Pharmacological characterization of central and peripheral type I and typeII adrenal steroid receptors in the prairie vole, a glucocorticoid-resistant rodent

The prairie vole (Microtus ochrogaster) has recently been shown to be gluco corticoid resistant; that is, the prairie vole adrenal axis is refractory t o dexamethasone challenge, and highly elevated basal corticosterone titers occur without apparent pathophysiology; This study investigates the physiol ogical correlates of glucocorticoid resistance in the prairie vole. We prov ide a detailed pharmacological characterization of intracellular type I and type II adrenal steroid receptors in peripheral tissues and the hippocampu s of the prairie vole and the Sprague Dawley rat, a corticosensitive rodent . Adrenalectomy markedly reduces, but does not eliminate, circulating gluco corticoids in the prairie vole. Nonetheless, molecular, cellular, and physi ological assays indicate adrenal insufficiency; salt appetite and dentate g yrus granule cell death are increased after adrenalectomy, suggesting vacan cy of the high affinity type I subtype of central adrenal steroid receptor. Analysis of adrenal steroid receptor binding constants and selectivity for endogenous and synthetic steroids in the vole and rat indicated that the v ole type I receptor is nearly identical to that of the rat in brain and per iphery. However, voles demonstrated a 2-fold lower type I receptor binding density in colon and hippocampus compared with that in rats. The vole type II receptor bound the endogenous glucocorticoid corticosterone with an 8- t o 10-fold lower affinity than the rat type II receptor and was expressed in lower densities in thymus and hippocampus. These data indicate physiologic al adaptations in the prairie vole adrenal axis consistent with other gluco corticoid-resistant species, such as the guinea pig and squirrel monkey.