D-Amphetamine reduces striatal substance P concentrations by presynaptic release of dopamine.

Single, but not repeated, doses of D-amphetamine sulfate cause dose-dependent reductions in substance P (SP) immunoreactive material within the rat striatum. A 10 mg/kg (i.p.) dose reduces SP levels from 1.37 to 0.97 pmol/10 mg tissue after 2 h. Similar reductions in striatal SP levels are observed after administration of methylphenidate (50 or 100 mg/kg). No changes in SP concentrations occur within the substantia nigra or hypothalamus after D-amphetamine. The amphetamine-induced decline in striatal SP is blocked by pretreating rats with alpha-methyl tyrosine methyl ester (225 mg/kg i.p.), or haloperidol (1, 3 or 10 mg/kg i.p.), or after the dopaminergic nigrostriatal tract has been lesioned using 6-hydroxydopamine. These data indicate that the mechanism by which D-amphetamine lowers striatal SP involves presynaptic release of dopamine from the terminals of nigrostriatal neurons.