Rats treated chronically with reserpine develop spontaneous oral dyskinesia. The present study examined the development of the oral dyskinesia during the course of reserpine treatment, and its persistence after termination of treatment. Rats were injected with either reserpine (1 mg/kg, s.c.) or vehicle once daily for 4 days and then every other day for 6 weeks. Oral dyskinesia developed rapidly, reaching a maximal level after 3 days. It persisted at a maximal level for up to 20 days after termination of reserpine treatment, and continued to persist above control level for at least 60 days. The reserpine-treated rats also exhibited stereotypy in response to acute injection of the D1-selective agonist SKF-38393 (10 mg/kg), which was not observed in control rats. In contrast to the oral dyskinesia, this altered sensitivity to SKF-38393 returned to normal within 20 days after terminating the reserpine treatment, suggesting that these two behavioral responses involve different neural mechanisms. Quantitative autoradiographic measurement of dopamine receptor subtypes revealed that both D1 and D2 receptors were increased in the caudate-putamen (Cpu) and nucleus accumbens. Only the increase in D2 receptor density in the CPu correlated with the persistence of the oral dyskinesia; both changes persisted following termination of the reserpine treatment, and their magnitude was less at 60 days than at 1 and 20 days post-treatment. These results may have important implications for tardive dyskinesia.