Evidence that a benzodiazepine receptor mechanism regulates the secretion of pituitary beta-endorphin in rats.

The effects of agents representing three classes of benzodiazepine receptor-acting drugs on circulating levels of beta-endorphin-like immunoreactivity (beta-END-LI) were examined in male rats. The active benzodiazepine receptor antagonists, ethyl-beta-carboline-3-carboxylate (beta-CCE, 30 mg/kg), methyl-beta-carboline-3-carboxylate (3 mg/kg), and 2-phenylpyrazolo [4,3-c]quinolin-3(5H)-one (CGS-8216, 3 mg/kg), all evoked 3- to 4-fold increases in plasma levels of beta-END-LI as compared to control values. The beta-CCE-induced rise in circulating beta-END-LI was significantly attenuated by pretreatment with the agonist diazepam (2.5 mg/kg) and the antagonist ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-alpha] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788, 10 mg/kg) but was unaltered by morphine (1 and 5 mg/kg). Ro 15-1788 also significantly attenuated the methyl-beta-carboline-3-carboxylate- and CGS-8216-induced release of pituitary beta-END-LI in vivo. Morphine (5 mg/kg) and diazepam (5 mg/kg) together, but neither alone, significantly reduced the rise in plasma beta-END-LI due to physical immobilization or foot shock. Pretreatment with dexamethasone (100 micrograms), an inhibitor of pituitary anterior lobe (AL) beta-END-LI secretion, completely prevented the plasma beta-END-LI increase due to beta-CCE. Chromatographic analysis of plasma beta-END-LI revealed that most of the beta-END-LI secreted in response to beta-CCE and CGS-8216 resembles beta-lipotropin (beta-LPH), a marker for beta-END-LI release from the AL, in molecular size. Results of in vitro studies indicate that the effects of the anxiogenic agents, beta-CCE and CGS-8216, on AL beta-END-LI release in vivo were not mediated by direct actions of these agents on the pituitary gland. Together, these findings suggest that an interaction exists between a benzodiazepine receptor mechanism(s) and regulation of hypothalamic corticotropin-releasing factor(s) which in turn controls beta-END-LI secretion from the AL of the rat pituitary gland.