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

BACKGROUND: Long‐term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D(2) receptor sensitization. We evaluated the effects of brexpiprazole on D(2) receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D(2) receptors in rats subchronically dosed with another atypical antipsychotic. METHODS: The maximum D(2) receptor density (B (max)) and apomorphine (a D(2) 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‐HT(2A) receptor agonist)‐induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days. RESULTS: Haloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED(50) 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. CONCLUSION: Brexpiprazole has a low risk of D(2) receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D(2) and 5‐HT(2A) receptors after a repeated administration of risperidone.