Pretreatment of rats with desmethylimipramine (DMI) (5 mg/kg) significantly antagonized the tetrabenazine (TBZ)-induced (3 mg/kg) depletion of cortical norepinephrine (NE) in rats. This protective effect of DMI was fully blocked by the specific alpha 2-adrenergic antagonist, RX 781094. The doses of DMI which antagonized the depleting effects of TBZ caused rapid, maximal reductions in cortical dihydroxyphenylalanine (DOPA) accumulation, effects which were also blocked by RX 781094. Like DMI, the alpha 2-adrenergic agonist, clonidine (50 micrograms/kg) decreased cortical DOPA accumulation and rapidly prevented the TBZ-evoked loss of NE in this brain region. On the other hand, doses of RX 781094 (0.5-2.0 mg/kg) which accelerated cortical DOPA synthesis, enhanced significantly the depleting effects of a threshold dose of TBZ (0.6 mg/kg). These findings suggest that DMI reduces the rate of TBZ-induced depletion of cortical NE by lowering NE turnover through the indirect stimulation of alpha 2-adrenoceptors.