THE DIAZOXIDE DERIVATIVE -3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE-S,S-DIOXIDE AUGMENTS AMPA-MEDIATED AND GABA-MEDIATED SYNAPTIC RESPONSES IN CULTURED HIPPOCAMPAL-NEURONS

The diazoxide derivative -3,4-dihydro-2H-1,2,4-benzothiadiazine-S,S-di oxide (IDRA21) enhances memory and learning in rodents, most likely by potentiating AMPAergic synaptic activity. We examined IDRA21's effect upon AMPAergic synaptic currents and whole-cell glutamate currents in cultured rat hippocampal neurons to determine whether IDRA21 was a pa rtial modulator of AMPA receptor desensitization and deactivation. Com parable to cyclothiazide, IDRA21 prolonged AMPAergic autaptic currents (5.6 times control, EC50 150 mu M) and slowed the rate of AMPA deacti vation (3 times control) following 1-ms applications of 1 mM glutamate to excised, outside-out membrane patches. IDRA21 also augmented autap tic GABA currents by 27 +/- 8.1%, although it had two opposing effects , reducing the peak amplitude versus prolonging autaptic GABA currents . IDRA21 (200 mu M) inhibited whole-cell GABA currents elicited by exo genously applied 1 mM GABA by 41 +/- 11%. At sufficient concentrations , IDRA21 reduced AMPA receptor desensitization and slowed the rate of deactivation, most consistent with full agonist activity with lower po tency compared to cyclothiazide. IDRA21 slightly augments GABAergic sy naptic currents. (C) 1998 Academic Press.