title: Exposure to the Synthetic Progestin, 17α-Hydroxyprogesterone Caproate During Development Impairs Cognitive Flexibility in Adulthood.
abstract: The synthetic progestin, 17α-hydroxyprogesterone caproate, is increasingly used for the prevention of premature birth in at-risk women, despite little understanding of the potential effects on the developing brain. Rodent models suggest that many regions of the developing brain are sensitive to progestins, including the mesocortical dopamine pathway, a neural circuit important for complex cognitive behaviors later in life. Nuclear progesterone receptor is expressed during perinatal development in dopaminergic cells of the ventral tegmental area that project to the medial prefrontal cortex. Progesterone receptor is also expressed in the subplate and in pyramidal cell layers II/III of medial prefrontal cortex during periods of dopaminergic synaptogenesis. In the present study, exposure to 17α-hydroxyprogesterone caproate during development of the mesocortical dopamine pathway in rats altered dopaminergic innervation of the prelimbic prefrontal cortex and impaired cognitive flexibility with increased perseveration later in life, perhaps to a greater extent in males. These studies provide evidence for developmental neurobehavioral effects of a drug in widespread clinical use and highlight the need for a reevaluation of the benefits and potential outcomes of prophylactic progestin administration for the prevention of premature delivery.
authors.affiliation: Department of Psychology and Center for Neuroscience Research (J.W., C.K.W.), University at Albany, Albany, New York 12222; and Department of Psychology (J.W.), Behavioral Neuroscience Division, University of Illinois at Urbana-Champaign, Champaign, Illinois 61820.
authors.forename: Jari
authors.initials: J
authors.lastname: Willing
authors.affiliation: Department of Psychology and Center for Neuroscience Research (J.W., C.K.W.), University at Albany, Albany, New York 12222; and Department of Psychology (J.W.), Behavioral Neuroscience Division, University of Illinois at Urbana-Champaign, Champaign, Illinois 61820.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Wagner
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D002208:Caproates / Q000009:adverse effects; D003072:Cognition Disorders / Q000209:etiology*; D018450:Disease Progression; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology; D011372:Progestins / Q000009:adverse effects*; D017207:Rats, Sprague-Dawley; D060865:Repetition Priming / Q000187:drug effects; D012727:Sex Characteristics; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000473:pathology
chemical_list: D002208:Caproates; D011372:Progestins; D019326:17-alpha-Hydroxyprogesterone