BENZODIAZEPINE-WITHDRAWAL-INDUCED GASTRIC-EMPTYING DISTURBANCES IN RATS - EVIDENCE FOR SEROTONIN RECEPTOR INVOLVEMENT

This study was performed in rats to determine if serotonin and its rec eptors are involved in the increase of gastric emptying (GE) induced b y benzodiazepine (BZ) withdrawal. GE was measured with a test meal (2 ml) containing 1 mu Ci/ml of Cr-51 sodium chromate administered in rat s, either previously receiving injections with diazepam (15 mg/kg/day i.p.) or with DMSO (0.9 ml/day i.p.) during 7 days. On the 8th day, an imals received the different serotonin (5-HT) agonists or antagonists, and flumazenil (BZ antagonist; 15 mg/kg i.p.) 30 and 15 min, respecti vely, before the test meal. Methiotepin (5-HT1 antagonist) either i.p. (0.1-1 mg/kg) or intracerebroventricularly (10 mu g/kg) had no effect on the increase of GE induced by precipitated-withdrawal. 8-OH-DPAT ( 5-HT1A agonist) administered i.c.v. (1-10 mu g/kg) dose dependently re duced GE increase. Administered i.p. (0.1 mg/kg), it blocked GE increa se in control and diazepam-withdrawn rats. Ritanserin (5-HT2 antagonis t) antagonized GE increase only when administered i.p. (0.1 mg/kg). Gr anisetron (5-HT3 antagonist) was active both i.p. (0.01-0.1 mg/kg) and intracerebroventricularly (1-10 mu g/kg). Administered intracerebrove ntricularly (1 mu g/kg) in diazepam-treated rats, 5-HTP mimicked the e ffect of flumazenil. It is concluded that diazepam-withdrawal increase s GE by stimulating central release of 5-HT and/or central activation of 5-HT neurons. At least central 5-HT3 receptors, and in less extend, peripheral 5-HT2 receptors are involved in this mechanism.