We investigated the effect of manganese on the morphology of cultured rat cortical astrocytes. Astrocytes exhibited flattened, polygonal morphology in the absence of stimulation, and differentiated into process-bearing stellate cells following exposure to MnCl(2). MnCl(2)-induced stellation was a reversible process, which depended on the presence of extracellular free manganese. MnCl(2)-induced stellation did not stop with the introduction of pertussis toxin, PD98059, SB203580, phorbol 12-myristat 13-acetate, SQ22536, or LY83583. Alternatively, MnCl(2)-induced stellation did stop when exposed to colchicine and sodium orthovanadate, suggesting the involvement of the cytoskeletal elements and orthovanadate-sensitive protein tyrosine phosphatase. MnCl(2) might function as a factor regulating astrocyte morphology.