Effects of peripheral benzodiazepine receptor ligands on hypothalamic-pituitary-adrenal axis function in the rat.
High concentrations of the "peripheral" benzodiazepine (pBZD) binding site ("receptor") have been described in the hypothalamus, the pituitary and the adrenal glands. This study was undertaken to examine the effects of ligands of this binding site on the hypothalamic-pituitary-adrenal axis (HPA). To accomplish this we administered graded doses of the pBZD receptor agonist 4-chloro-diazepam (Ro5-4864) i.v. to catheterized, freely moving adult male Sprague-Dawley rats. Serial blood samples for plasma adrenocorticotropin hormone (ACTH) and corticosterone determinations were drawn from the catheter before and after the injection of the drug. Ro5-4864 significantly stimulated ACTH and corticosterone secretion in a dose-dependent fashion. To examine whether this effect could be antagonized by the pBZD binding site antagonist PK 11195, we treated rats with PK 11195 at doses 10- and 50-times higher than Ro5-4864 before administration of a maximally effective dose of Ro5-4864. Neither dose of PK 11195 antagonized Ro5-4864-induced plasma ACTH or corticosterone elevations. However, this agent, given alone, stimulated ACTH and corticosterone release. Similarly, carbamazepine (CBZ), which binds to the pBZD binding site with low affinity, stimulated weakly the HPA in vivo, reaching statistical significance only at the highest dose tested. To examine the site(s) of action of these compounds on the HPA, we evaluated their effects on hypothalamic corticotropin-releasing hormone (CRH) and pituitary ACTH secretion in vitro. Ro5-4864 stimulated hypothalamic CRH, but not pituitary ACTH secretion. Neither PK 11195 nor CBZ had any agonist effect on hypothalamic CRH secretion in vitro, whereas both antagonized Ro5-4864-induced CRH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Calogero
A E
AE
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institute of Mental Health, Bethesda, Maryland.
Kamilaris
T C
TC
Bernardini
R
R
Johnson
E O
EO
Chrousos
G P
GP
Gold
P W
PW
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001665:Binding Sites; D002220:Carbamazepine / Q000494:pharmacology; D003292:Convulsants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D001570:Benzodiazepinones; D003292:Convulsants; D007546:Isoquinolines; D011963:Receptors, GABA-A; C028513:4'-chlorodiazepam; D002220:Carbamazepine; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; C037850:PK 11195