Poster Presentation The International Congress of Neuroendocrinology 2014

Insulin sensitizers block or reverse effects of prenatal Testosterone exposure on dopamine expression in the Ventral Tegmental Area in female sheep (#405)

Michael Lehman 1 , Casey Steadman 1 , Vasantha Padmanabhan 2 , Lique Coolen 2
  1. University of Mississippi Medical Center, Jackson, MS, United States
  2. University of Michigan, Ann Arbor, MI, USA

Female sheep exposed to excess testosterone (T) during prenatal life, display an array of endocrine deficits comparable to those observed in women with polycystic ovarian syndrome (PCOS), including insulin resistance, and increased risk for developing obesity and diabetes. Previously, we demonstrated increased food reward-seeking behavior in prenatal T-treated ewes. A neural substrate critical for such behavior is the mesolimbic dopaminergic system. Indeed, we recently showed increased dopamine expression in the ventral tegmental area (VTA) by prenatal T exposure. In the current study, we hypothesize that insulin receptor activation plays a critical role in the effects of prenatal T on the VTA dopamine system. We utilized prenatal and postnatal interventions with insulin sensitizers Rosiglitazone and Metformin to test this hypothesis. Ewes were exposed prenatally to T (twice weekly; 100 mg testosterone propionate; ~1.2 mg/kg) during gestational days 30-90 of the 147 gestation period (T; n=5) or vehicle (Control; C; n=7). In addition, prenatal T-treated and control females were co-treated prenatally with rosiglitazone (daily oral 8 mg/ewe; TR; n=7; and CR; n=6) or received postnatal treatments beginning at 8 weeks of age with insulin sensitizers rosiglitazone (daily oral 0.11 mg/kg; T+R; n=8; and C+R; n=6) or metformin (daily oral 7.1 mg/kg; T+M; n=4; and C+M; n=5). At two years of age, all ewes were ovariectomized and administered steroid hormones to mimic late follicular phase. Brains were harvested and VTA DA expression was analyzed using tyrosine hydroxylase (TH) immunohistochemistry. In addition, co-expression of TH with insulin receptors (IR) was determined. Prenatal T increased VTA TH expression and reduced IR expression in TH neurons. Moreover, both prenatal and postnatal insulin sensitizer treatment partially blocked or reversed these effects. These results indicate that prenatal T organizes the VTA dopamine system via actions on insulin receptors and further confirm the feasibility of insulin sensitizers as treatment options for PCOS women.