The effect of dopamine (DA) receptor blockade on the development of sensitization to the locomotor activating effects of systemic amphetamine and intra-ventral tegmental area (intra-VTA) morphine was investigated. Rats were pretreated with the D-1 DA receptor antagonist, SCH-23390 (0.04 or 0.2 mg/kg, i.p.) or one of two D-2 DA receptor antagonists, pimozide (0.5 mg/kg, i.p.) and Ro 22-2586 (0.2 mg/kg, i.p.), prior to each of 5 exposures to the sensitizing drug. SCH-23390 blocked the development of sensitization to amphetamine but not to intra-VTA morphine. Pimozide had the opposite effect and Ro 22-2586 had no effect on the development of sensitization to either amphetamine or intra-VTA morphine. All 3 antagonists, at the doses tested, completely blocked the acute locomotor activating effects of these two drugs. Pretreatment in separate animals with low autoreceptor doses of sulpiride (25 mg/kg, i.p. with amphetamine and 10 mg/kg, i.p. with intra-VTA morphine) slightly potentiated the acute locomotor effect and produced a slight enhancement of the sensitized response to amphetamine and intra-VTA morphine. Pretreatment with a higher dose of sulpiride (50 mg/kg, i.p.) blocked the acute locomotor effect of intra-VTA morphine but had no effect on the development of sensitization to this drug. These results suggest that the mechanisms underlying the development of sensitization to the locomotor activating effects of amphetamine and intra-VTA morphine are different even though these may ultimately result in similar changes in the activity of mesencephalic DA neurons. Implications of these findings for the differential involvement of D-1 and D-2 DA receptors and for neural hypotheses of behavioral sensitization are discussed.