Actions of two GABA(A) receptor benzodiazepine-site ligands that are mediated via non-gamma 2-dependent modulation

作者：Leppa Elli^*; Linden Anni Maija; Rabe Holger; Vekovischeva Olga Yu; Wulff Peer; Lueddens Hartmut; Wisden William; Korpi Esa R

来源：European Journal of Pharmacology, 2011, 666(1-3): 111-121.

DOI：10.1016/j.ejphar.2011.05.011

• GABA(A) receptor
• gamma 2 subunit
• Benzodiazepine
• Zolpidem
• DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate)
• Mouse model

The potent sedative-hypnotic zolpidem and the convulsant methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) act primarily by binding to the benzodiazepine site of the main inhibitory neurotransmitter receptor, the pentameric gamma-aminobutyric acid type A receptor (GABA(A)). This binding depends critically on the wild-type F77 residue of the GABA(A) receptor gamma 2 subunit. Mice with gamma 2 subunit F771 point mutation (gamma 2I77 mouse line) lose the high-affinity nanomolar binding of these ligands as well as their most robust behavioral actions at low doses. Interestingly, the gamma 2I77 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 gamma 2I77 mouse brain sections a significant amount of residual non-gamma 2 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 gamma 2I77 mice. DMCM had an agonistic action through a secondary, low-affinity non-benzodiazepine binding site of the GABA(A) receptor in the forebrain of gamma 2I77 mice, and this drug also fully displaced the residual benzodiazepine-site labeling. In behavioral tests, a high dose (20 mg/kg) of DMCM was sedative and modulated fear learning. DMCM, but not zolpidem, acted as an agonist in recombinant GABA(A) alpha 1/6 beta 3 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 gamma 2 subunit-containing benzodiazepine site of the GABA(A) receptor.

• 出版日期2011-9
• 单位河北医科大学