NEUROTOXICITY OF GLUCOCORTICOIDS IN THE PRIMATE BRAIN

Severe and prolonged physical and psychological stress is known to cau se brain damage; long-term torture victims in prison have later develo ped psychiatric disorders and cerebral cortical atrophy observed in CT scans (Jensen, Genefke, Hyldebrandt, Pedersen, Petersen, and Weile, 1 982). In nonhuman primates, we observed degeneration and depletion of the hippocampal neurons in African green monkeys that had been severel y abused by cagemates and died with complications of multiple gastric ulcers and adrenal cortical hyperplasia (Uno, Tarara, Else, Suleman an d Sapolsky, 1989). In our previous studies the administration of dexam ethasone (DEX) (5 mg/kg) to pregnant rhesus monkeys at 132 to 133 days of gestation induced degeneration and depletion of the hippocampal py ramidal and dentate granular neurons in the brains of 135-gestation-da y fetuses, and these changes were retained in the brains of fetuses at near term, 165 days of gestation (Uno, Lohmiller, Thieme, Kemnitz, En gle, Roecker, and Farrell, 1990). We also found that implantation of a cortisol pellet in the vicinity of the hippocampus in adult vervet mo nkeys induced degeneration of the CA3 pyramidal neurons and their dend ritic branches (Sapolsky, Uno, Rebert, and Finch, 1990). Thus, hippoca mpal pyramidal neurons containing a high concentration of glucocortico id receptors appear to be highly vulnerable to either hypercortisolemi a caused by severe stress or to exposure to exogenous glucocorticoids. To study the long-term postnatal sequelae of prenatal brain damage, e ight rhesus monkeys were treated with either DEX (5 mg/kg), 5 animals, or vehicle, 3 animals, at 132 to 133 days of gestation. After natural birth, all animals lived with their mothers for 1 year. At 9 months o f age, we found that DEX-treated animals had significantly high plasma cortisol at both base and post-stress (isolation) levels compared to age-matched vehicle-treated animals. Magnetic resonance images (MRI) o f the brain at 20 months of age showed an approximately 30% reduction in size and segmental volumes of the hippocampus in DEX-treated compar ed to vehicle-treated animals. Measurements of whole brain volume by M RI showed no significant differences between DEX and vehicle groups. P renatal administration of a potent glucocorticoid (DEX) induced an irr eversible deficiency of the hippocampal neurons and high plasma cortis ol at the circadian baseline and post-stress levels in juvenile rhesus monkeys. These results suggest that the hippocampus mediates negative feedback of cortisol release; a lack or deficiency of the hippocampal neurons attenuates this feedback resulting in hypercortisolemia. The hippocampal deficiency in rhesus monkeys induced by prenatal administr ation of DEX appears to be a good model for neuroendocrinological dysf unctions and hippocampal development in human juveniles whose mothers were exposed to severe stress or received a high dose of glucocorticos teroids during pregnancy. (C) 1994 Academic Press, Inc.