Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity

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.