Early postnatal stimulation of dopaminergic receptors D1 and D2 leads to receptor- and sex-specific behavioral alterations in prepubertal mice

Authors:
  • MMMuiara Aparecida Moraes
    Muiara Aparecida Moraes
  • BRBruna Resende
    Bruna Resende
  • LALaila Blanc Arabe
    Laila Blanc Arabe
  • BCBeatriz Campos Codo
    Beatriz Campos Codo
  • ARAna Luiza Araújo Lima Reis
    Ana Luiza Araújo Lima Reis
  • FMFlávio Afonso Gonçalves Mourão
    Flávio Afonso Gonçalves Mourão
  • MMMárcio Flávio Dutra Moraes
    Márcio Flávio Dutra Moraes

Abstract
Dopamine signaling regulates multiple neurodevelopmental processes and has been implicated in neuropsychiatric disorders. Importantly, dopaminergic imbalances may exert distinct effects depending on the developmental window. Here, we tested whether increased dopamine availability or selective stimulation of dopamine D1 or D2 receptors during early postnatal life induces sex-specific behavioral alterations in prepubertal mice. Male and female Swiss mouse pups received daily injections from postnatal day (PD) 1-5 of Saline, L-Dopa+benserazide, the D1 receptor agonist SKF-38393, or the D2 receptor agonist Quinpirole. Behavioral assessments were conducted during the prepubertal period (PD28–PD30) using the open field, light-dark box, elevated plus maze, novelty-suppressed feeding, forced swimming, and tail suspension tests. Early postnatal dopaminergic manipulations did not alter baseline locomotor activity. However, we observed sex- and receptor-specific behavioral alterations. Increased dopamine availability produced anxiolytic-like effects that differed between females and males. In contrast, selective receptor activation resulted in divergent behavioral effects. D1 receptor stimulation increased anxiety-like behavior in females and depressive-like behavior, reduced food intake, and attenuated weight loss after fasting in males. D2 receptor stimulation increased anxiety-like behavior in females and despair/depressive-like behavior in both sexes, while increasing food intake and reducing weight loss after fasting in males. Despite these behavioral changes, hippocampal volume assessed by structural MRI at PD30 was unaltered. Together, these findings demonstrate that transient dopaminergic perturbations during a specific early postnatal window lead to sex-specific prepubertal behavioral outcomes, highlighting dopamine receptor–specific mechanisms as critical determinants of developmental vulnerability relevant to neuropsychiatric disorders.