Shati/Nat8l and TMEM168 were identified from nucleus accumbens (NAcc), which received continuous methamphetamine treatments. Shati/Nat8l is a synthetic enzyme that produces N-acetylaspartate (NAA) from L-aspartate and acetyl-coenzyme NAA is converted into N-acetylaspartylglutamate (NAAG) by NAAG synthetase (NAAGS). NAAG works as a highly selective endogenous agonist for the metabotropic glutamate type 3 receptor (mGluR3). We attempted to microinjection of adeno associated virus (AAV) including Shati/Nat8l into mice NAcc. These NAcc-Shati/Nat8l mice showed attenuation of the pharmacological effects of methamphetamine. NAcc-Shati or TMEM168 mice were also produced by AAV strategy and these mice also attenuated the methamphetamine-induced hyper locomotion and place preference test. TMEM168 interacts with osteopontin in NAcc of mice and cultured cells. Further, osteopontin it self has suppressive effects of methamphetamine. TMEM168 enhances anxiety in the elevated-plus maze and light-dark box test. The anxiety is recovered by the treatment of antianxiety drug diazepam. There our serial studies demonstrate that investigation of drug dependence-related molecule could lead to new pathway for new target for psychiatric disease.