Effects of midazolam on the response of rats to chronic psychological stress

Objective To investigate the effects of different doses of midazolam (M) on chronic psychological stress (CPS)-induced changes in behavior, neuropeptide release and endothelin-1(ET-1) mRNA expression in the cardiovascular center in medulla oblongata in a rat model of CPS. Methods Male SD rats weighing 150-200 g were placed in a dark box for 25 min/day×7 days (adaptation stage). Those rate which were well adapted to the environment were chosen to undergo the 2nd stage training with irregular light-electric stimulation for 25 min/day×7 days (day 8-14) (complex stress stage) . On the 15th day the animals received only light stimulation (CPS stage). The animals were divided into 3 study groups (n = 8 each): the animals received intraperitoneal (IP) normal saline (NS) 1 ml (NS-study group) or midazolam 0.75 mg·kg-1 (low dose M-study group) or 1.5 mg·kg-1 in NS 1 ml (high dose M-study group) at 10 min before CPS training. There were 2 control groups which received only dark adaptation for 7 days. On the 7th day at 10 min before dark adaptation training the animals received NS 1 ml (NS-control group) or midazolam 1.5 mg·kg-1 in NS 1 ml IP (high dose Mcontrol group) . The behavior of the rats were evaluated at the end of each stage and scored (0 = quiet, 2 = very anxious). Plasma concentrations of ACTH and corticosterone were measured (radioimmunoassay) at the end of the experiment. Paraffin sections of medulla oblongata were used to determine ET-1 mRNA expression (in situ hybridization histochemistry) . Results The rats in NS-study group behaved more anxiously and had higher scores than those in high dose M-study group and the 2 control groups (P 0.05). The number of exploratory behavior measured after stress was significantly larger in the two control groups than in the NS-study group. The plasma ACTH and conticosterone concentrations were significantly higher in NS-study group than in other 4 groups. The ET-1 mRNA expression in the cardiovascular center was significantly higher in the 2 midazolam-study groups than in NS-study group. Conclusion Midazolam can decrease the CPS-induced changes in behavior and neuroendocrine function and inhibit to some extent the decrease in ET-1 mRNA expression induced by CPS.