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A positron emission tomography occupancy study of brexpiprazole at dopamine D₂ and D₃ and serotonin 5-HT_1A and 5-HT_2A receptors, and serotonin reuptake transporters in subjects with schizophrenia.

ABSTRACT: The objective of this study (NCT01854944) was to assess D₂/D₃, 5-HT_1A, 5-HT_2A and serotonin transporter (SERT) occupancies of brexpiprazole in adult subjects with schizophrenia in order to identify the in vivo pharmacologic profile that may be relevant to the antipsychotic, antidepressant, and side effect profiles of the drug. Subjects were grouped into three independent cohorts of four subjects each. All subjects underwent positron emission tomography (PET) scans with two different radiotracers at baseline prior to brexpiprazole administration, and again on Day 10 after daily doses of either 4 mg (Cohorts 1 and 2), or 1 mg (Cohort 3). Cohort 1 received scans with [¹¹C]-(+)-PHNO to measure D₂ and D₃ receptor occupancy and [¹¹C]CUMI101 to measure 5-HT_1A occupancy; Cohort 2 received [¹¹C]MDL100907 for 5-HT_2A occupancy and [¹¹C]DASB for SERT occupancy; Cohort 3 underwent scanning with [¹¹C]-(+)-PHNO and [¹¹C]MDL100907. Five female and seven male subjects, aged 42 ± 8 years (range, 28-55 years), participated in this study. Dose dependency was observed at D₂ receptors, with occupancies reaching 64 ± 8% (mean +/- SD) following 1 mg/day and 80 ± 12% following 4 mg/day. D₃ receptor availability increased following 1 mg brexpiprazole treatment and did not change with 4 mg. Robust and dose-related occupancy was also observed at 5-HT_2A receptors. Negligible occupancy (<5%) was observed at 5-HT_1A and SERT at 4 mg/day. In summary, brexpiprazole demonstrated in vivo binding to D₂ receptors and 5-HT_2A receptors at steady state after 10 days of daily administration in a dose dependent manner, while binding to D₃, 5-HT_1A receptors and SERT was not detectable with the radiotracers used for these targets. This pharmacologic profile is consistent with the observed antipsychotic and antidepressant effects.

SUBMITTER: Girgis RR

PROVIDER: S-EPMC7075883 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Serotoninergic (5-HT) neurons are powerful modulators of spinal locomotor circuits. Most studies on 5-HT modulation focused on the effect of exogenous 5-HT and these studies provided key information about the cellular mechanisms involved. Less is known about the effects of increased release of endogenous 5-HT with selective serotonin reuptake inhibitors. In mammals, such molecules were shown to destabilize the fictive locomotor output of spinal limb networks through 5-HT1A receptors. However, in tetrapods little is known about the effects of increased 5-HT release on the locomotor output of axial networks, which are coordinated with limb circuits during locomotion from basal vertebrates to mammals. Here, we examined the effect of citalopram on fictive locomotion generated in axial segments of isolated spinal cords in salamanders, a tetrapod where raphe 5-HT reticulospinal neurons and intraspinal 5-HT neurons are present as in other vertebrates. Using electrophysiological recordings of ventral roots, we show that fictive locomotion generated by bath-applied glutamatergic agonists is destabilized by citalopram. Citalopram-induced destabilization was prevented by a 5-HT1A receptor antagonist, whereas a 5-HT1A receptor agonist destabilized fictive locomotion. Using immunofluorescence experiments, we found 5-HT-positive fibers and varicosities in proximity with motoneurons and glutamatergic interneurons that are likely involved in rhythmogenesis. Our results show that increasing 5-HT release has a deleterious effect on axial locomotor activity through 5-HT1A receptors. This is consistent with studies in limb networks of turtle and mouse, suggesting that this part of the complex 5-HT modulation of spinal locomotor circuits is common to limb and axial networks in limbed vertebrates.NEW & NOTEWORTHY Little is known about the modulation exerted by endogenous serotonin on axial locomotor circuits in tetrapods. Using axial ventral root recordings in salamanders, we found that a serotonin reuptake blocker destabilized fictive locomotor activity through 5-HT1A receptors. Our anatomical results suggest that serotonin is released on motoneurons and glutamatergic interneurons possibly involved in rhythmogenesis. Our study suggests that common serotoninergic mechanisms modulate axial motor circuits in amphibians and limb motor circuits in reptiles and mammals.

Dataset Information

A positron emission tomography occupancy study of brexpiprazole at dopamine D₂ and D₃ and serotonin 5-HT_1A and 5-HT_2A receptors, and serotonin reuptake transporters in subjects with schizophrenia.

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A positron emission tomography occupancy study of brexpiprazole at dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors, and serotonin reuptake transporters in subjects with schizophrenia.

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OmicsDI is part of the ELIXIR infrastructure

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A positron emission tomography occupancy study of brexpiprazole at dopamine D₂ and D₃ and serotonin 5-HT_1A and 5-HT_2A receptors, and serotonin reuptake transporters in subjects with schizophrenia.