Gastrointestinal effects of diazepam-withdrawal are linked to activation of central cholecystokinin-ergic pathways in rats.

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 micrograms kg-1 abolished the flumazenil-induced withdrawal effect on the duodenum, whereas at a lower dose (1 microgram 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 micrograms kg-1, whereas similar blockade was obtained at a dose of 5 micrograms kg-1 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.