Investigations into the physiological role of muscarinic M2 and M4 muscarinic and M4 receptor subtypes using receptor knockout mice

Determination of muscarinic agonist-induced parasympathomimetic effects in wild type and M-2 and M-4 muscarinic receptor knockout mice revealed that M-2 receptors mediated tremor and hypothermia, but not salivation. The M-4 receptors seem to play a modest role in salivation, but did not alter hypothermia and tremor. In the M-2 knockout mice, agonist-induced bradycardia in isolated spontaneously beating atria was completely absent compared to their wild type litter mates, whereas agonist-induced bradycardia was similar in the M-4 knockout and wild type mice. The potency of carbachol to stimulate contraction of isolated stomach fundus, urinary bladder and trachea was reduced by a factor of about 2 in the M-2 knockout mice, but was unaltered in the M-4 knockout mice. The binding of the muscarinic agonist, [H-3]-oxotremorine-M, was reduced in cortical tissue from the M-2 knockout mice and to a lesser extent from the M-4 knockout mice, and was reduced over 90% in the brain stem of M-2 knockout mice. The data demonstrate the usefulness of knockout mice in determining the physiological function of peripheral and central muscarinic receptors. (C) 2001 Elsevier Science Inc. All rights reserved.