Genetic Regulation of Nicotine-Responsive Behaviors in the Nematode, C. elegans.

Abstract

At its core, addiction is a pathological state of motivation. While motivation itself is an adaptive psychological tool, when the motivation to seek out and engage a specific pharmacological agent, such as nicotine, or a biologically relevant stimulus, such as highly palatable food, exerts undue control over the behavior of an animal, the adaptive tool of motivation is transformed into the maladaptive state of addiction. The insulin signaling system plays a vital role in motivated behaviors, particularly in food-seeking behavior. The transient receptor potential (TRP) channels, meanwhile, are deeply involved in the sensory systems necessary for an organism to monitor its environment in order to locate biologically relevant stimuli. Here, we explore a role for the insulin signaling system in the locomotor response of nematodes to an acute nicotine challenge as well as a role for TRP channels in mediating nicotine-approach behavior in these animals. The studies presented here suggest novel models for how drugs of abuse can usurp adaptive motivational processes. We demonstrate that nematodes with a compromised insulin signaling system respond to an acute nicotine challenge as though it were a depressant rather than a stimulant. This effect persists in both genetic and pharmacologic manipulations of the insulin signaling system. We also demonstrate that C. elegans will chemotax to a source of nicotine and that vanilloid TRP channels are necessary for this behavior. The findings from the studies presented here may serve to identify novel therapeutic targets for the treatment of nicotine abuse, which is a leading public health concern throughout the developed world.