THE NEUROCHEMICAL AND ANXIOLYTIC-LIKE EFFECTS OF CENTANAFADINE IN PRECLINICAL ASSAYS IN THE RAT AND MOUSE

Background

Centanafadine is a norepinephrine (NE), dopamine (DA), and serotonin (5-HT) reuptake inhibitor (NDSRI) currently in clinical development. Overall, it has been shown to possess a favorable efficacy and safety profile in Phase 3 trials in adults, children, and adolescents with ADHD . Emerging clinical and nonclinical data suggest that the pharmacological profile of centanafadine may extend beyond core ADHD symptoms to associated features, including emotional dysregulation, executive dysfunction, and common psychiatric comorbidities such as anxiety . Anxiety-related disorders are frequently associated with dysregulation of monoaminergic neurotransmission. The objective of this study was to further characterize the neurochemical and behavioral effects of centanafadine in this regard using in vivo microdialysis and established preclinical models of anxiety-related behavior.

Methods

The neurochemical and behavioral effects of centanafadine were evaluated using microdialysis and established preclinical models of anxiety. Neurotransmitter levels were quantified in the rat prefrontal cortex (PFC) and ventral striatum (vSTR) following dosing of centanafadine (3, 10, and 30 mg/kg, orally). In mice, anxiety-like behavior was assessed using the marble burying test. Male mice received centanafadine (3, 10, 30, and 40 mg/kg, orally) or chlordiazepoxide (15 mg/kg, intraperitoneally) 60 or 30 mins prior to testing, respectively. Endpoints included the number of marbles buried and total distance traveled. In rats, anxietyrelated behavior was evaluated 1h after centanafadine dosing (3, 10 and 30 mg/kg, oral) using the elevated plus maze (EPM) and contextual fear conditioning (CFC) paradigms. For the EPM, endpoints included % time in the open arms, % open arm entries, and total arm entries. In the CFC, rats underwent a conditioning session followed by a test session conducted 24h later, with freezing behavior assessed during the test session.

Results

In this investigation centanafadine significantly increased levels of DA, NE, and 5-HT in the PFC, and 5-HT and DA in the vSTR of rats. At 30 mg/kg, peak increases in the PFC were: 5-HT 1638%, NE 739%, and DA 302%; in the vSTR: 5-HT 1590% and DA 219%. In mice, centanafadine significantly reduced the number of marbles buried following dosing at 30 and 40 mg/kg compared with vehicle-dosed animals without significantly affecting distance traveled. In rats, centanafadine increased open arm exploration in the EPM at the 30-mg/kg dose, including % time in the open arms, % open arm entries, and total arm entries compared with vehicle-dosed animals. In the CFC, centanafadine reduced freezing behavior at the 30-mg/kg dose when compared to vehicle-dosed animals.

Conclusions

In this investigation, centanafadine significantly increased levels of DA, NE and 5HT in the PFC and 5-HT and DA in the vSTR of rats. Centanafadine demonstrated an anxiolyticlike profile across several well-established mouse and rat assays. Notably, the efficacious dose range between species and assays was remarkably consistent and aligned with the microdialysis data, demonstrating centanafadine as an NDSRI in vivo.