Abstract
Nicotine, the primary addictive substance in tobacco, induces profound behavioral responses in mammals, but the underlying genetic mechanisms are not well understood. Here we develop a C. elegans model of nicotine-dependent behavior. We show that worms exhibit behavioral responses to nicotine that parallel those observed in mammals, including acute response, tolerance, withdrawal, and sensitization. These nicotine responses require nicotinic acetylcholine receptor (nAChR) family genes that are known to mediate nicotine dependence in mammals, suggesting functional conservation of nAChRs in nicotine responses. Importantly, we find that mutant worms lacking TRPC (transient receptor potential canonical) channels are defective in their response to nicotine and that such a defect can be rescued by a human TRPC channel, revealing an unexpected role for TRPC channels in regulating nicotine-dependent behavior. Thus, C. elegans can be used to characterize known genes as well as to identify new genes regulating nicotine responses.
| Original language | English |
|---|---|
| Pages (from-to) | 621-633 |
| Number of pages | 13 |
| Journal | Cell |
| Volume | 127 |
| Issue number | 3 |
| DOIs | |
| State | Published - Nov 3 2006 |
Funding
We thank William Schafer, Gary Schindelman, Patrick Hu, Raad Nashmi, and Craig Montell for comments and advice; Junichi Nakai for the G-CaMP plasmid; Millet Treinin for the deg-3 strain; Henry Lester for mouse nAChR cDNA plasmids; and Barbara Perry and Rahul Mahapatra for technical assistance. Z.F. was inspired to study nicotine by previous training with W.S. Some strains were obtained from the CGC and C. elegans Gene Knockout Consortium. P.W.S. is an HHMI investigator. This work was supported by USPHS training grants T32EY017878 (A.W.) and T32GM008322 (B.J.P.), the Howard Hughes Medical Institute (HHMI) (P.W.S.), NIDA grant 7R01DA018341-02 (P.W.S.), the University of Michigan BSSP program (X.Z.S.X.), and grants from the American Legacy Foundation via UMTRN and NIGMS (X.Z.S.X.). Z.F. and X.Z.S.X. conceived and designed the experiments. Z.F. and W.L. performed the experiments and analyzed the data. A.W., B.J.P., and E.R.L. helped perform some experiments and paper writing. P.W.S. contributed critical reagents, intellectual input, and help with paper writing. X.Z.S.X. and Z.F. wrote the paper.
| Funders | Funder number |
|---|---|
| Howard Hughes Medical Institute | |
| T32GM008322 | |
| T32EY017878 | |
| University of Michigan | |
| National Institute of Development Administration | 7R01DA018341-02 |