Labelled histamine was taken up into cultured glial cells of chick embryonic brain by a system with high affinity for histamine and diffusion. The active uptake, occurring at low concentrations of the amine, was Na+ dependent and gave an apparent Km of 0.24 microM and a Vmax of 0.31 pmol x mg protein-1 x min-1. The uptake was completely blocked by desmethylimipramine (Ki = 2.5 microM) and partially by the histamine agonists and histamine-N-methyltransferase blockers 4-methylhistamine and 2-methylhistamine (I30 values obtained were 2 microM and 5 microM). Other psychoactive drugs were either ineffective (imipramine) or they showed moderate inhibitory effects (amitriptyline and cocaine). Ouabain (100 microM) inhibited uptake by approximately 50%. Diffusion occurred at high concentrations of the amine, was insensitive to extracellular Na+, and was proportional to histamine concentration up to 1 mM. [3H]-Histamine, taken up into the cells, was metabolized and/or released. The spontaneous efflux of the radioactivity measured after 10 min of exposure to [3H]-histamine (when most of it was still unmetabolized), was moderately Ca++ dependent, accelerated by both reduced concentrations of extracellular Na+ and enhanced concentrations of K+ and inhibited by desmethylimipramine. After prolonged (60 min) incubation, histamine metabolites detected in the cells presented 78% of the chromatogram radioactivity and consisted of N tau-methylhistamine and N tau-methylimidazole acetic acid. These results indicate that at low nM concentrations, histamine is taken up and metabolized by (and released from) glial cells by an Na(+)-dependent system, and the intracellular metabolism seems to serve an increased uptake of the amine.