M(1)/M(3) and M(2)/M(4) muscarinic receptor double-knockout mice present distinct respiratory phenotypes

We investigated the role of muscarinic acetylcholine receptors in the control of breathing. Baseline breathing at rest and ventilatory responses to brief exposures to hypoxia (10% O(2)) and hypercapnia (3% and 5% CO(2)), measured by whole-body plethysmography in partially restrained animals, were compared in mice lacking either M(1) and M(3) or M(2) and M(4) muscarinic receptors, and in wild-type matched controls. M(1/3)R double-knockout mice showed at rest an elevated ventilation (V (E)) due to a large (57%) increase in tidal volume (V(T)). Chemosensory ventilatory responses were unaltered. M(2/4)R double-knockout mice were agitated and showed elevated V (E) and breathing frequency (f(R)) at rest when partially restrained, but unaltered V (E) and low f(R) when recorded unrestrained. Chemosensory ventilatory responses were unaltered. The results suggest that M(1) and M(3) receptors are involved in the control of tidal volume, while M(2) and M(4) receptors may be involved in the control of breathing frequency at rest and response to stress.