Abstracts
3427208
(#5) The Neurochemical and Anxiolytic-Like Effects of Centanafadine in Preclinical Assays in the Rat and Mouse
Abstract: Introduction: Emerging clinical and nonclinical data suggest that centanafadine's pharmacological profile may extend beyond core ADHD symptoms to associated features, including emotional dysregulation, executive dysfunction, and anxiety . This study characterized centanafadine's neurochemical and behavioral effects using in vivo microdialysis and established preclinical anxiety models.
Methods: Neurotransmitter levels were quantified in rat prefrontal cortex (PFC) and ventral striatum (vSTR) following centanafadine dosing. In mice, marble burying assessed anxiety-like behavior after centanafadine or chlordiazepoxide dosing 60 or 30min before testing, respectively; endpoints were marbles buried and distance traveled. In rats, elevated plus maze (EPM) and contextual fear conditioning (CFC) were used 1h after centanafadine dosing. EPM endpoints were % time in open arms, % open arm entries, and total arm entries. In CFC, rats were conditioned and tested 24h later for freezing.
Results: Centanafadine significantly increased dopamine, norepinephrine, and serotonin in the PFC, and serotonin and dopamine in the vSTR of rats. At 30mg/kg, peak increases in the PFC were: serotonin 1638%, norepinephrine 739%, and dopamine 302%; in the vSTR: serotonin 1590% and dopamine 219%. Centanafadine also significantly reduced marble burying in mice at 30 and 40mg/kg without affecting distance traveled, increased open arm exploration in the rat EPM at 30mg/kg, and reduced freezing in CFC at 30mg/kg vs vehicle.
Conclusions: Centanafadine showed an anxiolytic-like profile across established mouse and rat assays. Notably, the efficacious dose range between species and assays was remarkably consistent and aligned with microdialysis data, demonstrating centanafadine as a norepinephrine, dopamine, and serotonin reuptake inhibitor in vivo.
Short Description: This study aimed to further characterize the neurochemical and anxiolytic-like effects of centanafadine across established mouse and rat assays of anxiety, including marble burying, elevated plus maze, and contextual fear conditioning. Centanafadine increased monoamine levels in the prefrontal cortex and ventral striatum and showed an anxiolytic-like profile across species, supporting its activity as a norepinephrine, dopamine, and serotonin reuptake inhibitor in vivo.
Name of Sponsoring Organization(s): Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, United States
Methods: Neurotransmitter levels were quantified in rat prefrontal cortex (PFC) and ventral striatum (vSTR) following centanafadine dosing. In mice, marble burying assessed anxiety-like behavior after centanafadine or chlordiazepoxide dosing 60 or 30min before testing, respectively; endpoints were marbles buried and distance traveled. In rats, elevated plus maze (EPM) and contextual fear conditioning (CFC) were used 1h after centanafadine dosing. EPM endpoints were % time in open arms, % open arm entries, and total arm entries. In CFC, rats were conditioned and tested 24h later for freezing.
Results: Centanafadine significantly increased dopamine, norepinephrine, and serotonin in the PFC, and serotonin and dopamine in the vSTR of rats. At 30mg/kg, peak increases in the PFC were: serotonin 1638%, norepinephrine 739%, and dopamine 302%; in the vSTR: serotonin 1590% and dopamine 219%. Centanafadine also significantly reduced marble burying in mice at 30 and 40mg/kg without affecting distance traveled, increased open arm exploration in the rat EPM at 30mg/kg, and reduced freezing in CFC at 30mg/kg vs vehicle.
Conclusions: Centanafadine showed an anxiolytic-like profile across established mouse and rat assays. Notably, the efficacious dose range between species and assays was remarkably consistent and aligned with microdialysis data, demonstrating centanafadine as a norepinephrine, dopamine, and serotonin reuptake inhibitor in vivo.
Short Description: This study aimed to further characterize the neurochemical and anxiolytic-like effects of centanafadine across established mouse and rat assays of anxiety, including marble burying, elevated plus maze, and contextual fear conditioning. Centanafadine increased monoamine levels in the prefrontal cortex and ventral striatum and showed an anxiolytic-like profile across species, supporting its activity as a norepinephrine, dopamine, and serotonin reuptake inhibitor in vivo.
Name of Sponsoring Organization(s): Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, United States
