Accumulating evidence suggests that fetal exposure to antiepileptic drugs may produce long-lasting or even permanent alterations in behavior, neuronal activity and/or biochemistry of the CNS of the developing animal. Since anticonvulsant medications exert at least some of their effects by altering the effectiveness of GABA at postsynaptic receptors, the purpose of the proposed studies is to determine whether specific stimulation or blockade of GABA receptors during ontogeny could affect the postnatal development of the GABA system. This research will focus on the development of the postsynaptic GABA receptor complex (GABA-PRC) in an area which has a defined GABAergic input, the dorsal raphe nucleus (DRN). The presence of GABA receptors will be studied in the DRN using radioligand binding methods to identify and quantify their appearance. Subunits of the GABA-PRC will be characterized from animals at different postnatal ages both in membranes prepared from the DRN area and in slices of the DRN area by in vitro autoradiography. The appearance of functional responsivitity of GABAergic receptors will be assessed electrophysiologically using single cell recording and microiontophoretic techniques within the DRN of developing rats; the sensitivity of 5-HT containing neurons to GABA and GABA analogs will be tested in intact animals and in vitro slice preparations. These data will provide unique information about the appearance and functional development of postsynaptic GABA receptors in the DRN. The effect of prenatal exposure to GABA agonists and antagonists on postnatal development of neurons in this nucleus will then be examined. The appearance and maturation of the GABA-PRC in the DRN from treated pups will be characterized and compared with corresponding sites in age-matched control animals. Prenatally exposed and paired control pups will be compared electrophysiologically during postnatal development for functional maturation of GABA responsivity in DRN neurons. By examining the effects of the prenatal administration of drugs which specifically alter GABA synaptic transmission on the development of postsynaptic receptor sensitivity it may be possible to identify pathologies associated with developmental alterations in the GABA system.
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