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 μg/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 (CCK A receptor antagonist) at a dose as low as 10 ng/kg reduced the migrating myoelectric complex disruption induced by clonazepam. L365-260 (CCK B receptor antagonist) administered i.c.v reduced the migrating myoelectric complex disruption at 10-fold higher doses and loxiglumide (CCK A 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. It is concluded that (i) in a range of therapeutic doses, clonazepam alters the motility of the proximal small intestine in fasted rats and (ii) these effects could result from activation of central type receptors located peripherally and could be mediated through the central release of cholecystokinin (CCK) and/or activation of the central CCK neurons involving CCK A and CCK B receptors.