Sensitivity of dopamine D 2 receptors following long-term treatment with roxindole

Abstract

The selective presynaptic dopamine D 2 receptor agonist roxindole was studied in specific pre- and postsynaptic models in rats to see whether it induced changes in dopamine D 2 receptor sensitivity. Following treatment with 0.3 or 3 mg/kg per day i.p. for 21 days, the reversal of γ-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. potention of apomorphine-induced stereotypies. In a cotreatment paradigm with haloperidol (1 mg/kg per day p.o.), roxindole (10 mg/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 D 2 receptors. Nevertheless, in add-on clinical studies wirh neuroleptic, switching of treatment regimens should be performed gradually over several days until further experience is available.