MODULATION OF AMPA KAINATE RECEPTORS BY ANALOGS OF DIAZOXIDE AND CYCLOTHIAZIDE IN THIN SLICES OF RAT HIPPOCAMPUS/

Among the non-NMDA (non-N-methyl-D-aspartic acid) glutamate receptors, the AMPA no-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid) sel ective receptors are characterized by a fast occurring desensitization . We and others have searched for specific modifiers of the rapid dese nsitization of AMPA responses in hippocampal slices using the patch-cl amp technique. Aniracetam (1-(4-methoxybenzoyl)-2-pyrrolidinone) and d iazoxide (7-chloro-3-methyl-2H-1,2,4-benzo-thiadiazine 1,1-dioxide) (1 mM) increased glutamate-activated currents recorded from voltage-clam ped CA1 pyramidal neurons in presence of 5 muM MK-801 (dizocilpine; ro -5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine) by 2-5 fold. Cyclothi azide -5-en-2-yl-6-chloro-3,4-dihydro-2H-1,2,4-benzothia diazine-7-sul fonamide 1,1-dioxide) (100 muM), a chemical congener of diazoxide, com pletely removed the desensitization of the AMPA response measured with fast application in excised outside-out patches. At this concentratio n cyclothiazide produced an 18 fold enhancement of the glutamate curre nt. Eighteen diazoxide analogues (2H-1,2,4-benzothiadizines: IDRA 2-19 ) were then tested but none of them was as effective as diazoxide. Thr ee analogues of cyclothiazide (3,4-dihydro-2H-1,2,4-benzothia-diazines : IDRA 20-22) were also tested and none of them were as potent as the parent compound, However, IDRA 21 produced a response 3 times larger t han diazoxide. Moreover, while cyclothiazide and diazoxide potentiated kainate responses for all the doses that decreased AMPA receptor dese nsitization, IDRA 21, similarly to aniracetam, inhibited AMPA receptor desensitization preferentially. These results suggest that similarly to NMDA receptors the structure of AMPA receptors may include a center that regulates desensitization.