AIM:To study the expression of signal transduction molecules in the striatum G protein protein 4 (RGS4) and dopamine D2 receptor (D2) in conditioned place preference (CPP) rats treated with methamphetamine (meth).METHODS:METH dependence CPP model was established (1 week and 2 weeks of METH dependence groups),The protein expression of RGS4 and D2,inhibitory G protein alpha-subunit (Gαi),mitogenactivated protein kinase (MAPK) in striatum were determined by Western blotting (WB).The changes of cyclic adenosine monophosphate (cAMP) content in striatum of rats were determined by enzyme linked immunosorbent assay (ELISA).RESULTS:Compared with saline control group,the average time of rats in the methamphetamine-paired chamber for two groups was increased (P ＜ 0.05).Compared with saline control group,RGS4 protein expressions in the two METH dependent groups were reduced (P ＜0.01);compared with 1 week of METH dependence group,that of 2 weeks group was reduced significantly(P ＜ 0.05).D2,Gαi,MAPK protein and cAMP expressions in the two METH dependent groups were increased (P ＜ 0.01);compared with 1 week of METH dependence group,those of 2 weeks were increased significantly (P ＜ 0.05).CONCLUSION:RGS4 and D2 receptor signaling pathways in striatum have changed in METH dependent rats,RGS4 may be involved in the regulation of METH-dependent D2 receptor signaling pathway in METH dependent rats.