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United States Department of Agriculture

Agricultural Research Service

Research Project: Understanding and Mitigating the Adverse Effects of Poisonous Plants on Livestock Production Systems

Location: Poisonous Plant Research

Title: Effect of a nicotinic acetylcholine receptor agonists and antagonists on motor function in mice

Authors
item Welch, Kevin
item Pfister, James
item Lima, Flavia -
item Green, Benedict
item Gardner, Dale

Submitted to: Journal of Toxicology and Applied Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 26, 2012
Publication Date: February 1, 2013
Citation: Welch, K.D., Pfister, J.A., Lima, F.G., Green, B.T., Gardner, D.R. 2013. Effect of a nicotinic acetylcholine receptor agonists and antagonists on motor function in mice. Journal of Toxicology and Applied Pharmacology. 266(3): 366-74.

Interpretive Summary: The toxicity and teratogenicity of many plants are due to various toxins that bind to nAChRs including deltaline and methyllycaconitine (MLA) from larkspur (Delphinium) species as well as nicotine and anabasine from tobacco (Nicotiana) species. The primary result of these alkaloids acting at nAChRs is neuromuscular paralysis and respiratory failure. The overt clinical signs of mice poisoned with MLA have been described previously. The objective of this study was to further characterize the motor coordination deficiencies that occur upon exposure to a non-lethal dose of nAChR antagonists MLA and deltaline as well as nAChR agonists nicotine and anabasine. The results presented herein demonstrate an initial loss of muscle coordination for 1 to 2 min post exposure, with rapid recovery to near normal muscle control by 10 min. The data presented in this study clearly demonstrate that treatment of mice with both nAChR antagonists and agonists results in decreased motor function and coordination. These motor function deficits were highlighted by the inability of poisoned mice to traverse a balance beam, a decrease in limb grip strength, a decreased ability to maneuver a rotating rod, a lack of normal activity, and a measureable difference in muscle tremors and movement energy. However, these motor function deficits were very transient in mice dosed i.v., as treated mice are almost completely recovered by 10 min post-dosing. Furthermore, there was some evidence that mice treated with nAChR antagonists are affected differently than mice treated with nAChR agonists, potentially suggesting agonist versus antagonist differences. Finally, the data presented in this study highlight the fact that animals that survive poisoning episodes from nAChR antagonists or agonists will fully recover without lasting muscular function and coordination deficits.

Technical Abstract: Nicotinic acetylcholine receptors (nAChR) are ligand-gated cation channels found throughout the body, and serve to mediate diverse physiological functions. Muscle-type nAChR located in the motor endplate region of muscle fibers play an integral role in muscle contraction and thus motor function. The toxicity and teratogenicity of many plants (which results in millions of dollars in losses annually to the livestock industry) are due to various toxins that bind to nAChRs including deltaline and methyllycaconitine (MLA) from larkspur (Delphinium) species, and nicotine and anabasine from tobacco (Nicotiana) species. The primary result of the actions of these alkaloids at nAChRs is neuromuscular paralysis and respiratory failure. The objective of this study was to further characterize the motor coordination deficiencies that occur upon exposure to a non-lethal dose of nAChR antagonists MLA and deltaline as well as nAChR agonists nicotine and anabasine. We evaluated the effect of nAChR agonists and antagonists on the motor function and coordination in mice using a balance beam, grip strength meter, rotarod, open field analysis and tremor monitor. These analyses demonstrated that within seconds after treatment the mice had significant loss of motor function and coordination that lasted up to one min, followed by a short period of quiescence. Recovery to normal muscle coordination was rapid, typically within approximately 10 min post-dosing. However, mice treated with the nAChR agonists nicotine and anabasine required a slightly longer time to recover some aspects of normal muscle function in comparison to mice treated with the nAChR antagonists MLA or deltaline.

Last Modified: 4/16/2014
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