Abstract
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 modulator of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with cognitive-enhancing effects, on ( S)-AMPA-induced [ 3H]noradrenaline release in rat hippocampal and frontal cortex slices. ( S)-AMPA significantly increased [ 3H]noradrenaline release in rat hippocampus and frontal cortex slices, whereas S18986-1 (3–1000 μM) alone, was inactive. However, S18986-1 between 30 and 1000 μM potently enhanced (+200%) ( S)-AMPA-mediated [ 3H]noradrenaline release in both hippocampal and frontal cortex slices. The capacity of S18986-1 to potentiate [ 3H]noradrenaline release was specific for AMPA receptors as S18986-1 failed to potentiate either kainate and N-methyl- d-aspartate (NMDA)-mediated release of [ 3H]noradrenaline in rat hippocampal slices. Moreover, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[ f]quinoxaline-7-sulfonamide (NBQX) and 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5 H-2,3-benzodiazepine (GYKI-53655) but not (5 R,10 S)-(+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a, d]cyclohepten-5,10-imine ((+)-MK-801), inhibited ( S)-AMPA and S18986-induced stimulation of ( S)-AMPA-mediated [ 3H]noradrenaline release. In addition, S18986-1-induced stimulation of ( S)-AMPA-evoked [ 3H]noradrenaline release was markedly attenuated in the presence of tetrodotoxin (1 μM) and in Ca 2+-free buffer. S18986-1 enhanced ( S)-AMPA-mediated [ 3H]noradrenaline release to a greater extent than its corresponding ( R)-enantiomer S19024-1 and racemic mixture S17951-1. However, positive allosteric modulators of AMPA receptors such as aniracetam failed to potentiate AMPA-mediated noradrenaline release in hippocampal slices, whereas cyclothiazide potently enhanced ( S)-AMPA-mediated [ 3H]noradrenaline release. These results suggest that the capacity of S18986-1 to enhance AMPA receptor-mediated release of noradrenaline in rat hippocampus and frontal cortex, could contribute to the cognition enhancing mechanisms of S18986-1.
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