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Nonmuscarinic neurotoxicity of oxotremorine
Abstract:
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, benactyzine 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 or 15 mg/kg) unless given in conjunction with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Atropine effectively blocks peripheral effects of oxotremorine, but higher doses are needed for central effects like tremors and convulsions. Other drugs showed limited efficacy against oxotremorine-induced central toxicity.
Area of Science:
- Pharmacology
- Neuroscience
Background:
- Muscarinic agonists like oxotremorine induce a range of peripheral and central nervous system effects.
- Understanding the differential blockade of these effects by various agents is crucial for assessing their therapeutic potential and toxicity.
Purpose of the Study:
- To investigate the efficacy of different treatments in preventing peripheral parasympathetic actions, central effects, and lethality induced by the muscarinic agonist oxotremorine in rats.
Main Methods:
- Rats were administered varying doses of oxotremorine, and the incidence of effects such as lacrimation, salivation, tremor, convulsions, and death was recorded.
- The protective effects of pretreatments with atropine, scopolamine, benactyzine, benztropine, atropine methyl nitrate, and diazepam were evaluated.
Main Results:
- Atropine (5 mg/kg) completely prevented oxotremorine effects at lower doses, but higher oxotremorine doses ( > 5 mg/kg) induced atropine-insensitive tremor, convulsions, and death.
- Atropine significantly shifted the ED50 for peripheral effects but had a lesser impact on central effects.
- Other anticholinergic agents and diazepam showed limited efficacy against oxotremorine-induced central toxicity, especially when used alone.
Conclusions:
- Atropine is highly effective against peripheral muscarinic effects but less so against central oxotremorine toxicity.
- Central oxotremorine effects, including tremor, convulsions, and lethality, appear to be mediated by mechanisms not fully blocked by standard anticholinergic agents or diazepam.