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Allopregnanolone is a neurosteroid that has been reported to fluctuate during early developmental stages. Previous experiments reported the importance of neonatal endogenous allopregnanolone levels for the maturation of the central nervous system and particularly for the hippocampus. Changes in neonatal allopregnanolone levels have been related to altered adult behaviour and with psychopathological susceptibility, including anxiety disorders, schizophrenia and drug abuse. However, the mechanism underlying these changes remains to be elucidated. In the present study we assessed changes in hippocampal expression of α4 and δ GABAA receptor (GABAAR) subunits as a consequence of neonatal finasteride (a 5-α reductase inhibitor) administration during early development (PD6 to PD15) in male rats. We observed that the treatment altered the temporal window of the natural peak in the expression of these subunits during development. Additionally, the level of these subunits were higher than in non-handled and control animals in the adult hippocampus. We observed that in adulthood, neonatal finasteride-treated animals presented an anxiogenic-like profile in response to progesterone administration which was absent in the rest of the groups. In conclusion, these results corroborate the relevance of neonatal maintenance of neurosteroid levels for behavioural anxiety responses in the adult, and point to some of the mechanisms involved in this alterations.

Neurosteroids (NS) are well known to exert modulatory effects on ionotropic receptors. Recent findings indicate that NS could also act as important factors during development. In this sense, neonatal modifications of Allopregnanolone (Allop) levels during critical periods have been demonstrate to alter the morphology of the hippocampus but also other brain structures. The aim of the present work is to screen whether the alterations of Allop levels modify adult CA1 hippocampal response to NS administration. For this purpose, pups were injected with Allop (20 mg/kg s.c.), Finasteride (5α-reductase inhibitor that impedes Allop synthesis) (50 mg/kg s.c.) or Vehicle from postnatal day 5 (P5) to postnatal day 9 (P9). NS levels were tested at P5. To test the behavioural hippocampal response to NS in adulthood, animals were implanted with a bilateral cannula into the CA1 hippocampus at 80 days old and injected with Allop (0.2 μg/0.5 μl), Pregnenolone sulphate (5 ng/0.5 μl) or Vehicle in each hippocampus. After injections animals were tested in the Boisser test to assess exploratory behaviour, the elevated plus maze to assess anxiety and the passive avoidance to test aversive learning. Results indicate that alteration of neonatal Allop or pregnenolone levels (by Allop and Finasteride administration, respectively) suppressed intrahippocampal Allop anxiolytic effect in the EPM. Moreover our results also indicate that manipulation of neonatal Allop levels (Allop and Finast administration) alters exploratory and anxiety-like behaviour and impairs aversive learning in the adulthood. These data point out the role of Allop in the maturation of hippocampal function and behaviour., (Copyright © 2012. Published by Elsevier B.V.)

Background/aims: Recent findings suggest that neurosteroids are involved in brain development. The present study focused on the long-term effects of developmentally altered allopregnanolone (AlloP) levels on anxiety-like behavior in adulthood., Method: We administered AlloP (10 mg/kg) to rat pups once a day from the 5th to the 9th day after birth. A dose-response study on midazolam in the elevated plus maze test was carried out in adulthood (experiment 1) in order to screen GABAA-benzodiazepine function alterations. Given that the anxiety-like responses were not affected by AlloP, we doubled the initial AlloP dose (experiment 2). One group of pups was left undisturbed with their dams in order to control the effects of daily handling. Only males were behaviorally tested., Results: Neonatal AlloP administration (10 mg/kg) did not alter the behavioral response to midazolam in adulthood at the doses tested. Neonatal AlloP administration at the higher dose (20 mg/kg) induced an anxiolytic-like profile in adulthood (increased entries into and time spent in the open arms), without affecting motor activity. The behavioral effects of neonatal AlloP administration were both selective and independent of daily handling., Conclusion: Alterations in AlloP levels during maturation could partly explain the interindividual differences shown by adult subjects in response to environmental stress., (Copyright © 2011 S. Karger AG, Basel.)

Neurosteroids (NS) are substances synthesised de novo in the brain that have rapid modulatory effects on ionotropic receptors. Specifically, NS can act as positive allosteric modulators of GABAA receptors as pregnanolone or allopregnanolone (Allop), or GABAA negative modulators and NMDA positive modulators as pregnenolone (PREG) or dehydroepiandrosterone (DHEA) and their sulphate esters (PREGS and DHEAS). Given this, their role in anxiety and emotional disturbances has been suggested. In addition, NS such as PREGS or DHEAS have demonstrated a promnesic role in several learning tests. The aim of the present work is to highlight the role that the dorsal (CA1) hippocampus plays in the behavioural profile of NS such as Allop and PREGS in tests assessing exploration, anxiety and aversive learning in rats. For this purpose, animals were administered intrahippocampally with Allop (0.2μg/0.5μl), PREGS (5ng/0.5μl) or vehicle in each hippocampus, and tested in the Boissier and elevated plus maze (EPM) tests. For learning test we have chosen the passive avoidance paradigm. Results indicate that intrahippocampal administration of Allop enhances exploration, reflected in an increase in the total and the inner number of head-dips. Allop-injected animals also showed an increase in the percentage of entries into the open arms of the EPM, suggesting an anxiolytic-like profile. In addition, post-acquisition PREGS administration enhanced passive avoidance retention, while post-acquisition Allop administration had no effects on aversive learning retention. These results point out the important role of the dorsal (CA1) hippocampus in several NS behavioural effects, such as exploration, anxiety, learning and memory., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Thyroid hormone is essential for proper development of the mammalian CNS. Previous studies have documented a decrease in the ability of neonatal hypothyroid animals to learn and to habituate to maze tests and an increase in spontaneous activity. However, there is little information about the effects of perinatal (i.e. perinatal and postnatal) hypothyroidism on behaviour. The aim of the present work was to investigate the longitudinal effects of perinatal hypothyroidism on certain aspects of the behaviour in rats. Neuromotor competence was tested at 21, 40 and 60 days, novelty-directed exploratory behaviour and anxiety-related behaviour were evaluated at 40 and 60 days by means of the Boissier tests and associative learning ability was tested at 80 days by means of a step-through passive avoidance task. The persistence of the effects of perinatal hypothyroidism on psychomotor performance was highly dependent on the task examined. Perinatal hypothyroidism caused an increase of locomotor activity as revealed by the total distance travelled in the Boissier test and this increase also comprised a component of decreased anxiety-related behaviour. Methimazole-treated subjects also had higher head-dip scores than controls at 40 days while no differences were observed at 60 days. Finally, our results showed that methimazole-treated rats performed poorly in a passive avoidance learning task.

Background/Aims: Recent findings suggest that neurosteroids are involved in brain development. The present study focused on the long-term effects of developmentally altered allopregnanolone (AlloP) levels on anxiety-like behavior in adulthood. Method: We administered AlloP (10 mg/kg) to rat pups once a day from the 5th to the 9th day after birth. A dose-response study on midazolam in the elevated plus maze test was carried out in adulthood (experiment 1) in order to screen GABAA-benzodiazepine function alterations. Given that the anxiety-like responses were not affected by AlloP, we doubled the initial AlloP dose (experiment 2). One group of pups was left undisturbed with their dams in order to control the effects of daily handling. Only males were behaviorally tested. Results: Neonatal AlloP administration (10 mg/kg) did not alter the behavioral response to midazolam in adulthood at the doses tested. Neonatal AlloP administration at the higher dose (20 mg/kg) induced an anxiolytic-like profile in adulthood (increased entries into and time spent in the open arms), without affecting motor activity. The behavioral effects of neonatal AlloP administration were both selective and independent of daily handling. Conclusion: Alterations in AlloP levels during maturation could partly explain the interindividual differences shown by adult subjects in response to environmental stress. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Recent findings suggest that neurosteroids acting as GABAA modulators, as allopregnanolone (AlloP), not only play an important role in brain development, especially in the maturation of the hippocampus, but also in adult behaviour. The aim of the present work is to investigate whether the effects of adult CA1 intrahippocampal administrations of AlloP and pregnenolone sulphate (PregS), GABAA positive and negative modulators, respectively, on behavioural novelty responses measured in the open field test can be different depending on neonatal alterations (increase or decrease) of physiological AlloP levels. Rat pups received AlloP and a 5alpha-reductase inhibitor (finasteride) from the fifth to the ninth postnatal day. At maturity, a bilateral cannula was implanted into the hippocampus (CA1). Intrahippocampal AlloP and PregS decreased total locomotor activity in neonatal control rats. Instead, in neonatal AlloP rats only PregS decreased open field activity, whereas in neonatal finasteride rats the intrahippocampal injections (AlloP and PregS) did not affect locomotor activity. Also, the decrease in activity induced by PregS infusion was higher in neonatal AlloP rats than in controls. However, neonatal treatments did not affect any of the anxiety scores. Although intrahippocampal AlloP and PregS decreased inner activity and time spent in the first 5min independently of the neonatal treatment, the extremely low inner values do not allow a conclusion of anxiogenic effects. Results indicate that neonatal AlloP administration potentiates and neonatal finasteride decreases the effects of adult intrahippocampal PregS administration on open field locomotion, suggesting neurobiological adaptations that remain until adult age. [Copyright &y& Elsevier]

Abstract: 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 (10mg/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 (1mg/kg) and flumazenil (10mg/kg) on the locomotor habituation in adulthood. Whereas the behavioural responses to 0.75mg/kg of lorazepam or 3mg/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 0.75mg/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. [Copyright &y& Elsevier]

Abstract: Endogenous neurosteroid level fluctuations are related to several emotional and behavioral alterations. Neurosteroids also have important roles during neurodevelopment, with there being a relationship between modification of their levels in neurodevelopmental periods and behavioral alterations in adolescence and adulthood. Early maternal separation (EMS) is a stressful event that also alters neurodevelopment and adolescent and adult behaviors. The aim of the present study is to analyze the interaction between the effects of the neonatal alteration of allopregnanolone (AlloP), neurosteroid that increase its levels after acute stress presentation, and EMS on adolescent exploration and adult anxiety and sensorimotor gating in male rats. AlloP (10mg/kgs.c.) was administrated between postnatal day 5 (PN5) and PN9, and a single 24-hour period of EMS was carried out on PN9. Exploration was analyzed at PN40 and PN60. At adult age (PN85), anxiety was tested by means of the elevated plus-maze test (EPM), and sensorimotor gating by means of prepulse inhibition test (PPI). PPI deterioration has been considered as a reliable indicator of diseases such as schizophrenia. Results showed that the previous neonatal AlloP administration neutralized the effects of EMS in the adolescent exploration (increase of traveled distance and decrease of head-dips). In adult age, an anxiolytic-like profile was observed as a consequence of EMS. Finally, EMS and neonatal AlloP disrupted PPI. Taken together, these data show the important role that physiological neonatal AlloP levels and stressful events play in neural development, adult behavior and vulnerability to neurodevelopmental disorders such as schizophrenia. [Copyright &y& Elsevier]