Dextromethorphan and dextrorphan in rats: Common antitussives — Different behavioural profiles

Abstract

Dextromethorphan (DM), a widely used and well-tolerated centrally acting antitussive, has been tested in several clinical trials for its antiepileptic and neuroprotective properties. However, the use of DM in these new clinical indications requires higher doses than antitussive doses, which may therefore induce phencyclidine (PCP)-like side-effects (memory and psychotomimetic disturbances) through its metabolic conversion to the active metabolite dextrorphan (DX), a more potent PCP-like non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor than DM. Thus, we compared the behavioural effects in rats of intraperitoneal administration of DM and DX on motor activity in an open field 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 stereotyped behaviour with a slight ataxia for the highest dose. DX (20, 30, 40 mg/kg) induced a dose-dependent increase in locomotion and stereotypies (swaying, turning) with moderate ataxia. Assessments of learning 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 the 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 impair reference memory. Thus, the two antitussives DM and DX induced different behavioural effects suggesting sedative effects for DM and PCP-like effects for DX. However, PCP-like side-effects with DM remain possible through its metabolic conversion to DX, with very high doses and/or in extensive metabolizers and/or in aged subjects prone to cognitive dysfunction. Therefore, the identification of DM metabolism phenotype, an adapted prescription and a pharmacological modulation of the DM metabolism may avoid adverse effects.

Neuropsychotoxic and Neuroprotective Potentials of Dextromethorphan and Its Analogs

“…Similarly, DM has been reported to impair spatial learning in the Morris water maze in a dose-dependent manner (31), consistent with the water-maze effects of other NMDA-receptor antagonists (e.g., MK-801 and AP-5) reported by other investigators (26). On the other hand, the memory impairment caused by DX is more pronounced than that of DM (32), and the prolonged use of DM produces cognitive deterioration in humans (33).…”

Dextromethorphan as a Potential Neuroprotective Agent With Unique Mechanisms of Action

“…14,83,84 Although difficult to extrapolate human dose requirements from animal data, it seems that DM doses higher than typically used for antitussive effects (60 -120 mg/d, oral), and those used in most previous neuroprotection trials, are required for neuroprotection. 68,81,85 However, in the trial with HD patients, plasma concentrations were undetectable in some patients after DM doses that were up to 8 times the maximum antitussive dose. 72 One method for increasing the central bioavailability of DM is to coadminister the specific and reversible CYP2D6 inhibitor, quinidine, to protect DM from extensive first-pass elimination via the cytochrome P4502D6 enzyme.…”

“…Although this active metabolite is partially responsible for the neuroprotective effects in some models, 24,31,35 its action as a more potent phencyclidine (PCP)-like uncompetitive NMDA receptor antagonist is also associated with psychotomimetic disturbances. [85][86][87] Given the robust preclinical …”

Comparison of the Effects of Dextromethorphan, Dextrorphan, and Levorphanol on the Hypothalamo-Pituitary-Adrenal Axis

“…Furthermore, neither the discriminative stimulus (Gavend et al, 1995) nor the anticonvulsant (Kim et al, 2003) effects of dextromethorphan seem to result primarily from its metabolism to dextrorphan. Although some studies have found no difference between the jpet.aspetjournals.org behavioral syndromes produced by dextromethorphan and dextrorphan (Ishmael et al, 1998), others have found different behavioral profiles (Dematteis et al, 1998). The nature and the clinical relevance of the non-NMDA receptor-mediated effects of dextromethorphan are unknown.…”