The immediate vs. long-term effects of desmethylimipramine (DMI) or chlorimipramine (CMI) on cerebral blood flow (CBF) were determined in 17 rabbit brain regions using radioactively tagged microspheres (15 +/- 3 micron in diameter). A single administration of either drug did not alter average CBF or its regional distribution 1 h later. Desmethylimipramine, an agent which primarily blocks re-uptake in presynaptic noradrenergic neurons, significantly increased CBF when administered daily for 21 consecutive days. The regional effects of DMI were not restricted to those areas dense in noradrenergic receptors. Flow was significantly increased in the hypothalamus, olfactory cortex, globus pallidus-putamen and midbrain. These flow increases probably reflect integrated cerebral metabolic, synthetic and/or functional activity which were associated with altered receptor sensitivity and/or number, rather than a direct cerebral vasodilatory effect. In contrast, CMI, a tricyclic antidepressant which primarily blocks presynaptic re-uptake in serotonergic neurons, and produced sedation, had little effect on CBF when administered daily for 21 consecutive days. The immediate effects of these agents on presynaptic re-uptake was not associated with altered CBF. The long-term antidepressant activity of these two agents on receptor sensitivity was probably not correlated with CBF, as evidenced by the lack of effect which CMI had on this parameter. Rather, CBF response appears to be correlated with the therapeutic spectrum of DMI which increases psychomotor activity in retarded depression.