title: Agonistic effects of the beta-carboline DMCM revealed in GABA(A) receptor gamma 2 subunit F77I point-mutated mice.
abstract: Affinity of the inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) to the benzodiazepine binding site of the GABA(A) receptor is abolished by a phenylalanine (F) to isoleucine (I) substitution at position 77 of the gamma2 subunit. We tested the effects of DMCM in gene knockin gamma2I77 mice carrying this mutation. Unlike in wild-type mice, DMCM was not able to reverse the GABA-induced reduction of the picrotoxin-sensitive t-butylbicyclophosphoro-[35S]thionate ([35S]TBPS) binding to GABA(A) receptor channels in the forebrain sections of gamma2I77 mice. Accordingly, DMCM was not convulsant in the mutant mice even at doses 20-fold higher (60mg/kg, i.p.) than those producing convulsions in wild-type littermate controls (3 mg/kg, i.p.). Neither did DMCM raise the c-Fos levels in gamma2I77 mouse brain. DMCM additionally exhibits a less well described agonistic effect on GABA(A) receptors that is normally masked by its strong inverse agonist effect. DMCM agonistically enhanced the GABA-induced reduction in [35S]TBPS binding to the cerebellar granule cell layer in control and mutant mice. In vivo DMCM (20-60 mg/kg i.p.) produced modest anxiolytic-like effects in gamma2I77 mice as assessed by elevated plus maze and staircase tests, but no motor impairment was found in the rotarod test. The results suggest only minor agonistic efficacy for the beta-carboline DMCM.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, POB 63 (Haartmaninkatu 8), FI-00014 Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Leppä
authors.forename: O Y
authors.initials: OY
authors.lastname: Vekovischeva
authors.forename: A-M
authors.initials: AM
authors.lastname: Lindén
authors.forename: P
authors.initials: P
authors.lastname: Wulff
authors.forename: A
authors.initials: A
authors.lastname: Oberto
authors.forename: W
authors.initials: W
authors.lastname: Wisden
authors.forename: E R
authors.initials: ER
authors.lastname: Korpi
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002243:Carbolines / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017354:Point Mutation; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D021122:Protein Subunits / Q000819:agonists* / Q000235:genetics* / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism
chemical_list: D002243:Carbolines; D058785:GABA-A Receptor Agonists; C546280:Gabrg2 protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate