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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA004081-01A1
Application #
3209133
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1987-04-01
Project End
1990-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Hawaii
Department
Type
Schools of Medicine
DUNS #
121911077
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Blanchard, D C; Spencer, R L; Weiss, S M et al. (1995) Visible burrow system as a model of chronic social stress: behavioral and neuroendocrine correlates. Psychoneuroendocrinology 20:117-34
Ge, F; Hammer Jr, R P; Tobet, S A (1993) Ontogeny of Leu-enkephalin and beta-endorphin innervation of the preoptic area in male and female rats. Brain Res Dev Brain Res 73:273-81
Seatriz, J V; Hammer Jr, R P (1993) Effects of opiates on neuronal development in the rat cerebral cortex. Brain Res Bull 30:523-7
Blanchard, D C; Sakai, R R; McEwen, B et al. (1993) Subordination stress: behavioral, brain, and neuroendocrine correlates. Behav Brain Res 58:113-21
Hammer Jr, R P; Hori, K M; Blanchard, R J et al. (1992) Domestication alters 5-HT1A receptor binding in rat brain. Pharmacol Biochem Behav 42:25-8
Bridges, R S; Hammer Jr, R P (1992) Parity-associated alterations of medial preoptic opiate receptors in female rats. Brain Res 578:269-74
Blanchard, D C; Cholvanich, P; Blanchard, R J et al. (1991) Serotonin, but not dopamine, metabolites are increased in selected brain regions of subordinate male rats in a colony environment. Brain Res 568:61-6
Clow, D W; Hammer Jr, R P; Kirstein, C L et al. (1991) Gestational cocaine exposure increases opiate receptor binding in weanling offspring. Brain Res Dev Brain Res 59:179-85
Margulies, J E; Hammer Jr, R P (1991) Delta 9-tetrahydrocannabinol alters cerebral metabolism in a biphasic, dose-dependent manner in rat brain. Eur J Pharmacol 202:373-8
Hammer Jr, R P; Seatriz, J V; Ricalde, A R (1991) Regional dependence of morphine-induced mu-opiate receptor down-regulation in perinatal rat brain. Eur J Pharmacol 209:253-6

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