The Development of a C. Elegans Model of Nicotine Use and Aversion Resistance

Abstract

Nicotine addiction is an extremely costly and widespread issue that affects millions of people globally and current treatments have relatively low long term efficacy rates. This demonstrates the need for a greater understanding of nicotine addiction and its underlying mechanisms. This study created a C. elegans model of compulsive nicotine use. C. elegans, that were pretreated with nicotine (9.7 μM or 120 μM) from larval stage 4 to gravid adulthood, demonstrated reduced aversion to 10% nonanone in the presence of nicotine compared to untreated worms. The pretreatment concentration of 9.7 μM nicotine was chosen for further study due to its ability to induce aversion resistance without significant changes to locomotor speed, food preference, or benzaldehyde preference. This model was then applied to nicotinic acetylcholine (acr-5, acr-15, acr-16) and dopamine (dop-1, dop-2) receptor knockout mutants to determine the roles of these receptors in the development of aversion resistance. For the acr-5, acr-15, and acr-16 mutants, there was an increase in preference following the administration of 10% nonanone, regardless of pretreatment condition, suggesting that the removal of these receptors induces aversion resistance. For the dop-1 receptor mutant, 10-minute timepoint nicotine preference was reduced following preexposure. For the dop-2 receptor mutant, aversion was enhanced at the 5 mM and 50 mM test concentrations following the administration of 10% nonanone, suggesting that the dop-2 receptor is partially responsible for the development of aversion resistance. Additional research should be conducted to determine the underlying mechanisms of this drug induced aversion resistance. With current the lack of highly efficacious nicotine cessation drugs, this model could be used to test novel therapeutic drugs in a rapid high throughput manner.