Zhaoyang Feng et al. (2003) International Worm Meeting "C. elegans, a genetically tractable model for the study of nicotinic signaling"

Anthony Kempf, William Schafer, Zhaoyang Feng, Marika Orlov

[International Worm Meeting, 2003]

Nicotine abuse is the most critical but preventable public health problem. Although nicotinic acetylcholine receptor (nAChR) is identified as the main target of nicotinic signaling, the molecular and neuronal circuits of nicotinic signaling remain unknown. Using invertebrate models such as c. elegans or Drosophila metanogaster as animal models to study drug abuse has recently attracted the attention of researchers because of their simple nervous system, and the available powerful genetic tools in these models [Schafer WR, J. Neurosciences, 2002, Wolf FW and Heberlein U, Cur. Opp. in Neuroscience, 2003]. Utilizing a quantitative c. elegans behavior analysis system (Feng Z. et al, abstract in this meeting), a c. elegans locomotory acclimation behavior is identified and defined. Using this locomotory acclimation behavior as a behavioral assay, the c. elegans animals were found to response acutely to nicotine at a wild concentration range including concentrations close to physiological concentration in human blood after a cigarette consummation. This locomotory acclimation behavior is also found can be used in the study of nicotine adaptation, withdrawal, and possibly sensitization. The distinct roles of several nicotinic receptor subunits (unc-29, unc-38, and unc-63), Go and Gq signaling circuits, and several neuronal transmitters (dopamine, serotonin, glutamate) in the locomotory acclimation behavior, and their functions in nicotinic signaling are discussed.

Zhaoyang Feng et al. (2004) West Coast Worm Meeting "Dopamine signaling through D1-like receptors is required for nicotine dependence in Caenorhabditis elegans."

Megan Palm, Zhaoyang Feng, Marika Orlov, William R Schafer, Katie Kindt, Anthony Kempf

[West Coast Worm Meeting, 2004]

The molecular mechanisms underlying nicotine dependence, a process critical for nicotine addiction, are poorly understood. To address this question in C. elegans, we have used an automated tracking system to identify effects of withdrawal from chronic nicotine on locomotion behavior. Following mechanical stimulation, C. elegans shows a characteristic stimulation of locomotory activity followed by an exponential decrease in speed. Animals exposed to nicotine overnight show a significant increase in this deceleration rate following nicotine withdrawal, indicating that worms show nicotine dependence. The withdrawal effects on locomotion were dependent on the nicotinic receptor gene unc-38, and could be rescued by neuronal, but not muscle, expression of a wild-type unc-38 transgene. The effects of nicotine withdrawal on locomotion were also dependent on dopamine neurotransmission, as mutant defective in the dopamine biosynthetic gene cat-2 or in the dopamine receptor dop-1 do not exhibit withdrawal behavior. In addition, specific expression of wild-type unc-38 in dopaminergic neurons was sufficient to rescue the nicotine dependence defect of unc-38 loss-of-function mutants. Cell-specific laser ablation studies indicate that the dopaminergic ADE neurons are specifically required for nicotine dependence in our assay. Together, these results suggest a model by which chronic nicotine acts through UNC-38-containing nAChRs in the ADEs to control dopamine release.