Dexamethasone resistance among nonhuman primates associated with a selective decrease of glucocorticoid receptors in the hippocampus and a history of social instability.
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 micrograms/dl) versus a DEX-resistant subset (cortisol values of 9.2 +/- 2.0 micrograms/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.
Brooke
S M
SM
Department of Biological Sciences, Stanford University, Calif. 94305.
de Haas-Johnson
A M
AM
Kaplan
J R
JR
Manuck
S B
SB
Sapolsky
R M
RM
D000818:Animals; D001522:Behavior, Animal; D003907:Dexamethasone / Q000494:pharmacology*; D004351:Drug Resistance; D006624:Hippocampus / Q000502:physiology*; D006854:Hydrocortisone / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D009994:Osmolar Concentration; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012919:Social Behavior
D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D006854:Hydrocortisone