MK-801 ALTERS THE GABA(A) RECEPTOR COMPLEX AND POTENTIATES FLURAZEPAMS ANTISEIZURE EFFICACY

MK-801 is an uncompetitive allosteric antagonist that interferes with glutamate-gated calcium ion conductance through the NMDA receptor-asso ciated ionophore. In an outbred strain of mouse, MK-801 elicits episod es of explosive ''popping'' behaviors that may serve as a preclinical screening paradigm for novel antipsychotic medications. This investiga tion examined the effects of MK-801, at doses associated with the elic itation of popping, on the GABA, receptor complex in cerebral cortex, and flurazepam's ability to antagonize electrically precipitated seizu res. Twenty four hours after MK-801 administration, there was an incre ased density of the radiolabeled antagonist-preferring conformation of the central benzodiazepine binding site and a potentiation of fluraze pam's antiseizure efficacy. The data show that interference with NMDA receptor-mediated calcium ion conductance is associated with a relativ ely selective change in the GABA, receptor complex in cerebral cortex, and has functional behavioral consequences. Moreover, the data provid e additional evidence for a delicate balance between GABAergic and glu tamatergic transmission. Disturbance of this balance can have behavior al consequences for the animal.