Respiratory survival mechanisms in acetylcholinesterase knockout mouse.

ABSTRACT

Cholinergic neurotransmission ensures muscle contraction and plays a role in the regulation of respiratory pattern in the brainstem. Inactivation of acetylcholinesterase (AChE) by organophosphates produces respiratory failure but AChE knockout mice survive to adulthood. Respiratory adaptation mechanisms which ensure survival of these mice were examined in vivo by whole body plethysmography and in vitro in the neonatal isolated brainstem preparation. AChE-/- mice presented no AChE activity but unaffected butyrylcholinesterase (BChE) activity. In vivo, bambuterol (50-500 microg/kg s.c.) decreased BChE activity peripherally but not in brain tissue and induced apnea and death in adult and neonate AChE-/- mice without affecting littermate AChE+/+ and +/- animals. In vitro, bath-applied bambuterol (1-100 microm) and tetraisopropylpyrophosphoramide (10-100 microm) decreased BChE activity in the brainstem but did not perturb central respiratory activity recorded from spinal nerve rootlets. In vitro, the cholinergic agonists muscarine (50-100 microm) and nicotine (0.5-10 microm) induced tonic activity in respiratory motoneurons and increased the frequency of inspiratory bursts in AChE+/+ and +/- animals. These effects were greatly attenuated in AChE-/- animals. The results suggest that, in mice lacking AChE, (i) BChE becomes essential for survival peripherally but plays no critical role in central rhythm-generating structures and (ii) a major adaptive mechanism for respiratory survival is the down-regulated response of central respiratory-related neurons and motoneurons to muscarinic and nicotinic agonists.