To investigate the pharmacodynamics of tetrabenazine [1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-2-H-benzo(a)quinol izine-2- one; 1], the drug of choice in the control of Huntington's chorea and tardive dyskinesia, and its major metabolite, dihydrotetrabenazine (2), ip doses of 3 mg/kg of the drug and the metabolite were administered to rats. Animals were decapitated at 0.0, 0.5, 2, 5, and 12 h. Brain and serum concentrations of 1 and 2, and brain concentrations of dopamine, norepinephrine, and serotonin were measured. Time courses of 1 and 2 in the brain (site of action) were parallel to those in serum, indicating that the brain is a part of the central compartment for both compounds. Despite its greater polarity, 2 was able to readily cross the blood-brain barrier. The monoamine depletions at any time following the administration of 2 were at least equal to or greater than those observed following the administration of the same dose of 1. After both compounds, the maximum serum and brain concentrations and maximum depletions were observed with the first sample at 0.5 h, with dopamine and serotonin being the most and least affected, respectively. The brain levels of the amines returned to the control values a maximum of 12 h after ip injections of either 1 or 2. Sigmoidal relationships were found between the monoamine levels and the corresponding log brain or serum concentrations of 1 or 2. The concentration-response curves of 2 following the administration of 1 and 2 were superimposable, suggesting that the observed activity after tetrabenazine injection is mainly, if not entirely, due to the formation of the active metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)