Dexamethasone Resistance among Nonhuman Primates Associated with a Selective Decrease of Glucocorticoid Receptors in the Hippocampus and a History of Social Instability

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Abstract
We have studied some of the neuroendocrine and social correlates of dexamethasone resistance in a nonhuman primate population. Subjects were 51 male Macaca fascicularis monkeys with known behavioral histories and who had been given dexamethasone (DEX) suppression tests a week prior to killing. We compared the subset of monkeys who were most DEX responsive (post-DEX cortisol values of 3.1 ± 0.5 µg/dl) versus a DEX-resistant subset (cortisol values of 9.2 ± 2.0 µg/dl); we found two features that distinguished these groups: (a) DEX-resistant monkeys had significantly fewer available glucocorticoid receptor (GR) binding sites in the hippocampus; they did not differ in numbers of mineralocorticoid receptor (MR) sites in the hippocampus, nor in numbers for either receptor in the cortex or hypothalamus as a whole, (b) Animals had resided for a number of years in social groups that were either stable or were repeatedly destabilized by changing of group membership; the latter has been shown to constitute a sustained stressor. DEX-resistant animals were more than twice as likely to have come from an unstable group as were DEX-responsive monkeys. Rodent studies have shown that sustained stress can cause a selective downregulatory decrease in the numbers of hippocampal corticosteroid receptors, and that such a loss is associated with DEX resistance. The present data suggest similar associations in the primate, and may be of relevance to the DEX resistance observed in a subset of human depressives.

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