Programming effects of antenatal dexamethasone in the developing mesolimbic pathways

Abstract

Elevated glucocorticoids, during pregnancy, alter emotionality and increase propensity to drug abuse later in life, albeit through substrates and mechanisms are largely unknown. In this study, we examined whether antenatal glucocorticoid exposure induces enduring structural changes in the nucleus accumbens (NAcc), an important relay point in the reward limbic circuitry. To this end, rat dams were exposed to the synthetic glucocorticoid dexamethasone (DEX) on days 18 and 19 of gestation, and stereological tools were used to assess the total volume of, and neuronal numbers in, the NAcc, as well as the density of mesencephalic dopaminergic inputs from the ventral tegmental area (VTA) to the NAcc in their adult offspring. Further, we used measures of bromodeoxyuridine incorporation into NAcc cells to examine whether DEX-induced effects on cell proliferation represent another mechanism through which glucocorticoids alter the structure of mesolimbic pathways and might influence addictive behavior. Our studies show that exposure to DEX during late gestation results in significantly reduced volumes and cell numbers in the NAcc. The latter measure correlated strongly with a reduced rate of cell proliferation in DEX-exposed animals. Moreover, the treatment resulted in a decreased number of cells expressing tyrosine hydroxylase in the VTA and an impoverished dopaminergic innervation of the NAcc. These observations, which identify glucocorticoid-sensitive structures and neurochemical targets within the developing "reward pathway," pave way for future studies designed to understand how early life events can predispose individuals for developing drug dependence in adolescent and adult life.