Catecholamine receptors positively coupled to adenylate cyclase (AC) have been shown to undergo rapid desensitization after excessive stimulation. Because amphetamine (AMPH) is known to enhance dopamine (DA) release and striatal D1 DA receptors are positively coupled to AC, the effect of acute AMPH on D1 DA receptor function was examined. Doses of AMPH were chosen for their contrasting behavioral effects: 1 mg/kg, which enhances locomotor activity, and 5 mg/kg, which promotes intense, focused stereotypies. AMPH was administered S.C. 45 min before killing. Assay of striatal AC activity was performed by following the conversion of [alpha-32P]ATP to [32P]cyclic AMP. A dose of 5 mg/kg of AMPH, but not 1 mg/kg of AMPH, caused a 2-fold shift to the right in the dose-response curve for DA in stimulating AC activity when compared with saline controls. Basal activity and GTP-, guanosine 5'-(beta-gamma-imido)-triphosphate- and NaF-stimulated activity did not change. As a function of time after administration of 5 mg/kg of AMPH, desensitization was also observed at 25 min but not at 90 or 180 min. At no time point tested (25, 45 or 60 min) did 1 mg/kg of AMPH alter DA-stimulated AC activity. Desensitization of the DA-stimulated AC was also observed after a stereotypy-producing dose of methylphenidate (50 mg/kg at 40 min). These data demonstrate D1 DA receptor desensitization. This desensitization occurs after a stereotypy-producing dose of either AMPH or methylphenidate. A possible role for D1 DA receptor desensitization in stereotypy is suggested.