title: Actions of two GABAA receptor benzodiazepine-site ligands that are mediated via non-γ2-dependent modulation.
abstract: The potent sedative-hypnotic zolpidem and the convulsant methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) act primarily by binding to the benzodiazepine site of the main inhibitory neurotransmitter receptor, the pentameric γ-aminobutyric acid type A receptor (GABA(A)). This binding depends critically on the wild-type F77 residue of the GABA(A) receptor γ2 subunit. Mice with γ2 subunit F77I point mutation (γ2I77 mouse line) lose the high-affinity nanomolar binding of these ligands as well as their most robust behavioral actions at low doses. Interestingly, the γ2I77 mice offer a tool to study the actions of these substances mediated via other possible binding sites of the GABA(A) receptor. In ligand autoradiographic experiments, we discovered in γ2I77 mouse brain sections a significant amount of residual non-γ2 subunit-dependent benzodiazepine site binding enriched to the striatum and septum. Zolpidem only weakly affected this residual binding at micromolar concentrations, and only a high zolpidem dose (≥ 40 mg/kg) caused sedation and deficits in motor coordination in γ2I77 mice. DMCM had an agonistic action through a secondary, low-affinity non-benzodiazepine binding site of the GABA(A) receptor in the forebrain of γ2I77 mice, and this drug also fully displaced the residual benzodiazepine-site labeling. In behavioral tests, a high dose (20mg/kg) of DMCM was sedative and modulated fear learning. DMCM, but not zolpidem, acted as an agonist in recombinant GABA(A) α1/6β3 receptors studied using ligand binding and electrophysiological assays. Our results highlight the less well-known actions of high doses of DMCM and zolpidem that are not mediated via the γ2 subunit-containing benzodiazepine site of the GABA(A) receptor.
authors: Institute of Biomedicine, Pharmacology, POB 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. elli.leppa@helsinki.fi
authors: Elli
authors: E
authors: Leppä
authors: Anni-Maija
authors: AM
authors: Linden
authors: Holger
authors: H
authors: Rabe
authors: Olga Yu
authors: OY
authors: Vekovischeva
authors: Peer
authors: P
authors: Wulff
authors: Hartmut
authors: H
authors: Lüddens
authors: William
authors: W
authors: Wisden
authors: Esa R
authors: ER
authors: Korpi