Nicotine is an active compound in tobacco and has a rewarding effect may leads to dependence. Although nicotine dependence is elucidated by brain mechanisms, synaptic molecular underlying the dependence remains unclear. We hypothesized that reward signaling were mediated by calcium/calmodulin-dependent kinase II (CaMKII) and extracellular signal regulated kinase (ERK). To investigate the roles of both CaMKII and ERK on nicotine dependence, we first measured CaMKII and ERK phospohyrlation after establishment of nicotine dependence assessed by conditioned placed preference (CPP). Mice were first habituated to the CPP apparatus for five days, followed by a pre-conditioning test to determine the nicotine-paired compartment. Mouse entered conditioning training for one month in which 0.5 mg/kg nicotine was administered intraperitoneally followed by confinement in the designated compartment of CPP apparatus for 30 minutes. Four hours later, the same procedure was repeated, only this time saline was given instead of nicotine and the mouse was confined in the opposite of nicotine compartment. One day after conditioning, preference scores were measured to evaluate the nicotine dependence. Mice were sacrificed and their striatum were dissected out for immunoblotting analyses of CaMKII and ERK phosphorylation. CaMKII and ERK phosphorylation significantly increased  along with development of nicotine dependence.