Repeated administration of methamphetamine (MAP) results in an increased behavioral response to the drug during subsequent exposure. This phenomenon is called behavioral sensitization. Sensitization is an enduring phenomenon, and suggests chronic alterations in neuronal plasticity. MAP-induced sensitization has been proposed and widely investigated as an animal model of MAP psychosis and schizophrenia. However, little is known about the molecular mechanisms underlying MAP-induced sensitization. 2-DE-based proteomics allows us to examine global changes in protein expression in complex biological systems and to propose hypotheses concerning the mechanisms underlying various pathological conditions. In the present study, we examined protein expression profiles in the striatum of MAP-sensitized rats using 2-DE-based proteomics. Repeated administration of MAP (4.0 mg/kg, once a day, intraperitoneal (i.p.)) for 10 days significantly augmented the locomotor response to an MAP challenge injection (1.0 mg/kg, i.p.) on day 11. This enhanced activity was maintained even after a week of drug abstinence. 2-DE analysis revealed 42 protein spots were differentially regulated in the striatum of MAP-sensitized rats compared to control. Thirty-one protein spots were identified using MALDI-TOF, including synapsin II, synaptosomal-associated protein 25 (SNAP-25), adenylyl cyclase-associated protein 1 (CAP1), and dihydropyrimidinase-related protein 2 (DRP2). These proteins can be related to underlying mechanisms of MAP-induced behavioral sensitization, indicating cytoskeletal modification, and altered synaptic function.