Brexpiprazole has a low risk of dopamine D 2 receptor sensitization and inhibits rebound phenomena related to D 2 and serotonin 5-HT 2A receptors in rats

Long-term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D receptor sensitization. We evaluated the effects of brexpiprazole on D receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D receptors in rats subchronically dosed with another atypical antipsychotic. The maximum D receptor density (B ) and apomorphine (a D 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 , 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-HT receptor agonist)-induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days. Haloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED of anti-apomorphine-induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the B 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. Brexpiprazole has a low risk of D receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D and 5-HT receptors after a repeated administration of risperidone.