Nonmuscarinic neurotoxicity of oxotremorine
Witkin, J.M.; Alvarado-Garcia, R.; Lee, M.A.; Witkin, K.M.
Journal of Pharmacology and Experimental Therapeutics 241(1): 34-41
1987
ISSN/ISBN: 0022-3565 PMID: 3572794 Document Number: 288933
The ability of various treatments to prevent peripheral parasympathetic actions, central effects and lethality of the muscarinic agonist oxotremorine was studied in rats. The percentage of animals exhibiting effects of oxotremorine was dose and time dependent. The ED50 for producing lacrimation, salivation, tremor, convulsions and death was 2.5, 1.3, 1.6, 3.2, and 8.3 mg/kg i.p., respectively. Pretreatment with 5 mg/kg of atropine completely prevented all observable effects of oxotremorine at doses of 5 mg/kg and below. Doses of oxotremorine in excess of 5 mg/kg produced tremor, generalized clonic convulsions and death that could not be prevented by atropine when given at up to 160 mg/kg; lacrimation and salivation were not present in atropine-treated rats. In the presence of 40 mg/kg of atropine, ED50 values for oxotremorine were shifted more than 12-fold for lacrimation, salivation and tremor, whereas convulsions and death were maximally altered by a factor of 2. Scopolamine, benaclyzine and benztropine were also incapable of completely preventing tremor, convulsions and death induced by 10 or 15 mg/kg of oxotremorine. Atropine methyl nitrate had effects comparable to atropine sulfate on lacrimation, salivation and lethality induced by oxotremorine (10 or 15 mg/kg) but had no effect on tremor or convulsions. A similar profile of atropine-insensitive effects was produced by pilocarpine and arecoline. Doses of diazepam 4 times higher (4 mg/kg) than necessary to prevent tonic-clonic convulsions induced by pentylenetetrazol were ineffective against tremor, convulsions or death produced by oxotremorine (10 to 15 mg/kg) unless given in conjunction with atropine. The nicotinic antagonist mecamylamine (3-10 mg/kg) was an effective antagonist of l-nicotine but was without effect against oxotremorine even in rats initially given atropine. The results of these experiments indicate that high doses of muscarinic agonists have neurotoxic actions that are nonmuscarinic in nature.