Dextromethorphan Potentiation of d-Amphetamine-Induced Behavior and Neurodegeneration in Rats

Dextromethorphan (25-200 mg/kg/day) potentiated the behavioral and toxic effects of d-amphetamine sulfate (7-35 mg/kg/day). Rats (Rattus norvegicus) were administered these drugs alone and in combination continuously for 2 days. Dextromethorphan shifted d-amphetamine-induced behaviors to resemble higher dose behaviors, though there was no dose effect of dextromethorphan. Dextromethorphan increased the incidence of neurodegeneration in the neostriatum and the cerebral cortex (determined histologically) at every dose of d-amphetamine. These effects may be related to the known antagonistic actions of dextromethorphan on voltage-dependent calcium channels or on N-methyl-D-aspartate receptors or may involve alteration of amphetamine metabolism through interactions with the cytochrome P-450 enzyme, CYP2D6, for which both dextromethorphan and d-amphetamine are ligands.