The aim of this study was to investigate the effects of sowthistle (Ixeris dentata, IXD) on development and expression of nicotine-induced locomotor sensitization and underlying neuronal activation reflected by c-Fos expression in rats. Rats were pretreated with IXD 30 min before a daily injection of nicotine during an 8-day development phase and then challenged with nicotine after a 6-day withdrawal period. In another set of experiments, same IXD doses were administered once 30 min before nicotine challenge. Daily IXD treatment during development phase was not effective in blocking nicotine-induced locomotor sensitization in rats. However, a single IXD treatment after the development and withdrawal periods of nicotine sensitization significantly alleviated sensitized locomotor behavior on day 15. These behavioral results were coincident with significant inhibition of nicotine-induced c-Fos expression in the nucleus accumbens. These results indicated that IXD pretreatment significantly blocked the expression, but not the development of nicotine-induced locomotor sensitization in rats.