Regulation of glutamate efflux by excitatory amine acid receptors: Evidence for tonic inhibitory and phasic excitatory regulation

Several biochemical and electrophysiological studies have proposed the presence of presynaptic receptors that potentiate the release of excitatory amino acids (EAA). However, these studies have utilized exogenous EAA agonists and thus have assessed the autoregulation of EAA release during conditions of receptor hyperstimulation, and not during base line conditions. The aim of the present study was to address the question of whether there is a tonic autoregulation of base line EAA release. It was demonstrated that in the hippocampus and the striatum of freely moving rats, basal outflow of glutamate (Glu) and aspartate (Asp) are increased, in a dose-dependent manner, by local application of the antagonists of N-methyl-D-aspartate (NMDA) or non-NMDA receptors, suggesting that there is an ongoing tonic inhibition of aspartate and Glu outflow by different subtypes of EAA receptors. Subsequently, to investigate the effect EAA receptor- hyperstimulation on Glu outflow, a comprehensive study of the effect of various doses of ionotropic and metabotropic EAA agonists on the extracellular levels of Glu was performed. At high concentrations, agonists of all known subtypes of EAA receptors induced (large) increases in extracellular levels of Glu and in most cases caused behavioral stimulation and/or convulsion. This suggests that during conditions of high agonist availability, such as the massive Glu release thought to occur during pathological conditions, a positive feedback presynaptic mechanism may overcome the autoregulatory mechanism operating during base line conditions.