HUMAN BRAIN N-METHYL-D-ASPARTATE RECEPTORS REGULATING NORADRENALINE RELEASE ARE POSITIVELY MODULATED BY HIV-1 COAT PROTEIN GP120

Objective: To investigate the effect of HIV-II gp120 on the function o f glutamate receptors of the N-methyl-D-aspartate (NMDA) type in the h uman brain. Design: The monitoring of neurotransmitter release from su perfused isolated nerve endings is widely recognized as a technique ap propriate for the study of neurotransmitter release and to attribute a precise localization to the site(s) of action of drugs able to modula te release. Methods: Synaptosomes (pinched-off nerve endings) were pre pared from fresh human brain tissue samples removed during neurosurger y, labelled with [H-3]-noradrenaline and superfused at a rate of 0.5 m l/min with NMDA in the presence of gp41, gp160, gp120 or the V3 loop, with or without NMDA receptor antagonists. Fractions of superfusate we re collected and measured for radioactivity. Results: NMDA elicited a glycine-sensitive release of [3H]-noradrenaline from human brain synap tosomes. HIV-1 gp120 potentiated the NMDA (1 mM)-evoked [H-3]-noradren aline release (maximal effect similar to 110% at 1 nM). The release el icited by NMDA plus gp120 was prevented by the classical NMDA receptor antagonists dizocilpine or 7-chlorokynurenic acid, as well as by mema ntine. The potentiation by gp120 of the NMDA-evoked [H-3]-noradrenalin e release was mimicked by gp160 but not by gp41. The effect of gp120 w as retained by the V3 loop. Finally, gp120 reversed (1 nM) and surmoun ted (10 nM) the antagonism by 10 mu M 7-chlorokynurenate of the NMDA-e voked [H-3]-noradrenaline release. Conclusion: gp120 binds directly th rough the V3 loop at noradrenergic axon terminals in human brain neoco rtex and may alter the function of presynaptic NMDA receptors mediatin g regulation of noradrenaline release.