N-ACETYL-ASPARTYLGLUTAMATE MODULATION OF N-METHYL-D-ASPARTATE-STIMULATED [H-3] NOREPINEPHRINE RELEASE FROM RAT HIPPOCAMPAL SLICES

The release of preloaded radiolabeled norepinephrine ([H-3]NE) from sl ices of rat hippocampus can be stimulated by excitatory amino acids th at interact with the N-methyl-D-aspartate (NMDA) receptor. The acidic dipeptide N-acetyl-L-aspartylglutamate (NAAG) is colocalized with NE i n the cell bodies of locus coeruleus (the origin of the noradrenergic projections to the hippocampus) and the hippocampus itself. The functi on of NAAG in these neurons has not been demonstrated, although eviden ce exists that it may serve as a neuromodulator in other neuronal path ways. NAAG inhibited the release of [H-3]NE stimulated by NMDA and L-g lutamate in a concentration-related manner. The maximal inhibition pro duced by NAAG was about 25% of the control release stimulated by 25 mu M NMDA. The effects observed were caused by the intact dipeptide and n ot the degradation artifacts produced by the enzyme N-acetylated-alpha -linked-acidic dipeptidase because N-acetyl-L-aspartate had no signifi cant effect on the release and L-glutamate was stimulatory. The activi ty of this enzyme appears to be suppressed under the assay conditions used. Although the addition of glycine did not enhance NMDA-stimulated release, 7-chlorokynurenate and 1-hydroxy-3-aminopyrrolidone-2 decrea sed the release in a concentration-dependent manner. Furthermore, the attenuation produced by NAAG plus 7-chlorokynurenate or 1-hydroxy-3-am inopyrrolidone-2 was greater than the inhibitory actions of either gly cine antagonist alone. Similarly, NAAG produced additional inhibition over that produced by either of two different voltage-dependent calciu m channel blockers. These findings suggest that NAAG may serve as a mo dulator of excitatory amino acid-mediated NE release in the hippocampu s. The site of action of NAAG is most likely not through the glycine b inding site nor the L or N type of voltage-dependent calcium channel.