Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, <i>in vivo</i> phosphoinositide hydrolysis, and pilocarpine‐induced seizure activity

Abstract

Abstract Muscarinic agonist‐induced parasympathomimetic effects, in vivo phosphoinositide hydrolysis and seizures were evaluated in wild‐type and muscarinic M 1 –M 5 receptor knockout mice. The muscarinic agonist oxotremorine induced marked hypothermia in all the knockout mice, but the hypothermia was reduced in M 2 and to a lesser extent in M 3 knockout mice. Oxotremorine‐induced tremor was abolished only in the M 2 knockout mice. Muscarinic agonist‐induced salivation was reduced to the greatest extent in M 3 knockout mice, to a lesser degree in M 1 and M 4 knockout mice, and was not altered in M 2 and M 5 knockout mice. Pupil diameter under basal conditions was increased only in the M 3 knockout mice. Pilocarpine‐induced increases in in vivo phosphoinositide hydrolysis were completely absent in hippocampus and cortex of M 1 knockout mice, but in vivo phosphoinositide hydrolysis was unaltered in the M 2 –M 5 knockout mice. A high dose of pilocarpine (300 mg/kg) caused seizures and lethality in wild‐type and M 2 –M 5 knockout mice, but produced neither effect in the M 1 knockout mice. These data demonstrate a major role for M 2 and M 3 muscarinic receptor subtypes in mediating parasympathomimetic effects. Muscarinic M 1 receptors activate phosphoinositide hydrolysis in cortex and hippocampus of mice, consistent with the role of M 1 receptors in cognition. Muscarinic M 1 receptors appear to be the only muscarinic receptor subtype mediating seizures.