D1/D2-dopamine receptor agonist dihydrexidine stimulates inspiratory motor output and depresses medullary expiratory neurons

Abstract

It is now accepted that dopamine plays an important neuromodulatory role in the central nervous control of respiration. D1, D2, and D4 subtypes of the receptor seem to be important players, but the assignment of various respiratory tasks to specific subtypes of the dopamine receptor is a work in progress. In the present investigation, dihydrexidine (DHD), a full dopamine receptor agonist with affinity for both D1- and D2-subtypes of receptor, was tested for its effects on inspiratory neurons and motor output and on membrane potential properties of medullary bulbospinal expiratory augmenting expiratory neurons in the pentobarbital anesthetized adult cat. The effects of DHD were compared with those of the highly selective D1-dopamine receptor (D1R) agonists SKF-38393 and 6-chloro-APB. DHD increased the intensity and duration of inspiratory motor output. Phrenic nerve discharge intensity was increased and prolonged, contributing to elevated inspiratory effort and duration when spontaneous breathing was monitored with tracheal pressure measurements. Intracellular recording from rostral medullary inspiratory neurons revealed that DHD, like SKF-38393, increases and prolongs inspiratory phase membrane depolarization, resulting in a longer and more intense discharge of action potentials. Remarkably, DHD had opposite effects on Aug-E neurons. Membrane potential was hyperpolarized, and action potential discharges were suppressed or abolished. In association with reduction of discharge intensity, action potential half width was reduced and after-hyperpolarization increased. The stimulatory action of DHD on inspiratory motor output is attributed to D1R effects, while the depression of Aug-E neurons seems to be linked to D2R actions on the postsynaptic membrane.