GASTROINTESTINAL EFFECTS OF DIAZEPAM-WITHDRAWAL ARE LINKED TO ACTIVATION OF CENTRAL CHOLECYSTOKININ-ERGIC PATHWAYS IN RATS

The influence of flumazenil-precipitated diazepam withdrawal on intest inal myoelectric activity and colonic transit was evaluated, in diazep am-dependent rats. Administered intraperitoneally, flumazenil (15 mg k g(-1)) induced a strong stimulation of the duodenal spiking activity l asting 197 +/- 20 min, and accelerated colonic transit corresponding t o 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 L3 65260 administered intracerebroventricularly at a dose of 10 mu kg(-1) abolished the flumazenil-induced withdrawal effect on the duodenum, w hereas at a lower dose (1 mu g kg(-1)) only L365260 was able to antago nize this effect. In the same way, devazepide, loxiglumide and L365260 suppressed the effect of precipitated withdrawal on colonic transit w hen administered intracerebroventricularly at a dose of 10 mu g kg(-1) , whereas similar blockade was obtained at a dose of 5 mu g kg(-1) wit h L365260, and 10 ng kg(-1) with PD135-158. It is concluded that in ra ts precipitated diazepam-withdrawal altered intestinal motility and co lonic transit and that these effects are mediated by central release o f cholecystokinin (CCK) or activation of CCK-ergic neurons.