Prenatal antiandrogen flutamide affects mesocorticolimbic dopaminergic system development in rats

PALLARÉS, M.E.; PALLARÉS, H.M.; ADROVER , E.; BAIER, C.J.; ANTONELLI, M.C.

San Diego, California

Congreso; 43rd annual meeting of the Society for Neuroscience; 2013

Society for Neuroscience

We have previously demonstrated that prenatal stress (PS) can exerts an impairment of midbrain dopaminergic system (DA) metabolism especially after puberty, suggesting a particular sensitivity of DA system to variations in gonadal hormones peaks. Additionally, the onset ages of numerous clinical studies related to DA dysfunctions in men closely parallels the onset and decline ages of the adolescent period. We further demonstrated that the hypothalamic-pituitary-testicular axis status of male rats exposed to PS was altered since age-dependent changes on the external genitalia, pituitary and testicular hormones profiles and spermatogenesis rate were found. Since the developing forebrain DA system was shown to be influenced by androgen exposure, and since PS was shown to disrupt perinatal testosterone surges, the aim of this research was to evaluate if decreased androgen levels by the prenatal administration of an antiandrogen to pregnant rats during late gestation, might affect the dopaminergic system development.Pregnant rats were treated daily from gestational day 14th to 21st with either vehicle (VEH: 5% ethanol-propylene glycol) or 10 mg/kg flutamide (FLU). Our results show that FLU reduced anogenital distance of male progeny and induced a delay in the completion of testis descend in all evaluated ages in comparison to VEH rats. Moreover malformation of penis, cryptorchidisim and atrophied seminal vesicle were also observed on FLU offspring. Morphological studies in mesocorticolimbic DA areas revealed that FLU males presented a decrease on the number of MAP2 immunoreactive neurons in comparison with VEH suggesting that prenatal FLU induce a reduction in the dendritic arborization of mesencephalic structures, impairing normal connectivity between areas. Our results demonstrated that prenatal androgen manipulations induce similar consequences as PS suggesting that one of the possible mechanisms of action of prenatal insults could be by affecting the organizational role of androgens and differentially modulating their activational role on brain development.