Comparison of the effects of chlordiazepoxide and CL 218,872 on serum corticosterone concentrations in rats

Fifteen minute exposure to a novel environment plus 120 dB sound stimulation produced a three-fold increase in serum corticosterone concentrations in rats. A low dose of intraperitoneally (IP) administered chlordiazepoxide (CDP) (5 mg/kg) attenuated this response, whereas a higher dose (20 mg/kg) elevated corticosterone concentrations in rats not subjected to sound stress. Parallel results were obtained after intracerebroventricular (ICV) drug administration, with a low dose of CDP (5 micrograms) reducing the sound stress response and higher doses (25 and 50 micrograms) increasing corticosterone concentrations in unstressed animals. Thus, despite the presence of benzodiazepine (BDZ) receptors at every level of the hypothalamic-pituitary-adrenocortical axis, it appears that BDZs alter the activity of this system via an interaction with BDZ receptors in brain. CL 218,872 (2.5-20 mg/kg), a novel non-BDZ anxiolytic compound, did not attenuate the corticosterone elevation produced by sound stimulation, and also failed to alter baseline corticosterone concentrations in unstressed animals. The fact that CL 218,872 is a selective agonist for brain Type I BDZ receptors suggests that BDZs are not influencing corticosterone secretion through an interaction with this BDZ receptor subtype. Furthermore, these results indicate that stress (as measured by pituitary-adrenocortical activation) can be dissociated from anxiety (as measured by conflict paradigms), thus challenging the validity of the corticosteroid stress test as a screening procedure for anxiolytic activity.