POSTNATAL DAT INHIBITION RESCUES ASD-LIKE BEHAVIOR IN THE VALPROATE RAT MODEL

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social behavior and cognition. Growing evidence indicates that altered dopaminergic signaling, including dysregulation of dopamine transporter (DAT) function, contributes to ASD-related phenotypes. Here, we investigated whether early postnatal selective DAT inhibition affects behavioral outcomes and dopaminergic markers in a rat model of ASD induced by prenatal sodium valproate (NaVP) exposure.
Pregnant Wistar rats received NaVP (600 mg/kg, i.p.) on gestational day 12.5. Male offspring were treated with the selective DAT inhibitor CE-123 (10 mg/kg, i.p.) once daily from postnatal day (PND) 10 to 23. During adolescence (PND 25–42), animals underwent behavioral testing assessing social interaction, social novelty recognition, declarative and spatial memory, anxiety-like behavior, locomotor activity, and aversive memory. Dopamine transporter and D2 receptor expression were subsequently analyzed in the prefrontal cortex, hippocampus, and amygdala.
Prenatal NaVP exposure produced ASD-like alterations, including impaired social novelty discrimination, deficits in declarative, spatial, and aversive memory, increased anxiety-like behavior, and changes in locomotor activity. These behavioral abnormalities were accompanied by increased DAT and D2 receptor expression in corticolimbic regions. Early postnatal treatment with CE-123 alleviated NaVP-induced behavioral deficits and was associated with normalization of DAT and D2 receptor expression, without inducing non-specific locomotor stimulation.
Overall, these findings support a role for dopamine reuptake mechanisms in ASD-related social and cognitive alterations and demonstrate that developmental modulation of DAT function induces lasting behavioral and molecular effects.