The effects of pretreatment with either SCH 23390, a selective D-1 antagonist or YM-09151-2, a selective D-2 antagonist, on methamphetamine (MAP)-induced changes in the substance P and TRH system were investigated. A single dose of 4 mg/kg of MAP reduced the striatal level of substance P 30 min after injection. This reduction was reversed by pretreatment with YM-09151-2 but not with SCH 23390. Repeated administration of 4 mg/kg of MAP for 14 days reduced specific substance P and TRH binding in the striatum at 1 h, but not at 48 h, after the last injection. The reduction of striatal substance P receptor binding was prevented by pretreatment YM-09151-2 but not SCH 23390 prior to each MAP administration. The reduction of striatal TRH receptor binding was prevented by pretreatment with either antagonist. These results indicate that changes in striatal substance P level and substance P receptor binding induced by subchronic MAP treatment are mediated via activation of D-2 but not D-1 receptors by MAP-released dopamine, while changes in striatal TRH receptor binding are mediated via both D-1 and D-2 receptors.