EVIDENCE FOR A ROLE OF PRESYNAPTIC AMPA RECEPTORS IN THE CONTROL OF NEURONAL GLUTAMATE RELEASE IN THE RAT FOREBRAIN

The role of presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepion ic acid (AMPA) receptors in controlling the neuronal release of excita tory amino acids has been investigated. Stimulation of presynaptic AMP A receptors by the endogenous agonist L-glutamate, or by (R,S)-AMPA, d ose-dependently enhanced the Ca2+-dependent, tetrodotoxin-insensitive, electrically-stimulated release of [H-3]D-aspartate from rat forebrai n slices. This AMPA receptor-mediated response showed marked stereosel ectivity with the activity residing solely in the (S)-isomer. (R)-AMPA was inactive in this respect. AMPA-evoked responses were significantl y enhanced in the presence of the AMPA receptor desensitization inhibi tor, cyclothiazide (10 mu M). Moreover, responses to both AMPA and glu tamate were inhibited by competitive (NBQX) and non-competitive (GYKI 52466) AMPA receptor-selective antagonists in a dose-dependent manner. These results provide strong support far the existence of presynaptic AMPA receptors acting to enhance the synaptic release of excitatory a mino acids in the mammalian forebrain. Such a positive feedback system may play an important functional role in physiological (e.g., long-te rm potentiation) and/or pathological (e.g., epileptogenesis) processes in the mammalian central nervous system. AMPA-type autoreceptors may provide new targets for drug action. (C) 1997 Elsevier Science B.V.