The role of dopaminergic mechanisms in opiate- and psychostimulant- induced long-term locomotor sensitization was investigated. To that aim, rats were behaviourally sensitized with morphine or amphetamine and 3 weeks after cessation of treatment challenged with various direct and indirect dopamine agonists. Both morphine- and amphetamine-pretreated rats displayed sensitization of the locomotor effects of amphetamine, cocaine, and the selective dopamine reuptake inhibitor GBR-12909. Sensitization of the locomotor stimulant effects of the dopamine D2/D3 receptor agonist quinpirole was observed in amphetamine- but not morphine-pretreated rats. In contrast, morphine-, but not amphetamine-pretreated rats appeared hyposensitive to the locomotor inhibitory effects of a low, presumably D2- autoreceptor selective, dose of quinpirole. Neither pretreatment induced sensitization to the dopamine D1/D2 agonist apomorphine or the dopamine D1 agonist SKF-82958. In fact, the locomotor stimulant effects of SKF-82958 appeared to be decreased in animals pre-exposed to amphetamine. These results suggest that functional changes in presynaptic dopamine release mechanisms represent common neuroadaptations involved in the long-term expression of morphine- and amphetamine-induced locomotor sensitization. Presynaptic dopamine D2 and postsynaptic D2 and/or D3 receptors are differentially involved in the expression of morphine- and amphetamine-induced locomotor sensitization. In a parallel study, we report that all of the drugs that elicited sensitized locomotor responses in morphine- or amphetamine- pretreated rats caused reinstatement of previously extinguished heroin- or cocaine-seeking behaviour, respectively. Taken together, these data suggest a marked relationship between drug-seeking behaviour and drug sensitization.