In the tetrabenazine (TBZ) model of depression, the cerebromicrocirculation was discovered to respond abnormally to metabolic demand as mimicked by the administration of CO2. Altered responsivity of cerebral blood flow and effective permeability of the blood--brain barrier to changes in PaCO2 were found. These physiologic defects coincided temporally with TBZ-induced depletion of central norepinephrine and dopamine and with the development of the behavioral effects of TBZ (the end points used to test the antidepressant potential of experimental drugs). Pretreatment with amitriptyline (a standard antidepressant and amine reuptake inhibitor) prevented the development of these TBZ-induced abnormalities in the cerebromicrocirculation, just as it prevented the behavioral effects.