title: Increased hypothalamic [3H]flunitrazepam binding in hypothalamic-pituitary-adrenal axis hyporesponsive Lewis rats.
abstract: We have previously demonstrated that susceptibility of Lewis (LEW/N) rats to inflammatory disease, compared to relatively resistant Fischer (F344/N) rats, is related to deficient glucocorticoid counter-regulation of the immune response resulting from deficient corticotropin-releasing hormone (CRH) responsiveness to inflammatory and other stress mediators. The GABA/benzodiazepine receptor complex is an important negative modulator of CRH secretion and responsiveness to excitatory stimuli. In this study, we have examined in vitro binding of [3H]flunitrazepam to hypothalamic membrane preparations from LEW/N and F344/N rats. LEW/N rats had significantly more hypothalamic benzodiazepine binding sites (Bmax) than F344/N rats, but there were no differences in benzodiazepine binding affinities (Kd) between these two strains. The differences in benzodiazepine receptor number were consistent with the respective plasma corticosterone levels in the two strains, and with previous work indicating a negative correlation between corticosterone levels and benzodiazepine binding site number. Adrenalectomy of F344/N rats increased benzodiazepine binding to levels comparable to LEW/N animals and treatment of adrenalectomized F344/N rats with DEX resulted in lowering of benzodiazepine Bmax to levels that did not differ significantly from those of intact F344/N rats. There was no significant change in receptor number in either adrenalectomized or DEX-treated LEW/N rats. These findings suggest that basal benzodiazepine receptor differences between these strains may be partially related to strain differences in corticosterone levels, however that additional factors may contribute to maintenance of these differences in LEW/N rats. Since benzodiazepines attenuate hypothalamic CRH secretion through GABAergic inhibition, we suggest that strain differences in receptor number could also augment strain differences in hypothalamic-pituitary-adrenal axis function through differential sensitivity to GABA-mediated feedback.
authors.affiliation: Unit on Neuroendocrine Immunology and Behavior, NICHD, Bethesda, MD 20892.
authors.forename: C C
authors.initials: CC
authors.lastname: Smith
authors.forename: E
authors.initials: E
authors.lastname: Hauser
authors.forename: N K
authors.initials: NK
authors.lastname: Renaud
authors.forename: A
authors.initials: A
authors.lastname: Leff
authors.forename: S
authors.initials: S
authors.lastname: Aksentijevich
authors.forename: G P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: R L
authors.initials: RL
authors.lastname: Wilder
authors.forename: P W
authors.initials: PW
authors.lastname: Gold
authors.forename: E M
authors.initials: EM
authors.lastname: Sternberg
mesh_terms: D000315:Adrenalectomy; D000704:Analysis of Variance; D000818:Animals; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D010913:Pituitary-Adrenal System / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013045:Species Specificity
chemical_list: D011963:Receptors, GABA-A; D005445:Flunitrazepam; D003907:Dexamethasone; D003345:Corticosterone