Injury to many regions of the central nervous system, including the striatum, results in a periwound or 'abortive' sprouting response. In order to directly evaluate whether macrophages play an important role in stimulating periwound sprouting, osteopetrotic (op/op) mice, which when young are deficient in a variety of macrophage subtypes, were given striatal wounds and the degree of dopaminergic sprouting subsequently assessed. Two weeks postinjury, significantly fewer wound macrophages were present in the striata of op/op mice compared with controls (144 +/- 30.1 in op/op mice vs. 416.6 +/- 82.3 in controls, P < 0.005, analysis performed on a section transecting the middle of the wound). Dopamine transporter immunohistochemistry revealed a marked decrease in the intensity of periwound sprouting in the op/op group of animals. Quantification of this effect using [H3]-mazindol autoradiography confirmed that periwound sprouting was reduced significantly in the op/op mice compared with controls (71.4 +/- 21.7 fmol/mg protein in op/op mice vs. 210.7 +/- 27.1 fmol/mg protein in controls, P < 0.0005). In the two groups of animals the magnitude of the sprouting response in individuals was closely correlated with the number of wound macrophages (R = 0.83, R2 = 0.69). Our findings provide strong support for the crucial involvement of macrophages in inducing dopaminergic sprouting after striatal injury.