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-isoxazolepropionic acid (AMPA) receptors in controlling the neuronal release of excitatory amino acids has been investigated. Stimulation of presynaptic AMPA receptors by the endogenous agonist L-glutamate, or by (R,S)-AMPA, dose-dependently enhanced the Ca(2+)-dependent, tetrodotoxin-insensitive, electrically-stimulated release of [3H]D-aspartate from rat forebrain slices. This AMPA receptor-mediated response showed marked stereoselectivity with the activity residing solely in the (S)-isomer. (R)-AMPA was inactive in this respect. AMPA-evoked responses were significantly enhanced in the presence of the AMPA receptor desensitization inhibitor, cyclothiazide (10 microM). Moreover, responses to both AMPA and glutamate were inhibited by competitive (NBQX) and non-competitive (GYKI 52466) AMPA receptor-selective antagonists in a dose-dependent manner. These results provide strong support for the existence of presynaptic AMPA receptors acting to enhance the synaptic release of excitatory amino acids in the mammalian forebrain. Such a positive feedback system may play an important functional role in physiological (e.g., long-term potentiation) and/or pathological (e.g., epileptogenesis) processes in the mammalian central nervous system. AMPA-type autoreceptors may provide new targets for drug action.