Effects of neonatal flutamide treatment on hippocampal neurogenesis and synaptogenesis correlate with depression-like behaviors in preadolescent male rats

• Published in: Neuroscience Vol. 169; no. 1; pp. 544 - 554
• Main Authors: Zhang, J.M., Tonelli, L., Regenold, W.T., McCarthy, M.M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 11.08.2010; Elsevier
• Subjects: androgen; Androgen Antagonists - administration & dosage; Androgen Antagonists - pharmacology; Androgen receptors; Androgens - physiology; Animals; Animals, Newborn; Anxiety - physiopathology; Biological and medical sciences; Dentate Gyrus - drug effects; Dentate Gyrus - pathology; depression; Depression - physiopathology; DNA Replication - drug effects; Exploratory Behavior - drug effects; flutamide; Flutamide - administration & dosage; Flutamide - pharmacology; Food Preferences - drug effects; Fundamental and applied biological sciences. Psychology; hippocampus; Hippocampus - drug effects; Hippocampus - pathology; Male; neurogenesis; Neurogenesis - drug effects; Neuroglia - drug effects; Neurology; Neurons - drug effects; Neurons - ultrastructure; Pyramidal Cells - drug effects; Pyramidal Cells - ultrastructure; Rats; Sexual Maturation - drug effects; Sexual Maturation - physiology; Sucrose; Swimming; Synapses - drug effects; Vertebrates: nervous system and sense organs; flutamide; DG; EPM; E; PND; MDD; FLU; DHT; CA1; SPT; neurogenesis; Tfm; OFT; PBS; androgen; hippocampus; DAB; BDNF; FST; ER; GFAP; AR; NOT; NSFT; LD; MAP-2; depression; BrdU; the forced swim test; dihydrotestosterone; the novelty-suppressed feeding test; androgen receptor; embryonic day; postnatal day; 5-bromo-2′-deoxyuridine-5′-monophosphate; Cornu Ammonis 1; the sucrose preference test; dentate gyrus; the open field test; glial fibrillary acidic protein; brain derived neurotrophic factor; the novel object test; the Light/Dark (LD) box; diaminobenzidine; estrogen receptor; the elevated plus maze test; major depressive disorder; phosphate buffered saline; the testicular feminization mutation; microtubal associated protein-2; Human; Androgen; Rat; Synaptogenesis; Rodentia; Central nervous system; Male; Neurogenesis; Preadolescent; Encephalon; Vertebrata; Mammalia; Flutamide; Animal; Behavior; Sex steroid hormone; Hippocampus
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.03.029

The prevalence of major depressive disorder (MDD) in adult men is roughly half that of women. Clinical evidence supports a protective effect of androgens against depressive disorders in men. The developing brain is subject to androgen exposure but a potential role for this in depression during adulthood has not been considered. In order to explore this question we treated newborn male rat pups with the androgen receptor antagonist flutamide to block endogenous androgen action and then conducted behavioral tests prior to puberty. Depression-like behaviors were assessed with the Forced Swim Test (FST) and the Sucrose Preference Test (SPT), and anxiety-like behaviors were assessed with the Open Field Test (OFT) and the Novelty-Suppressed Feeding Test (NSFT). Compared to the vehicle-treated controls, neonatal-flutamide treatment caused a significant increase in depression-like behaviors in preadolescent male rats but did not cause any significant difference in anxiety-like behaviors. In separate experiments, male pups with and without flutamide treatment were injected with 5-bromo-2′-deoxyuridine-5′-monophosphate (BrdU) from postnatal day (PND) 1 to 4 to label newly produced cells or the hippocampi were Golgi-Cox imbedded and pyramidal neurons visualized. Three lines of evidence indicate neonatal flutamide treatment inhibits hippocampal neurogenesis and neuronal dendritic spine formation in preadolescent male rats. Compared to vehicle controls, flutamide treatment significantly decreased (1) the number of microtubal associated protein-2+ (MAP-2) neurons in the CA1 region, (2) the number of MAP-2+ neurons in the dentate gyrus (DG) region of the hippocampus, and (3) the density of dendritic spines of pyramidal neurons in the CA1 region. However, there was no effect of flutamide treatment on the number of glial fibrillary acidic protein (GFAP)+ or GFAP+/BrdU+ cells in the hippocampus. This study suggests that the organizational effect of androgen-induced hippocampal neurogenesis is antidepressant.