Nicotine-motivated behavior in Caenorhabditis elegans requires the nicotinic acetylcholine receptor subunits acr-5 and acr-15

Signaling at nicotinic acetylcholine receptors in Caenorhabditis elegans controls many behaviors, including egg‐laying and locomotor activity. Here, we show that C. elegans approaches a point source of nicotine in a time‐, concentration‐ and age‐dependent manner. Additionally, nicotine paired with butanone under starvation conditions prevented the reduced approach to butanone that is observed when butanone is paired with starvation alone and pairing with nicotine generates a preference for the tastes of either sodium or chloride over baseline. These results suggest nicotine acts as a rewarding substance in C. elegans. Furthermore, the nicotinic receptor antagonist mecamylamine, the smoking cessation pharmacotherapy varenicline, mutation of the dop‐1 and dop‐2 dopamine receptors, and mutations of either acr‐5 or acr‐15, two nicotinic receptor subunit genes with sequence homology to the mammalian α7 subunit, all reduced the nicotine approach behavior. These two mutants also were defective at associating the presence of nicotine with butanone under starvation conditions and acr‐5 mutation could obviate the effect of pairing nicotine with salts. Furthermore, the approach deficit in acr‐15 mutants was rescued by selective re‐expression in a subset of neurons, but not in muscle. Caenorhabditis elegans may therefore serve as a useful model organism for nicotine‐motivated behaviors that could aid in the identification of novel nicotine motivational molecular pathways and consequently the development of novel cessation aids. We provide evidence for nicotine reward in Caenorhabditis elegans, dependent on both dopamine and acetylcholine signaling. Caenorhabditis elegans both approaches a point source of nicotine and exhibits preference for sodium, chloride, or butanone previously paired with nicotine, independent from nicotine's locomotor effects. Caenorhabditis elegans may serve as a useful model organism that could aid in the identification of novel nicotine motivational molecular pathways and consequently the development of novel smoking cessation aids.