The management of mental and neurological illnesses during pregnancy and lactation raises complex clinical issues. There have been vast changes in the pharmacological armamentarium available to these disorders, but clinical reproductive safety data regarding these compounds is limited and slow to accumulate due to the ethical and logistical complexities of conducting such clinical research. Furthermore, peripheral measures of neurotropic medication concentrations (e.g. infant serum, breast milk) may not reflect the magnitude of fetal or neonatal central nervous system (CNS) exposure to these compounds. In this context, laboratory animal models present an invaluable means to study the developmental impact of CNS exposure to neurotropic medication. Using a rodent model, this project quantifies offspring CNS exposure by measuring the brain concentrations of numerous neurotropic medications delivered during pregnancy or lactation and assessing the rate of offspring clearance of these medications after delivery. In addition, this project assesses the functional impact of CNS exposure by measuring alterations, if any, in the density and regional distribution of medication-specific neurotransmitter receptors and transporters that are associated with drug administration. The project also models the impact of genetic polymorphism of hepatic microsomal enzymes upon offspring CNS exposure by duplicating the experiments in a rodent strain genetically deficient of a hepatic isoenzyme. Finally, this project contributes a clear translational component to the overall SCOR by utilizing commonly prescribed medications for the treatment of neurological and psychiatric conditions during pregnancy. Further, this project will be responsive to the clinical experience of the other projects, e.g. should a new medication that is not included in the present application emerge as a primary treatment modality, methodology will be rapidly developed to obtain CNS exposure data.
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