HIV-1 ENVELOPE PROTEIN GP120 POTENTIATES NMDA-EVOKED NORADRENALINE RELEASE BY A DIRECT ACTION AT RAT HIPPOCAMPAL AND CORTICAL NORADRENERGICNERVE-ENDINGS

Exposure of rat or human neocortical or hippocampal tissue to glutamat e receptor agonists elicits a Ca2+-dependent, exocytotic-like release of previously accumulated [H-3]noradrenaline through activation of bot h N-methyl-D-aspartate (NMDA) and lpha-amino-3-hydroxy-5-methyl-4-isox azolepropionic acid (AMPA) receptors colocalized on the noradrenergic axon terminals. Here we show that the NMDA (100 mu M)-evoked release o f [H-3]noradrenaline from superfused thin layers of isolated rat hippo campal or cortical nerve endings was potentiated when the human immuno deficiency virus type 1 coat protein gp120 was added to the superfusio n medium concomitantly with NMDA. The effect of gp120 (10 pM to 3 nM) on the 100 mu M NMDA-evoked release of [H-3]noradrenaline was concentr ation-dependent; the maximal effect (similar to 140% potentiation) was reached at 100 pM of gp120. The protein was inactive on its own. The [H-3]noradrenaline release evoked by NMDA (100 mu M) + gp120 (100 pM) was prevented by classical NMDA receptor antagonists, as well as by 10 mu M memantine. Neither the release evoked by NMDA nor that elicited by NMDA + gp120 was sensitive to the nitric oxide synthase inhibitor N -G-nitro-L-arginine, suggesting no involvement of nitric oxide. The [H -3]noradrenaline release elicited by 100 mu M AMPA was unaffected by g p120. The protein potentiated the release evoked by 100 mu M glutamate ; the effect of 100 pM gp120 was quantitatively identical to that of 1 mu M glycine, with no apparent additivity between gp120 and glycine. The antagonism by 1 mu M 7-chloro-kynurenic acid of the NMDA-induced [ H-3]noradrenaline release was reversed by glycine or gp120. The data a re compatible with gp120 acting directly as a powerful positive allost eric modulator at a neuronal NMDA receptor.