Neonatal allopregnanolone increases novelty-directed locomotion and disrupts behavioural responses to GABAA receptor modulators in adulthood

Recent findings indicate that neurosteroids could act as important modulators during brain development. The aim of the present work is to screen whether developmentally altered AlloP levels may have long-lasting effects on behaviour and influence the emotional response to several GABAA receptor modulating drugs in adulthood. Acute allopregnanolone administration (10 mg/kg) in the fifth postnatal day: (1) provoked long-term effects, as an increase of the novelty-directed locomotor activity and a decrease of its habituation in the open field in adult rats; (2) altered GABAA receptor response in adulthood, as reflected by the disruption of the effects of midazolam (1 mg/kg) and flumazenil (10 mg/kg) on the locomotor habituation in adulthood. Whereas the behavioural responses to 0.75 mg/kg of lorazepam or 3 mg/kg of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) were not affected, although lorazepam decreased locomotor activity in both neonatal AlloP and control rats, probably related to the sedative properties of the dose tested. Also, in the elevated plus-maze, the anxiolytic effects of lorazepam were observed in controls, but not in neonatal allopregnanolone-treated rats. This suggests that neonatal allopregnanolone decreases sensitivity to the anxiolytic effects of lorazepam at a dose of 0.75 mg/kg. Results suggest that alterations in neonatal allopregnanolone could result in an altered GABAA receptor response in adulthood that is evident behaviourally. These results point out the importance of the maturation of the endogenous neurosteroid mechanisms in the brain related to locomotor response to novelty and the responses to GABAA modulators in adulthood. This work opens future directions focused on the effects of acute and long-lasting neonatal alterations of AlloP levels on vulnerability to psychopathology in adulthood.