Neonatal finasteride induces anxiogenic-like profile and deteriorates passive avoidance in adulthood after intrahippocampal neurosteroid administration.
Recent findings indicate that neurosteroids could act as important keys during the brain development. Fluctuations in neonatal allopregnanolone (AlloP) could result in altered pharmacological properties of the GABA(A) receptor system in adulthood. Recent studies demonstrated that neurosteroids play a critical role in regulating normal neurodevelopment in the hippocampus. The aim of the present work is to screen whether developmentally altered neurosteroid levels influence the behavioral response to adult intrahippocampal administration of AlloP, a GABA(A) positive modulating neurosteroid, and pregnenolone sulfate (PregS), a GABA(A) negative modulator in rats. For this purpose, pups received AlloP (10 mg/kg, s.c.), a 5alpha-reductase inhibitor (finasteride, 50 mg/kg, s.c.) or vehicle from the fifth to the ninth postnatal day. At maturity (i.e. 90 days old) a bilateral cannula was implanted into the hippocampus. After recovery from surgery, animals received an administration of AlloP (0.2 microg/0.5 microl), PregS (5 ng/0.5 microl) or vehicle in each hippocampus 5 min before they were tested in the elevated plus maze (EPM) and immediately after the passive avoidance training session, and retention was tested 24 h later. Results indicated that neonatal finasteride treatment deteriorated passive avoidance retention and elicited an anxiogenic-like effect in the EPM test in adulthood, as seen by the reduction of open arm entries and in the time spent in the open arms. Intrahippocampal PregS administration also disrupted passive avoidance, possibly related to its anxiogenic profile. Fluctuations in neonatal AlloP affect the aversive learning and the anxiety-related behavior in adulthood, and this effect could be in part mediated by alterations of the mature functions of the hippocampus, possibly via the GABA(A) receptor. These data point to the role of GABAergic neurosteroids in critical periods of vulnerability that influence normal development of GABAergic pathways in the CNS.
Departament de Psicobiologia i Metodologia en Ciències de la Salut, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
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Martín-García
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Darbra
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Pallarés
D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000139:chemically induced; D001362:Avoidance Learning / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology*; D012739:Gonadal Steroid Hormones / Q000008:administration & dosage*; D006624:Hippocampus / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D011280:Pregnanolone / Q000008:administration & dosage*; D011284:Pregnenolone / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D012739:Gonadal Steroid Hormones; D011963:Receptors, GABA-A; C018370:pregnenolone sulfate; D018120:Finasteride; D011284:Pregnenolone; D011280:Pregnanolone