02938nas a2200385   4500000000100000000000100001008004100002260001200043653001400055653003800069653003100107653002200138653002400160653002700184100001800211700001300229700002400242700002400266700002200290700002400312700002600336700002100362700002200383700001900405700001600424700002200440700002000462700002100482245015300503856004700656300001200703490000700715520181600722022001402538       2017                            d  c2017-0210aAddiction10aDevelopment of the nervous system10aDevelopmental neurogenesis10aNeural Stem Cells10aNeurological models10aPluripotent Stem Cells1 aChun-Ting Lee1 aJia Chen1 aAbigail A. Kindberg1 aRaphael M. Bendriem1 aCharles E. Spivak1 aMelanie P. Williams1 aChristopher T. Richie1 aAnnelie Handreck1 aBarbara S. Mallon1 aCarl R. Lupica1 aDa-Ting Lin1 aBrandon K. Harvey1 aDeborah C. Mash1 aWilliam J. Freed00aCYP3A5 Mediates Effects of Cocaine on Human Neocorticogenesis: Studies using an In Vitro 3D Self-Organized hPSC Model with a Single Cortex-Like Unit  uhttps://www.nature.com/articles/npp2016156  a774-7840 v423 aBecause of unavoidable confounding variables in the direct study of human subjects, it has been difficult to unravel the effects of prenatal cocaine exposure on the human fetal brain, as well as the cellular and biochemical mechanisms involved. Here, we propose a novel approach using a human pluripotent stem cell (hPSC)-based 3D neocortical organoid model. This model retains essential features of human neocortical development by encompassing a single self-organized neocortical structure, without including an animal-derived gelatinous matrix. We reported previously that prenatal cocaine exposure to rats during the most active period of neural progenitor proliferation induces cytoarchitectural changes in the embryonic neocortex. We also identified a role of CYP450 and consequent oxidative ER stress signaling in these effects. However, because of differences between humans and rodents in neocorticogenesis and brain CYP metabolism, translation of the research findings from the rodent model to human brain development is uncertain. Using hPSC 3D neocortical organoids, we demonstrate that the effects of cocaine are mediated through CYP3A5-induced generation of reactive oxygen species, inhibition of neocortical progenitor cell proliferation, induction of premature neuronal differentiation, and interruption of neural tissue development. Furthermore, knockdown of CYP3A5 reversed these cocaine-induced pathological phenotypes, suggesting CYP3A5 as a therapeutic target to mitigate the deleterious neurodevelopmental effects of prenatal cocaine exposure in humans. Moreover, 3D organoid methodology provides an innovative platform for identifying adverse effects of abused psychostimulants and pharmaceutical agents, and can be adapted for use in neurodevelopmental disorders with genetic etiologies.  a1740-634X