Diazepam attenuation of restraint stress-induced corticosterone levels is enhanced by prior exposure to repeated restraint.

Prior research has demonstrated that diazepam decreases hypothalamic-pituitary-adrenal cortex (HPA) axis activity in stressful contexts but, paradoxically, acts as a stimulator of basal axis activity. Also, several investigators have reported that low doses of diazepam are not effective in reducing stress-induced corticosterone (CORT) levels, yet similar doses typically produce anxiolytic effects on behavioral measures of fear and anxiety. We have examined the effects of diazepam on plasma CORT levels in male Sprague-Dawley rats utilizing a repeated restraint paradigm. Consistent with most literature, diazepam administered IP (1.5, 3.0, or 6.0 mg/kg) 1 h prior to restraint increased non-stress, baseline plasma CORT levels in a dose-dependent fashion. During the first exposure to the 1 h restraint-stress procedure, CORT levels of diazepam-injected rats did not differ from the stress levels of controls except at the 60-min stress time point in those subjects receiving 6.0 mg/kg. However, diazepam at all three doses was able to attenuate the stress-induced increase in CORT following 5 days of diazepam+restraint treatment. Using the 3.0 mg/kg dose as a probe, it was found that this effect was not dependent on the repeated administration of diazepam, but rather on repeated exposure to restraint. These results suggest that repeated restraint produces a change in neural sensitivity to benzodiazepines.