Substantial increases in the nigral concentration of substance P-like immunoreactivity (SPLI) were observed after subacute administration of the indirect dopamine agonist, methamphetamine (METH, 15 mg/kg every 6 hr; five doses). The effect was opposite, and thus consistent, with the reduction of SPLI levels previously reported in nigral tissue after pharmacological blockade of the nigrostriatal dopaminergic activity. In addition, subacute METH treatment increased SPLI concentrations in other structures associated with the basal ganglia, such as the striatum and entopeduncular nucleus, but not in the hypothalamus or dorsal raphe nucleus. Subacute treatment with d-amphetamine exerted METH-like effects on the substance P neurons of the basal ganglia, whereas haloperidol completely antagonized the METH effect. The possibility that monoaminergic systems help mediate the response of the substance P system to subacute METH treatment is examined.