title: MK-801 alters the GABAA receptor complex and potentiates flurazepam's antiseizure efficacy.
abstract: MK-801 is an uncompetitive allosteric antagonist that interferes with glutamate-gated calcium ion conductance through the NMDA receptor-associated ionophore. In an outbred strain of mouse, MK-801 elicits episodes of explosive "popping" behaviors that may serve as a preclinical screening paradigm for novel antipsychotic medications. This investigation examined the effects of MK-801, at doses associated with the elicitation of popping, on the GABAA receptor complex in cerebral cortex, and flurazepam's ability to antagonize electrically precipitated seizures. Twenty four hours after MK-801 administration, there was an increased density of the radiolabeled antagonist-preferring conformation of the central benzodiazepine binding site and a potentiation of flurazepam's antiseizure efficacy. The data show that interference with NMDA receptor-mediated calcium ion conductance is associated with a relatively selective change in the GABAA receptor complex in cerebral cortex, and has functional behavioral consequences. Moreover, the data provide additional evidence for a delicate balance between GABAergic and glutamatergic transmission. Disturbance of this balance can have behavioral consequences for the animal.
authors.affiliation: Psychiatry Service, Department of Veterans Affairs Medical Center, Washington, DC 20422, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Deutsch
authors.forename: C H
authors.initials: CH
authors.lastname: Park
authors.forename: L G
authors.initials: LG
authors.lastname: Lukacs
authors.forename: C
authors.initials: C
authors.lastname: Morn
authors.forename: L
authors.initials: L
authors.lastname: Koetzner
authors.forename: J
authors.initials: J
authors.lastname: Mastropaolo
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001570:Benzodiazepinones / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004357:Drug Synergism; D004597:Electroshock; D005479:Flurazepam / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: D000927:Anticonvulsants; D001570:Benzodiazepinones; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D007546:Isoquinolines; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D016291:Dizocilpine Maleate; C037476:tert-butylbicyclophosphorothionate; D005479:Flurazepam; C037850:PK 11195