Acute intravenous administration of the selective D1 receptor blocker SCH-23390 resulted in an enhanced respiratory motor output as evidenced by the phrenic nerve activity, whereas local perfusion into the region of nucleus tractus solitarii had no effect. The increase in phrenic nerve activity was accompanied by a concomitant increase in the release of substance P in the region of nucleus tractus solitarii as measured by in vivo microdialysis technique. Chronic administration of SCH-23390 via subcutaneously implanted Alzet mini osmotic pumps, significantly decreased the level of preprotachykinin-A mRNA in the region of respiratory relay neurons in nucleus tractus solitarii but was without effect in the ventral medullary surface structure, wherein the central chemoreceptors are thought to be located. A smaller, but significant decrease was also seen in the striatum. The results suggest that chronic treatment with SCH-23390 leads to a disinhibition of an inhibitory dopaminergic input to the neurons in nucleus tractus solitarii from a suprapontine level, which may account for a subsequent inhibition of tachykinin-containing neurons in the nucleus tractus solitarii, the relay station for respiratory reflexes.