Clonazepam-induced intestinal motor disturbances are linked to central nervous system release of cholecystokinin in rats.
The central and peripheral effects of clonazepam (central benzodiazepine receptor agonist) on intestinal myoelectrical activity and the origin of the effects were evaluated in conscious rats, chronically fitted with Nichrome electrodes implanted on the jejunum and with an intracerebroventricular (i.c.v.) cannula. Administered intraperitoneally (i.p.) in 12-h fasted rats, clonazepam (0.05 to 0.5 mg/kg) dose dependently disrupted jejunal cyclic migrating myoelectric complexes, characterizing the fasted state, which were replaced by a permanent irregular spiking activity, lasting 259 +/- 37 min for clonazepam at the dose of 0.5 mg/kg. This disruption of migrating myoelectric complexes occurred after a delay which increased with increasing clonazepam doses. In contrast, injected i.c.v. at doses from 1 microgram/kg to 1 mg/kg, clonazepam did not alter the migrating myoelectric complexes pattern of the small intestine. Injected i.p., flumazenil (central benzodiazepine receptor antagonist) (1 mg/kg) but not PK 11-195 (peripheral benzodiazepine receptor antagonist) (5 mg/kg) suppressed the effects of i.p. clonazepam (0.1 mg/kg). Administered i.c.v., 10 min prior to clonazepam (0.1 mg/kg i.p.), devazepide (CCKA receptor antagonist) at a dose as low as 10 ng/kg reduced the migrating myoelectric complex disruption induced by clonazepam. L365-260 (CCKB receptor antagonist) administered i.c.v reduced the migrating myoelectric complex disruption at 10-fold higher doses and loxiglumide (CCKA receptor antagonist) injected i.c.v, at 100-fold higher doses. When administered i.p. neither devazepide nor L365-260 affected the duration of migrating myoelectric complex disruption induced by clonazepam (0.1 mg/kg i.p.) or its delay of occurrence at doses lower than 0.1 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)
Bonnafous
C
C
Department of Pharmacology-Toxicology, INRA, Toulouse, France.
Martinez
J
J
Fargeas
M J
MJ
Buéno
L
L
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002998:Clonazepam / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004576:Electromyography / Q000187:drug effects; D058787:GABA-A Receptor Antagonists; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007583:Jejunum / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D058787:GABA-A Receptor Antagonists; D002998:Clonazepam; D002766:Cholecystokinin