HIV-1-associated cognitive/motor complex is a frequent neurological complication of the acquired immunodeficiency syndrome (AIDS). The pathogenesis of this syndrome implicates immunopathological and toxic events such as the production of cytokines. The HIV envelope glycoprotein gp120 seems also to play a major role in this process. Gp120 could produce a slow neuronal death probably via the release of neurotoxic factors by CNS macrophages/monocytes. NMDA antagonists and Ca2+ channel blockers in vitro have a powerful neuroprotective effect against gp120 neurotoxicity. The purpose of the present work is to determine whether gp120-induced neurotoxicity is associated with an abnormal neuronal depolarization induced by putative neurotoxins. We have compared in vitro the neuroprotective effects of Tetrodotoxin a Na+ channel blocker, the Ca2+ channel blocker nifedipine and the NMDA antagonist MK-801 in primary cortical neurons taken from embryonic rat and intoxicated with gp120. We observed comparable neuroprotective effects with the 3 precited compounds suggesting that gp120-induced neurotoxic factors act on Na+ channels, NMDA receptors and Ca2+ channels in a cascade of cellular events. We confirmed that the presence of macrophages is needed to trigger a marked gp120-induced neurotoxicity. These results underline the fact that depolarization is an important component of gp120 neurotoxicity in primary neuronal cultures.