CHLORDIAZEPOXIDE ATTENUATES STRESS-INDUCED ACCUMULATION OF CORTICOTROPIN-RELEASING FACTOR MESSENGER-RNA IN THE PARAVENTRICULAR NUCLEUS

Corticotropin-releasing factor (CRF) plays a role in coordinating endocrine, autonomic and behavioral responses to stressful stimuli. Benzodiazepines exert many effects which are antithetical to those of CRF, including anxiolysis and suppression of the Pituitary-adrenal axis. Although there is evidence that benzodiazepines can modulate several electrophysiological and behavioral responses to exogenous CRF, we questioned whether this class of drug might also affect CRF biosynthesis as well. We have shown previously that footshock stress increases CRF mRNA levels as monitored by in situ hybridization histochemical techniques in the paraventricular nucleus (PVN) and Barrington's nucleus (the pontine micturition center). We report here the effects of the potent benzodiazepine, chlordiazepoxide (CDP), on stress-induced CRF mRNA accumulation in these two regions. Male albino rats were exposed to electrical footshock (1.5 mA, 1-s duration, 60 times/30 min) twice daily for 4 days and sacrificed 24 h after the last shock session. Either CDP (1, 2.5, 5 or 10 mg/kg) or saline was given i.p. 30 min before each stress. Sections were hybridized with an S-35-labeled prepro-CRF cRNA probe. Relative levels of CRF mRNA were quantified by densitometry of the autoradiography with X-ray film. CRF mRNA concentrations were significantly increased in both the PVN and Barrington's nucleus after stress, and CDP attenuated these increases in the PVN. By contrast, CDP did not affect CRF mRNA accumulation in Barrington's nucleus after stress. The results suggest that the benzodiazepine, CDP, suppresses stress-induced pituitary adrenal activation at least in part through inhibition of CRF production in the PVN. The CRF systems in the PVN and Barrington's nucleus, which we reported earlier as varying in their sensitivity to glucocorticoids, also differ with respect to their responses to benzodiazepines.