title: Involvement of presynaptic 5-HT1Areceptors in the low propensity of brexpiprazole to induce extrapyramidal side effects in rats.
abstract: Previous studies have shown that partial and full 5-HT1Areceptor agonists reduce antipsychotic-induced catalepsy. Consequently, some antipsychotics combining balanced efficacy between dopamine (DA) D2antagonism or partial agonism and 5-HT1Areceptor 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-HT1Aagonistic 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-HT1Areceptors. 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-HT1Areceptors 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-HT1Areceptor 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-HT1Areceptors in the anticataleptic effect of brexpiprazole. The selective 5-HT2Aantagonist M100907 (0.10mg/kg, s.c.) had no effect on haloperidol-induced catalepsy, arguing against a major role of 5-HT2Areceptors 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-HT1Aagonist 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-HT1Areceptors, while that of aripiprazole is less sensitive to 5-HT1Areceptor antagonism.
authors.affiliation: Synaptic Transmission In Vivo, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: CMOM@lundbeck.com.
authors.forename: Cedric
authors.initials: C
authors.lastname: Mombereau
authors.affiliation: Sunred Pharma Consulting ApS, Svend Gønges Vej 11ADK, 2680 Solrød Strand, Denmark.
authors.forename: Jørn
authors.initials: J
authors.lastname: Arnt
authors.affiliation: Synaptic Transmission In Vivo, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
mesh_terms: D000818:Animals; D000068180:Aripiprazole / Q000633:toxicity; D001480:Basal Ganglia Diseases / Q000139:chemically induced*; D002375:Catalepsy / Q000139:chemically induced; D004298:Dopamine / Q000032:analysis; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015363:Quinolones / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D012701:Serotonin / Q000032:analysis; D013876:Thiophenes / Q000633:toxicity*
chemical_list: D010879:Piperazines; D011725:Pyridines; D015363:Quinolones; D013876:Thiophenes; D044282:Receptor, Serotonin, 5-HT1A; C000591922:brexpiprazole; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D000068180:Aripiprazole; D006220:Haloperidol; D004298:Dopamine
keywords: 5-HT(1A) receptor agonists; Aripiprazole; Brexpiprazole; Catalepsy; D(2) receptor agonists; Microdialysis