CLONAZEPAM-INDUCED INTESTINAL MOTOR DISTURBANCES ARE LINKED TO CENTRAL-NERVOUS-SYSTEM RELEASE OF CHOLECYSTOKININ IN RATS

The central and peripheral effects of clonazepam (central benzodiazepi ne receptor agonist) on intestinal myoelectrical activity and the orig in of the effects were evaluated in conscious rats, chronically fitted with Nichrome electrodes implanted on the jejunum and with an intrace rebroventricular (i.c.v.) cannula. Administered intraperitoneally (i.p .) in 12-h fasted rats, clonazepam (0.05 to 0.5 mg/kg) dose dependentl y disrupted jejunal cyclic migrating myoelectric complexes, characteri zing the fasted state, which were replaced by a permanent irregular sp iking 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 con trast, injected i.c.v. at doses from 1 mug/kg to 1 mg/kg, clonazepam d id 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 rec eptor 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/k g i.p.), devazepide (CCK(A) receptor antagonist) at a dose as low as 1 0 ng/kg reduced the migrating myoelectric complex disruption induced b y clonazepam. L365-260 (CCK(B) receptor antagonist) administered i.c.v reduced the migrating myoelectric complex disruption at 10-fold highe r doses and loxiglumide (CCK(A) receptor antagonist) injected i.c.v, a t 100-fold higher doses. When administered i.p. neither devazepide nor L365-260 affected the duration of migrating myoelectric complex disru ption induced by clonazepam (0.1 mg/kg i.p.) or its delay of occurrenc e at doses lower than 0.1 mg/kg. It is concluded that (i) in a range o f therapeutic doses, clonazepam alters the motility of the proximal sm all 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) rece ptors.