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

2003; Wiley; Volume: 17; Issue: 7 Linguagem: Inglês

10.1046/j.1460-9568.2003.02588.x

1460-9568

Frank P. Bymaster, Petra A. Carter, Masahisa Yamada, Jesús Gomeza, Jürgen Wess, Susan E. Hamilton, Neil M. Nathanson, David L. McKinzie, Christian C. Felder,

Memory and Neural Mechanisms

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.