This project will quantitatively assess the effect of opiate compounds or opiate antagonists on neuronal development in the rat medial preoptic area of the hypothalamus (MPOA). The results will elucidate the mechanism of normal neuronal growth, the influence of endogenous opiates on brain growth, the consequence of prenatal narcotic exposure on brain development, and putative aberrant developmental mechanisms which could lead to mental retardation. Time-pregnant female rats will be given morphine sulfate (either 20 mg/kg/day, 10 mg/kg/day, or 2 mg/kg/day), morphine and naloxone (10 mg/kg/day and either 20 mg/kg/day (high antagonist dose) or 2 mg/kg/day (low antagonist dose), respectively), naloxone (either 20 mg/kg/day, 5 mg/kg/day, or 2 mg/kg/day) [D-Ala2]Met-enkephalinamide (either 20 mg/kg/day, 10 mg/kg/day or 5 mg/kg/day) or saline vehicle by subcutaneously-implanted, four-week duration osmotic minipump beginning at postinfertilization day 12. In addition, a group of pups born to control mothers will be placed with morphine-treated mothers and killed at postfertilization days 32 and 82 and additional groups of prenatally-morphine-treated pups will be cross-fostered to control mothers and reared to postfertilization days 32 and 82. Thus, animals will have had either gestational, gestation-lactational, or lactational exposure to drugs. Brain samples from both sexes will be removed on postfertilization days 22, 24, 26, 28,32 and 82, and prepared for quantitative microscopy. Analysis of completely impregnated, randomly-selected, Golgi-stained MPOA neurons will utilize a computer-assisted, Quantitative Morphometry System to obtain data on neuronal size and pattern and extent of dendritic arborization. These data will be compared across age, sex, and experimental condition to determine the effect of opiates or opiate antagonists administered during the critical period of sexual brain differentiation on MPOA neuron growth and development. The mechanism of action of opiates will be investigated by assaying steroid hormone levels, MPOA opiate receptor density, and endogenous hypothalamic opiate levels in similarly-treated animals.
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