Neurobehavioral teratology due to hypoxic exposure in newborn rats

ABSTRACT

BACKGROUND AND PURPOSE: Neurobehavioral teratology is a term used for the postnatal effects on behavior of prenatal exposure to drug or to specific environment. Perinatal hypoxia is a major risk factor for development of behavioral abnormalities, such as cerebral palsy, mental retardation and learning disability. The objective of this study is to investigate the effects of neonatal hypoxia on long-term changes of behavior and neurochemical system and to learn the role of 5-hyroxytryptamine(5-HT) in hypoxic stress. METHODS: Sprague-Dawley rats were grouped by hypoxia and/or 5-HT receptor antagonist treatment. Exposure to 100% N2 gas was done in postnatal day(PND) 2 for 12 minutes. NAN-190 HBr or ketanserin tartrate or both were injected intraperitoneally 30 minutes before exposure to hypoxic environment. Rats were weighed periodically and examined the eye opening. Wire maneuver test was done on PND 22. Between PND 40-55 and PND 63-84, explorative behavior test and Rota-Rod test were done serially. They were sacrificed in PND 100, and aminergic neurotransimitters and their metabolites were measured by High Performance Liquid Chromatography - Electrochemical Detection(HPLC ECD) system. Receptor binding assay was done using 8-OH-DPAT and ketanserin HCl in brain cortex. RESULTS: The group treated with 5-HT receptor antagonist and hypoxia showed higher death rate than 5-HT receptor antagonist or hypoxia alone. There were no differences in weight gain, eye opening, and the result of wire maneuver test among each groups. In explorative behavior test, NAN+N2 group in male and NAN group in female showed markedly increased activities. In Rota-Rod test, NAN and NAN+N2 groups in both male and female showed decreased motor coordination. There were no differences in the concentration of aminergic neurotransmitters and their metabolites, when measured in PND 100 according to the brain sites. There were no differences in pKd of 5-HT receptors measured on PND 100. But Bmax of 5-HT1A receptor were low in N2, NAN and NAN+N2 groups. NAN and NAN+N2 groups showed elevated Bmax of 5-HT2A/2C receptor. CONCLUSION: Exposure to hypoxia in neonatal period causes long-lasting neurobehavioral changes with neurochemical abnormalities, and 5-HT receptor activity has a role in that mechanism.