An increasing number of infants are being born to mothers addicted to heroin and methadone. The offspring, which are exposed to drugs in utero, are often born passively addicted to the opiates. The long-lasting effects of maternal opiate abuse on neuronal development in the offspring and the neuroendocrine consequences have not been extensively studied. A substantial amount of neuronal maturation occurs during the perinatal period and insults during this time could result in permanent functional alterations. Most drugs of abuse, including opiates and cocaine, are believed to work via similar mechanisms involving neurotransmitters, especially dopamine. The primary goal of this proposal is to examine the effects of perinatal opiate exposure on the hypothalamic neurotransmitter systems which contribute to the overall regulation of prolactin secretion. The endogenous opioid peptides and serotonin increase prolactin secretion by acting at a central site, whereas dopamine from the tuberoinfundibular neurons suppresses prolactin release by a direct action on anterior pituitary lactotrophs. The opioid-induced prolactin rise involves both dopaminergic and serotonergic components. Morphine will be administered by pellet implantion to pregnant rats during mid to late pregnancy and/or directly to the offspring during early postnatal life. Offspring will be evaluated during the neonatal, prepubertal, and adult stages of life. The functional integrity of the neuroendocrine regulation of prolactin secretion will be evaluated by pharmacolgoical challenges to the opioid, dopaminergic and serotonergic systems. Neurotransmitter synthesis is an important neuronal process which is subject to regulation and serves as an index of neuronal activity. Dopamine and serotonin synthesis in the nerve terminals will be measured by in vitro accumulation of L-dihydroxyphenylalanine in the stalk-median eminence and 5-hydroxytryptophan in the medial basal hypothalamus after incubation with a decarboxylase inhibitor. Tyrosine hydroxylase is the rate limiting enzyme in the dopaminergic biosynthetic pathway. The relative differences in mRNA concentration and enzyme quantity for tyrosine hydroxylase will be evaluated by in situ hybridization and immunocytochemistry, respectively.
The specific aims of this proposal are 1) to establish a model of opiate dependence in which to study the effects of perinatal opiate exposure on neuroendocrine function in the offspring, 2) to assess the prolactin response to serotonergic, dopaminergic and opioid challenges at selected ages after perinatal morphine administration and 3) to examine the effects of perinatal morphine exposure on dopamine and serotonin synthesis and on tyrosine hydroxylase gene expression in the medial basal hypothalamus.
| Arbogast, L A; Soares, M J; Robertson, M C et al. (1993) A factor(s) from a trophoblast cell line increases tyrosine hydroxylase activity in fetal hypothalamic cell cultures. Endocrinology 133:111-20 |
