We studied the effects of organic and inorganic mercury (Hg) on the uptake of L-[³H] glutamate (L-GLU) in cultured mouse astrocytes. Following exposure to mercuric chloride (MC) [0.2 approximately 5.0 µM], selective and dose-dependent inhibition of L-GLU uptake to 50% of control levels was observed, whereas 2-deoxyglucose (2-DG) uptake was not significantly affected. Methylmercuric chloride (MMC) also inhibited L-GLU uptake but 50% reduction was reached only at a concentration of 10 µM. Inhibition of L-GLU uptake by MMC appears to be closely linked to voltage-sensitive calcium channels as evidenced by the lack of L-GLU uptake inhibition by MMC in calcium-free medium or in the presence of the channel blocker verapamil. Exposure to a variety of divalent metallic ions, including CuCl₂, FeCl₂ and ZnCl₂, did not affect L-GLU uptake in astrocytes in vitro. Exposure to PbCl₂, however, resulted in a decline in L-GLU uptake, though to a much smaller degree than that observed with Hg compounds. Selective impairment of astroglial L-GLU transport may represent a critical early pathogenetic feature of Hg-induced neurotoxicity.