A PRESYNAPTIC N-METHYL-D-ASPARTATE AUTORECEPTOR IN RAT HIPPOCAMPUS MODULATING AMINO-ACID RELEASE FROM A CYTOPLASMIC POOL

A possible role of the N-methyl-D-aspartate receptor (NMDA-R) as a pre synaptic autoreceptor was investigated using Percoll-purified hippocam pus nerve terminals (synaptosomes). This preparation contained only a neglectable amount of postsynaptic structures. Two main effects of NMD A were observed. First, NMDA dose-dependently (10-100 mu M) and in the absence of Mg2+, stimulated basal release of aspartate and glutamate, but not of GABA. MK801 (10 mu M), an open NMDA-R-channel blocker, red uced this effect even below control levels, indicating endogenous NMDA -R activation. By superfusing synaptosomes, which prevents a tonic rec eptor occupation, also basal GABA release was stimulated by NMDA. The NMDA-induced potentiation of amino acid superfusate levels was blocked both by MK801 and Mg2+ (1 mM), was slow in onset and returned to base line after NMDA-removal, The NMDA-effect was also found in the absence of extracellular Ca2+, suggesting that amino acids were released from a non-vesicular (cytoplasmic) pool. Secondly, in KCI-depolarized syna ptosomes exposed to 1 mM Mg2+, NMDA did not affect the release of the amino acids. MK801, however, reduced the KCl-evoked Ca2+-independent r elease of aspartate and glutamate, but not of GABA. L-trans-PDC, the s elective inhibitor of the glutamate/aspartate transporter, prevented t his MK801-effect, suggesting a coupling between NMDA-Rs and these tran sporters. These data provide evidence for a presynaptic NMDA autorecep tor in rat hippocampus. We speculate on the role of this NMDA-R to dep olarize the presynaptic membrane by Naf-entry, which may induce revers al of amino acid transporters and thereby releasing amino acids from a cytoplasmic pool.