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Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine‐induced seizure activity
Author(s) -
Bymaster Frank P.,
Carter Petra A.,
Yamada Masahisa,
Gomeza Jesus,
Wess Jürgen,
Hamilton Susan E.,
Nathanson Neil M.,
McKinzie David L.,
Felder Christian C.
Publication year - 2003
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2003.02588.x
Subject(s) - muscarinic acetylcholine receptor , knockout mouse , pilocarpine , oxotremorine , muscarinic acetylcholine receptor m4 , muscarinic agonist , muscarinic acetylcholine receptor m1 , endocrinology , agonist , muscarinic acetylcholine receptor m3 , medicine , chemistry , muscarinic acetylcholine receptor m2 , in vivo , receptor , pharmacology , biology , neuroscience , biochemistry , epilepsy , microbiology and biotechnology
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.