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: S I Deutsch, C H Park, L G Lukacs, C Morn, L Koetzner, J Mastropaolo
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 51 Issue 4 Pg. 909-15 (Aug 1995) ISSN: 0091-3057 [Print] United States
• PMID: 7675876 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticonvulsants
• Benzodiazepinones
• Bridged Bicyclo Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Convulsants
• Isoquinolines
• Receptors, GABA-A
• 4'-chlorodiazepam
• Dizocilpine Maleate
• tert-butylbicyclophosphorothionate
• Flurazepam
• PK 11195

Topics

• Animals
• Anticonvulsants (pharmacology)
• Behavior, Animal (drug effects)
• Benzodiazepinones (pharmacology)
• Bridged Bicyclo Compounds (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic
• Cerebral Cortex (drug effects, metabolism)
• Convulsants (pharmacology)
• Dizocilpine Maleate (pharmacology)
• Drug Synergism
• Electroshock
• Flurazepam (pharmacology)
• Isoquinolines (pharmacology)
• Kinetics
• Male
• Mice
• Receptors, GABA-A (drug effects)