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.
Bonnafous
C
C
Department of Pharmacology I.N.R.A., Toulouse, France.
Martinez
J
J
Bueno
L
L
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020109:Devazepide; D003975:Diazepam / Q000009:adverse effects*; D005442:Flumazenil / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D005772:Gastrointestinal Transit / Q000187:drug effects*; D008297:Male; D010671:Phenylurea Compounds; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; C058121:L 365260; D005442:Flumazenil; D002766:Cholecystokinin; D020109:Devazepide; D003975:Diazepam