Evidence that nicotine acetylcholine receptors are not the main targets of cotinine toxicity.

The toxicity of nicotine, cotinine and their mixtures was studied in Mus musculus mice as well their effects on growth after repetitive administration to young mice. The affinity constants of the two alkaloids for the nicotinic acetylcholine receptors (nAChRs) of Torpedo and rat brain membranes were determined. The administration of these alkaloids produced distinct symptoms of intoxication. Nicotine was 100-fold more toxic than cotinine and 10-fold more rapid than cotinine at producing respiratory arrest. The affinity of nicotine for both subtypes of nAChRs was > 100-fold higher than that of cotinine. Repetitive administrations of nicotine caused weight loss, whereas that of cotinine caused weight gain (P < 0.01). The administration of the two alkaloids as mixtures to mice caused significantly (P < 0.01) higher mortality than theoretically expected. Furthermore, hexamethonium pretreatment reduced by 2-fold (P < 0.01) the toxicity of nicotine but enhanced by 1.6-fold (P < 0.01) that of cotinine and was without effects on toxicity of mixtures. We suggest that nAChRs are not the main targets of cotinine toxicity.