(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide: (S18986-1) a positive modulator of AMPA receptors enhances (S)-AMPA-mediated [H-3]noradrenaline release from rat hippocampal and frontal cortex slices

The present study describes the effect of (S)-2,3-dihydro-[3,4]cyclopentano -1,2,4-benzothiadiazine-1,1-dioxide (S18986-1), a positive allosteric modul ator of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA ) receptors with cognitive-enhancing effects, on(S)-AMPA-induced [H-3]norad renaline release in rat hippocampal and frontal cortex slices. (S)-AMPA sig nificantly increased [H-3]noradrenaline release in rat hippocampus and fron tal cortex slices, whereas S18986-1 (3-1000 mu M) alone, was inactive. Howe ver, S18986-1 between 30 and 1000 mu M potently enhanced (+200%) (S)-AMPA-m ediated [H-3]noradrenaline release in both hippocampal and frontal cortex s lices. The capacity of S18986-1 to potentiate [H-3]noradrenaline release wa s specific for AMPA receptors as S18986-1 failed to potentiate either kaina te and N-methyl-D-aspartate (NMDA)-mediated release of [H-3]noradrenaline i n rat hippocampal slices. Moreover, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-be nzo[f]quinoxaline-7-sulfonamide (NBQX) and 1-(4-aminophenyl)-3-methylcarbam oyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI-536 55) but not (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine ((+)-MK-801), inhibited (S)-AMPA and S18986-induced stimulation of (S)-AMPA-mediated [H-3]noradrenaline release. In addition, S18986-1-indu ced stimulation of (S)-AMPA-evoked [3H]noradrenaline release was markedly a ttenuated in the presence of tetrodotoxin (1 mu M) and in Ca2+-free buffer. S18986-1 enhanced (S)-AMPA-mediated [H-3]noradrenaline release to a greate r extent than its corresponding (R)-enantiomer S19024-1 and racemic mixture S17951-1. However, positive allosteric modulators of AMPA receptors such a s aniracetam failed to potentiate AMPA-mediated noradrenaline release in hi ppocampal slices, whereas cyclothiazide potently enhanced (S)-AMPA-mediated [H-3]noradrenaline release. These results suggest that the capacity of S18 986-1 to enhance AMPA receptor-mediated release of noradrenaline in rat hip pocampus and frontal cortex, could contribute to the cognition enhancing me chanisms of S18986-1. (C) 2000 Elsevier Science B.V. All rights reserved.