In 1991, routine biotoxin monitoring of bivalve molluscs at aquaculture sites along the eastern shore of Nova Scotia, Canada revealed a group of novel seafood toxins called spirolides, whose origin was the dinoflagellate Alexandrium ostenfeldii. Result from this preliminary study in rodents demonstrates a highly toxic lethal response in rats and mice after intraperitoneal injections of lipophilic extracts. To elucidate the modes of action and toxicologic pathology, brain and internal organs were examined by histology and various biomarkers of neural injury were monitored by immunohistochemistry (IH) and/or transcriptional analysis. The histological and transcriptional data showed that the effects of spirolides are species dependent for mice and rats. Histopathology showed that in the mouse brain, the hippocampus and brain stem appeared to be the major target regions but no histological changes were observed in the rat. Transcriptional analysis in the mouse brain showed no alterations in the biomarkers whereas in the rat brain there were major changes in the markers of neuronal injury. These biomarkers included the early injury markers HSP-72, c-jun and c-fos which are essential for converting stimuli into intracellular changes within neurons. The potential effects of spirolides were also evaluated with respect to different subtypes of the acetylcholine receptors (AChRs) since earlier reports showed these as putative targets. Both the muscarinic and nicotinic AChRs were found to be upregulated. Hence, transcriptional and immunohistochemical analysis does provide insight to the molecular mechanisms of this novel group of shellfish toxins. No histological changes were observed in other tissues.