Brexpiprazole has a low risk of dopamine D2 receptor sensitization and inhibits rebound phenomena related to D2 and serotonin 5-HT2A receptors in rats.

Abstract

BackgroundLong‐term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D2 receptor sensitization. We evaluated the effects of brexpiprazole on D2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D2 receptors in rats subchronically dosed with another atypical antipsychotic.MethodsThe maximum D2 receptor density (B max) and apomorphine (a D2 receptor agonist)‐induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for B max, 6 or 30 mg/kg for stereotypy) for 21 days. Then, effects of oral administrations of brexpiprazole (3 mg/kg), aripiprazole (10 mg/kg), and olanzapine (3 mg/kg) against increases in apomorphine‐induced hyperlocomotion and (±)‐2,5‐dimethoxy‐4‐iodoamphetamine hydrochloride (DOI: a 5‐HT2A receptor agonist)‐induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days.ResultsHaloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED50 of anti‐apomorphine‐induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the B max and apomorphine‐induced stereotypy. Brexpiprazole (3 mg/kg) and olanzapine (3 mg/kg) significantly suppressed both increases in apomorphine‐induced hyperlocomotion and also DOI‐induced head twitches in rats subchronically treated with risperidone, but aripiprazole (10 mg/kg) significantly suppressed only apomorphine‐induced hyperlocomotion.ConclusionBrexpiprazole has a low risk of D2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D2 and 5‐HT2A receptors after a repeated administration of risperidone.