Atypical antipsychotic drug modulates early life infection induced impairment of hypothalamic-pituitary-adrenal axis: An age related study in mice

Abstract

Evidences from human and animal studies indicate that exposure to infection during early life act as a stressor to impair the hypothalamic-pituitary-adrenal (HPA) axis and may be one of the contributing factors of mental illness of later life. Several atypical antipsychotic drugs (AAPDs) proved to be effective in alleviating psychiatric illness through normalization of HPA axis. However, AAPD are least tried to evaluate their efficacy in modulation of HPA axis impaired under infection. The present study elucidated that the treatment with AAPD paliperidone (PAL: 0.025 mg/kg/bw and 0.05 mg/kg/bw) during periadolescence period (postnatal day 35- postnatal day 56) dose-dependently normalized the HPA axis of the female mice who were gestationally (gestational day 15 and 17) exposed to bacterial endotoxin lipopolysaccharide (LPS: 800 μg/kg/bw; intraperitoneally). The effectiveness of PAL treatment in counteracting the LPS induced hyperactivity of HPA axis was age-related, better observed at postnatal day 120 than at postnatal day 200. The PAL modulation of HPA axis reflected at different levels: inhibition of hypothalamic CRF expression and reduction in plasma levels of adrenocorticotropin and corticosterone. Histopathological alterations such as hypertrophy and/or hyperplasia in cortical zona fasciculata as well as medullary chromaffin cells of adrenal also normalized on PAL treatment. The comparatively long wash out period after drug treatment (postnatal day 57- postnatal day 200) along with age related hormonal imbalance could be correlated to less effectiveness of PAL on HPA axis at postnatal day 200. PAL modulation of HPA axis might be through maintenance of cytokines and reproductive axis homeostasis.