Alterations in neonatal neurosteroids affect exploration during adolescence and prepulse inhibition in adulthood

Abstract

Allopregnanolone (AlloP) is a neurosteroid that plays an important role during neural development. Alterations of endogenous neonatal allopregnanolone levels alter the localisation and function of GABA neurons in the adult brain and affect behaviour in adulthood. We have carried out research into the effects of an increase (AlloP administration) or a decrease (administration of finasteride, inhibitor of the AlloP synthesis) of neonatal AlloP levels during the fifth to ninth postnatal days in male Wistar rats on the novelty exploration (Boissier test) at adolescent ages (40 and 60 days old), and on the prepulse inhibition achievement in adulthood (85 days). We also investigated the role of a GABA(A) modulator (midazolam, 1, 1.75 or 2.5mg/kg body weight) in the long-lasting behavioural changes in adulthood (85 days). Results indicate that neonatal finasteride decreases both novelty-exploration (head-dipping and locomotion) and anxiety-relevant scores (the distance travelled in and the number of entries into the central zone) at adolescent age, along with a reduction in body weight and general locomotion. Also, neonatal AlloP administration decreases prepulse inhibition in adulthood. Prepulse inhibition disruption was only partially reproduced decreasing the neonatal AlloP levels by means of finasteride administration. Although there was no interaction between neonatal neurosteroid manipulation and adult benzodiazepine treatments, the effects of midazolam were dose-dependent: the lowest dose of midazolam increased whereas the highest disrupted the expected progressive reduction of the startle response (and the consequent improvement of the PPI percentage) after the gradual increase in prepulse intensity. Reduced prepulse inhibition of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. Alterations of AlloP levels during maturation could partly explain the inter-individual differences shown by adult subjects in response to novelty (exploration) and in the sensorimotor gating and prepulse inhibition. Also, abrupt changes in neonatal levels of AlloP could be related to a susceptibility to neurodevelopmental disorders.