Objective: To study the effect of rhynchophylline on N-methyl D-aspartate receptor subtype 2B subunit in hippocampus of Methamphetamine-induced conditioned place preference (CPP) mice. Methods: Place preference mice models were established by methamphetamine; the expression of NR2B was observed by immunohistochemistry technique and Western blot. Results: Methamphetamine (4 mg/kg)-induced place preference mice model was successfully established; ketamine (15 mg/kg), rhynchophylline (40 mg/kg) and rhynchophylline (80 mg/kg) can eliminate place preference; Immunohistochemistry showed that the number of NR2B-positive neurons in hippocampus was increased in the methamphetamine model group, whereas less NR2B-positive neurons were found in the ketamine group, low and high dosage rhynchophylline group. Western blot showed that the expression of NR2B protein was significantly increased in the model group, whereas less expression was found in the ketamine group, low and high dosage rhynchophylline group. Conclusions: NR2B plays an important role in the formation of methamphetamine-induced place preference in mice. Rhynchophylline reversed the expression of NR2B in the hippocampus demonstrates the potential effect of mediates methamphetamine induced rewarding effect. (C) 2014 Elsevier Inc. All rights reserved.