The overall focus of the research remains that of understanding the influences on neural development and later function that may be mediated via interactions at the level of membrane receptors. Many psychotherapeutic drugs act at this level. Research conducted in this laboratory has demonstrated pronounced effects on the noradrenergic (NE) innervation to the hypothalamus following in-utero exposure to diazepam (DZ), effects that are related to the binding of the drug to the central type benzodiazepine (BZ) receptor. Studies are now proposed to investigate the relationship between the BZ receptor and hypothalamic NE neurons and determine how these neurons are permanently influenced by the prenatal exposure. Specifically: (1) Do the effects on the NE neurons induced by the exposure involve changes in calcium uptake and/or (2) alterations in intracellular pools of NE in the hypothalamus? (3) What accounts for the apparent selectivity of the effect on hypothalamic NE neurons? Are a high percentage of BZ receptors in the hypothalamus presynaptically located on NE terminals in that region or is there a particular subtype of the central receptor in that region? Is the specificity of the in-utero exposure related to the relationship of hypothalamic NE-containing neurons to peptide-containing neurons, particularly those containing CRF and/or vasopressin? (4) What accounts for the delayed appearance of the effects induced by the prenatal exposure until after 4-5 weeks postnatal age? Are events related to puberty responsible? (5) Does DZ interaction with BZ receptors during fetal life influence the hypothalamic NE neurons at that time? Where in this region are the receptors located during the critical period for exposure? (6) Will physiologic stimuli such as restraint stress activate the BZ receptor during gestation and induce results similar to those observed following DZ exposure? Prenatal DZ exposure also induces alterations in the acoustic startle response and its potentiation by background noise, effects that appear unrelated to an influence at the central type receptor. Additionally, DZ administered to adult rats appear to inhibit the potentiated response via more than one mechanism. Continued analysis of this observation will assist in determining (1) whether there are different anxiolytic mechanisms and (2) whether prenatal DZ exposure influences the appearance of the different mechanisms. These studies will provide information on how DZ can influence the developing nervous system thereby yielding knowledge on neural interaction that can regulate development.
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