The objectives of this research are to establish the effects on rat offspring of diazepam therapy during pregnancy. To date our research has demonstrated that exposure to diazepam during the third week of gestation produces both developmental delays and long-term alterations in behavior and a reduction in hypothalamic noradrenaline levels that is pronounced in adult animals. These lasting changes are not related to postnatal drug persistence in the brain. Considering the amount of this drug that is prescribed in this country, these findings of lasting consequences following early developmental exposure necessitate a more thorough understanding of the induced effects. The proposed research is designed to answer four questions: (1) What are the mechanisms whereby early developmental exposure to DZ induces long-lasting effects on hypothalamic NA? The studies are designed to evaluate our hypothesis that binding of the drug to specific receptor sites in the hypothalamus during critical stages of neural development may alter function of peptides essential for the ingrowth of NA fibers, synaptogenesis, and/or synaptic function. We will analyze NA levels, peptide immunocytochemistry and develop a tissue culture model. (2) What are the functional implications to the organism of a reduction in hypothalamic NA? We will evaluate the turnover of NA in the hypothalamus as well as the hormonal response to stress, and using in-vitro methods, we will analyze mechanisms in NA neurons which may account for the drug-induced alterations in turnover which we have seen to date. (3) Is diazepam therapy for maternal stress beneficial to the offspring? While some literature reports suggest that concurrent diazepam therapy can prevent effects on the progeny from maternal stress, some of our initial results suggest that the effects to the progeny of the therapy and the condition may be synergistic. We will measure the effect of stress and/or drug on hypothalamic NA levels and turnover and on specific peptides. (4) Is the effect of prenatal DZ on auditory temporal acuity specific for that class of drugs? This behavior has been found to be remarkably similar in rats and humans, and evaluation of this function will assist us in determining questions which can be asked clinically with respect to early drug exposure.
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