Involvement of presynaptic 5-HT receptors in the low propensity of brexpiprazole to induce extrapyramidal side effects in rats.

Previous studies have shown that partial and full 5-HT receptor agonists reduce antipsychotic-induced catalepsy. Consequently, some antipsychotics combining balanced efficacy between dopamine (DA) D antagonism or partial agonism and 5-HT receptor agonism have a low propensity to induce extrapyramidal side effects (EPS), as reflected by low cataleptogenic activity in rodents. In the present experiments, we attempted to explore the importance of pre- and postsynaptic 5-HT agonistic properties of brexpiprazole and aripiprazole in the context of neurological side-effect liabilities. Additional measures of prefrontal cortical serotonin (5-HT) and DA levels using microdialysis were used to support that brexpiprazole has a preferential agonist effect on presynaptic 5-HT receptors. Brexpiprazole (3.0 and 10mg/kg, p.o.) as well as aripiprazole (8.0 and 30mg/kg, p.o.) failed to induce catalepsy in rats. Brexpiprazole (10mg/kg, p.o.) significantly reduced the cataleptic response induced by haloperidol (0.63mg/kg, s.c.), while aripiprazole (1.0-100mg/kg, p.o.) failed to reverse the effect of haloperidol and only showed a numeric decrease at 10mg/kg, (p.o.). When 5-HT receptors were blocked by the selective antagonist, WAY100635 (1.0mg/kg, s.c.), cataleptogenic properties of brexpiprazole (10mg/kg; p.o), but not aripiprazole (8.0 and 30mg/kg, p.o.) were unmasked. The ("biased") 5-HT receptor agonists F15599 (postsynaptic preference) and F13714 (presynaptic preference) had differential effects on haloperidol-induced catalepsy: F13714 (0.16mg/kg, s.c.) counteracted catalepsy, whereas F15599 (0.040mg/kg, s.c.) had no significant effect at regionally-selective doses. These data support a role of presynaptic 5-HT receptors in the anticataleptic effect of brexpiprazole. The selective 5-HT antagonist M100907 (0.10mg/kg, s.c.) had no effect on haloperidol-induced catalepsy, arguing against a major role of 5-HT receptors in the cataleptogenic profile of brexpiprazole. The findings with brexpiprazole were supported using microdialysis studies: Brexpiprazole (3.0 and 10mg/kg, p.o.) decreased extracellular 5-HT levels in the medial prefrontal cortex (mPFC), while it failed to affect extracellular DA in the same samples, suggesting that the 5-HT agonist properties of brexpiprazole may be preferentially presynaptic. In conclusion, these results confirm that brexpiprazole and aripiprazole have low propensities to induce EPS. However, the low EPS risk of brexpiprazole is more likely dependent on its agonist properties on presynaptic 5-HT receptors, while that of aripiprazole is less sensitive to 5-HT receptor antagonism.