Gastrointestinal Effects of Diazepam-withdrawal are Linked to Activation of Central Cholecystokinin-ergic Pathways in Rats

Abstract

Abstract The influence of flumazenil-precipitated diazepam withdrawal on intestinal myoelectric activity and colonic transit was evaluated, in diazepam-dependent rats. Administered intraperitoneally, flumazenil (15 mg kg−1) induced a strong stimulation of the duodenal spiking activity lasting 197 ± 20 min, and accelerated colonic transit corresponding to a significantly (P < 0·05) increased value of the geometric centre (3.52 ± 0.23 vs 2·44 ± 0·1 for the control). Both devazepide and L365260 administered intracerebroventricularly at a dose of 10 μg kg−1 abolished the flumazenil-induced withdrawal effect on the duodenum, whereas at a lower dose (1 μg kg−1) only L365260 was able to antagonize this effect. In the same way, devazepide, loxiglumide and L365260 suppressed the effect of precipitated withdrawal on colonic transit when administered intracerebroventricularly at a dose of 10 μg kg−1, whereas similar blockade was obtained at a dose of 5 μg kg−I with L365260, and 10 ng kg−1 with PD135–158. It is concluded that in rats precipitated diazepam-withdrawal altered intestinal motility and colonic transit and that these effects are mediated by central release of cholecystokinin (CCK) or activation of CCK-ergic neurons.