DEXTROMETHORPHAN AND DEXTRORPHAN IN RATS - COMMON ANTITUSSIVES - DIFFERENT BEHAVIORAL PROFILES

Dextromethorphan (DM), a widely used and web-tolerated centrally actin g antitussive, has been tested in several clinical trials for its anti epileptic and neuroprotective properties. However, the use of DM in th ese new clinical indications requires higher doses than antitussive do ses, which may therefore induce phencyclidine (PCP)-like side-effects (memory and psychotomimetic disturbances) through its metabolic conver sion to the active metabolite dextrorphan (DX), a more potent PCP-like non-competitive antagonist at the N-methyl-D-aspartate (NMDA) recepto r than DM. Thus, we compared the behavioural effects in rats of intrap eritoneal administration of DM and DX on motor activity in an open fie ld and on learning and memory in the Morris water maze. DM (20, 30, 40 mg/kg) produced a dose-dependent decrease in both locomotion and ster eotyped behaviour with a slight ataxia for the highest dose. DX (20, 3 0, 40 mg/kg) induced a dose-dependent increase in locomotion and stere otypies (swaying, turning) with moderate ataxia Assessments of learnin g and memory were performed with lower doses of DM (10, 20, 30 mg/kg) and DX (5, 10, 15 mg/kg) because of motivational deficits (40 mg/kg of DM, 20-40 mg/kg of DX) and motor disorders (30, 40 mg/kg of DX) in th e cue learning procedure. DX (10, 15 mg/kg) impaired spatial learning with a long-lasting effect for the highest dose whereas 5 mg/kg of DX and DM (10-30 mg/kg) did not. Only 15 mg/kg of DX appeared to slightly impair working memory. DM (10-30 mg/kg) and DX (5-15 mg/kg) did not i mpair reference memory. Thus, the two antitussives DM and DX induced d ifferent behavioural effects suggesting sedative effects for DM and PC P-like effects for DX. However, PCP-like side-effects with DM remain p ossible through its metabolic conversion to DX, with very high doses a nd/or in extensive metabolizers and/or in aged subjects prone to cogni tive dysfunction. Therefore, the identification of DM metabolism pheno type, an adapted prescription and a pharmacological modulation of the DM metabolism may avoid adverse effects. (C) Elsevier, Paris.