Ventilatory stimulation by dopamine-receptor antagonists in the mouse

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Abstract
1 Ventilation was measured by a plethysmographic method in awake mice before and after intraperitoneal injection of neuroleptic drugs to test the hypothesis that dopaminergic mechanisms modulate control of breathing in this species. 2 Dose-dependent augmentation of ventilation at rest and during hypoxia, and reduced ventilation during hypercapnia was demonstrated for haloperidol, droperidol, prochlorperazine and chlorpromazine (P < 0.05 or less for each drug). 3 Doses of drugs causing maximal increase of the ventilatory response to hypoxia were linearly related (r = 0.98, P < 0.001) to in vitro affinity of the drugs for dopamine receptors. 4 Despite presumed equal dopamine-receptor blockade, the drugs had unequal effects on the ventilatory response to hypoxia. Droperidol augmented hypoxic ventilation to 290% of the control value, chlorpromazine to 250% control, prochlorperazine to 190% control and haloperidol to 120% control. These differences in efficacy were in the same order as the affinities of the drugs for α-adrenoceptors. 5 The effect of combined haloperidol (90 nmol kg−1) and varying doses of phentolamine (175–900 nmol kg−1) was assessed to test the hypothesis that α-antagonism was a factor in determining the increase in ventilation following dopamine blockade. Phentolamine caused dose-dependent augmentation of the ventilatory effects of haloperidol (P < 0.01) but had no ventilatory effect when given alone. 6 Carotid body resection in anaesthetized mice abolished the stimulation of hypoxic ventilation caused by droperidol. 7 It is concluded that dopaminergic mechanisms in the carotid body modulate ventilatory control in the awake mouse. The drugs most effective in augmenting hypoxic ventilation are those that block both dopamine and α-adrenoceptors.