Involvement of presynaptic 5-HT1A receptors in the low propensity of brexpiprazole to induce extrapyramidal side effects in rats

Highlight
- Brexpiprazole has low cataleptogenic activity due to balanced 5-HT1A/D2 activity.
- Dialysis proposes preferential brexpiprazole effect on presynaptic 5-HT1A receptors.
- Aripiprazole has low cataleptogenic activity, primarily driven by D2 agonism.
- 5-HT1A agonists reverse catalepsy by preferential effect on presynaptic receptors.

Previous studies have shown that partial and full 5-HT1A receptor agonists reduce antipsychotic-induced catalepsy. Consequently, some antipsychotics combining balanced efficacy between dopamine (DA) D2 antagonism or partial agonism and 5-HT1A 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-HT1A 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-HT1A receptors.Brexpiprazole (3.0 and 10 mg/kg, p.o.) as well as aripiprazole (8.0 and 30 mg/kg, p.o.) failed to induce catalepsy in rats. Brexpiprazole (10 mg/kg, p.o.) significantly reduced the cataleptic response induced by haloperidol (0.63 mg/kg, s.c.), while aripiprazole (1.0-100 mg/kg, p.o.) failed to reverse the effect of haloperidol and only showed a numeric decrease at 10 mg/kg, (p.o.).When 5-HT1A receptors were blocked by the selective antagonist, WAY100635 (1.0 mg/kg, s.c.), cataleptogenic properties of brexpiprazole (10 mg/kg; p.o), but not aripiprazole (8.0 and 30 mg/kg, p.o.) were unmasked.The (“biased”) 5-HT1A receptor agonists F15599 (postsynaptic preference) and F13714 (presynaptic preference) had differential effects on haloperidol-induced catalepsy: F13714 (0.16 mg/kg, s.c.) counteracted catalepsy, whereas F15599 (0.040 mg/kg, s.c.) had no significant effect at regionally-selective doses. These data support a role of presynaptic 5-HT1A receptors in the anticataleptic effect of brexpiprazole. The selective 5-HT2A antagonist M100907 (0.10 mg/kg, s.c.) had no effect on haloperidol-induced catalepsy, arguing against a major role of 5-HT2A receptors in the cataleptogenic profile of brexpiprazole.The findings with brexpiprazole were supported using microdialysis studies: Brexpiprazole (3.0 and 10 mg/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-HT1A 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-HT1A receptors, while that of aripiprazole is less sensitive to 5-HT1A receptor antagonism.