ABSTRACT: Although the mechanism of action for larkspur alkaloids has been described, little informa- tion is available on the variation of the physiological response of individual animals to larkspur alkaloids. Anecdotal observations and pilot studies in cattle in- dicate that there is animal-to-animal variation in re- sponse to a debilitating dose of larkspur alkaloids. The objective of this study was to determine whether there is variation in susceptibility of different strains of mice to larkspur alkaloid toxicosis and to identify factors responsible for the variation that could then be used as a model for studies in cattle. The acute toxicity of methyllycaconitine (MLA) in 9 different inbred strains of mice was compared. The rank order, from most to least susceptible, was A/J > B10 > FVB > BALB/c > C57Bl/6 > NZW > C3H > DBA >129. The calcu- lated LD 50 ranged from 3.3 ± 0.2 to 5.8 ± 0.8 mg/kg of BW. The toxicokinetic profiles of MLA in the sus- ceptible A/J strain and the more resistant 129 strain were compared to determine whether their differences in susceptibility were due to differences in their abil- ity to eliminate MLA. The differences in toxicokinetic variables observed did not explain the differences in susceptibility. The protein expression of various nico- tinic acetylcholine receptor (nAChR) subunits was also compared between the more resistant 129 strain and the susceptible A/J strain. The 129 strain of mice had twice the amount of α7 nAChR subunit expression as the A/J strain, which was in direct proportion to the approximately 2-fold difference in LD 50 . There was also a significant difference (P < 0.05) in expression of the α3 and α5 nAChR subunits between the 129 and A/J strains, with the 129 strain having a greater expression in each case. These data suggest that the increased sus- ceptibility of the A/J mice could be due to a reduced expression of nAChR subunits. Similar analyses need to be made in cattle to determine whether there is a difference between breeds in susceptibility to larkspur poisoning and to identify the factors that regulate their susceptibility to larkspur poisoning. This information would be useful for livestock producers in their breed- ing, culling, and grazing management programs to re- duce or prevent larkspur poisoning on rangelands. Key words: Delphinium, larkspur, lethal dose 50%, methyllycaconitine, mouse strain ©2009 American Society of Animal Science. All rights reserved. J. Anim. Sci. 2009. 87:1558–1564 doi:10.2527/jas.2008-1577 INTRODUCTION Larkspur (Delphinium spp.) is a toxic plant located in the foothill and mountain rangelands of the west- ern United States (Pfister et al., 1999). The toxicity of larkspur plants is due to the more than 18 nord- iterpenoid alkaloids, each with varying degrees of af- finity, and potency at nicotinic acetylcholine receptors (nAChR; Macallan et al., 1988; Dobelis et al., 1999). Previous research has demonstrated that the physio- logical effects of methyllycaconitine (MLA), one of the more abundant toxic alkaloids in larkspur, is attribut- able to its high affinity to nAChR in muscle and ner- vous systems (Benn and Jacyno, 1983; Stegelmeier et al., 1998). Methyllycaconitine has been shown to be a potent and selective competitive antagonist with nano- molar affinity at α7 nAChR and micromolar affinity at other nAChR (Ward et al., 1990; Alkondon et al., 1992; Lopez et al., 1998; Daly, 2005). Although the mechanism of action for larkspur al- kaloids has been described, little information is avail- able on the variation in animal responses to larkspur alkaloids. Anecdotal observations and pilot studies in cattle (Green et al., 2009) indicated that there is varia- tion in response to a debilitating dose of larkspur. The susceptibility of cattle to larkspur alkaloids acting at nAChR may be due to genetic differences, which cause changes in nAChR number or function. It has been well Investigation of the susceptibility of various strains of mice to methyllycaconitine toxicosis 1 K. D. Welch, 2 B. T. Green, K. E. Panter, D. R. Gardner, J. A. Pfister, D. Cook, and B. L. Stegelmeier USDA-ARS Poisonous Plant Research Laboratory, Logan, UT 84341 1 The authors thank Kendra Dewey, Anita McCollum, Ed Knop- pel, and Scott Larsen for their expert technical support. 2 Corresponding author: Kevin.Welch@ars.usda.gov Received October 22, 2008. Accepted December 9, 2008. 1558 Published December 5, 2014