidem on GABAA receptors in the hippocampus. However, some residual effects of zolpidem may involve receptors that do not contain the c2 subunit.