The selective presynaptic dopamine D2 receptor agonist roxindole was studied in specific pre- and postsynaptic models in rats to see whether it induced changes in dopamine D2 receptor sensitivity. Following treatment with 0.3 or 3 mg/kg per day i.p. for 21 days, the reversal of gamma-butyrolactone-induced striatal dihydroxyphenylalanine accumulation was unchanged as compared to that after acute treatment. The efficacy of roxindole in this model was not decreased after long-term treatment. Likewise, treatment for 19 days with up to 10 mg/kg per day i.p. failed to induce behavioral supersensitivity, i.e. potentiation of apomorphine-induced stereotypies. In a cotreatment paradigm with haloperidol (1 mg/kg per day p.o.), roxindole (10mg/kg per day i.p.) did not alter the behavioral supersensitivity measured after a drug washout phase as compared to the effect of haloperidol alone; however, stereotypies were observed after termination of haloperidol but continuation of roxindole treatment. In contrast, roxindole (10 mg/kg i.p.) induced only weak stereotypies in haloperidol-sensitized rats when given after the washout phase instead of apomorphine. The results indicate that roxindole induces neither desensitization of presynaptic nor supersensitization of postsynaptic dopamine D2 receptors. Nevertheless, in add-on clinical studies with neuroleptics, switching of treatment regimens should be performed gradually over several days until further experience is available.