A single exposure to the tremorgenic mycotoxin lolitrem B inhibits voluntary motor activity and spatial orientation but not spatial learning or memory in mice

• Published in: Toxicon (Oxford) 2019-10, Vol.168, p.58-66
• Main Authors: Combs, M.D., Hamlin, A., Quinn, J.C.
• Format: Article
• Language: English
• Subjects: Animals; Coordination; Escape Reaction - drug effects; Indole Alkaloids - toxicity; Indoles - toxicity; Lolitrem B; Memory; Memory - drug effects; Mice, Inbred C57BL; Motor Activity - drug effects; Mycotoxins - toxicity; Orientation, Spatial - drug effects; Paxilline; Spatial learning; Spatial Learning - drug effects; Tremor; Tremor - chemically induced; Tremor - psychology; Voluntary movement
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/j.toxicon.2019.06.228

The indole diterpenoid toxin lolitrem B is a tremorgenic agent found in the common grass species, perennial ryegrass (Lolium perenne). The toxin is produced by a symbiotic fungus Epichloë festucae (var. lolii) and ingestion of infested grass with sufficient toxin levels causes a movement disorder in grazing herbivores known as ‘ryegrass staggers’. Beside ataxia, lolitrem B intoxicated animals frequently show indicators of cognitive dysfunction or exhibition of erratic and unpredictable behaviours during handling. Evidence from field cases in livestock and controlled feeding studies in horses have indicated that intoxication with lolitrem B may affect higher cortical or subcortical functioning. In order to define the role of lolitrem B in voluntary motor control, spatial learning and memory under controlled conditions, mice were exposed to a known dose of purified lolitrem B toxin and tremor, coordination, voluntary motor activity and spatial learning and memory assessed. Motor activity, coordination and spatial memory were compared to tremor intensity using a novel quantitative piezo-electronic tremor analysis. Peak tremor was observed as frequencies between 15 and 25Hz compared to normal movement at approximately 1.4–10Hz. A single exposure to a known tremorgenic dose of lolitrem B (2 mg/kg IP) induced measureable tremor for up to 72 h in some animals. Initially, intoxication with lolitrem B significantly decreased voluntary movement. By 25 h post exposure a return to normal voluntary movement was observed in this group, despite continuing evidence of tremor. This effect was not observed in animals exposed to the short-acting tremorgenic toxin paxilline. Lolitrem B intoxicated mice demonstrated a random search pattern and delayed latency to escape a 3 h post intoxication, however by 27 h post exposure latency to escape matched controls and mice had returned to normal searching behavior indicating normal spatial learning and memory. Together these data indicate that the tremor exhibited by lolitrem B intoxicated mice does not directly impair spatial learning and memory but that exposure does reduce voluntary motor activity in intoxicated animals. Management of acutely affected livestock suffering toxicosis should be considered in the context of their ability to spatially orientate with severe toxicity. [Display omitted] •Single exposure to lolitrem B toxin (2 mg/kg) causes tremor lasting up to 72 hours in mice.•Tremor quantitation is accurately measured mi