Nur-related 1 (Nurr1) and nerve growth factor inducible-B (NGFI-B) constitute closely related subgroups of the nuclear receptor superfamily. One to three hours after 4 mg/kg acute methamphetamine (METH) administration, the levels of Nurr1 mRNA were significantly higher in the prelimbic (PrL), primary motor (M1) and primary somatosensory (S1) cortices and ventral tegmental area (VTA), as compared with the basal level. Pretreatment with 0.5 mg/kg of SCH23390 prevented the acute METH-induced increase in Nurr1 mRNA levels in these brain regions. One to three hours after 4-mg/kg acute METH administration, the levels of NGFI-B mRNA increased significantly in the PrL, M1, S1, striatum, and nucleus accumbens core (AcbC). Pretreatment with either 0.5 mg/kg of MK-801 or 0.5 mg/kg of SCH23390 prevented the acute METH-induced increase in NGFI-B mRNA levels in these brain regions. The levels of mRNAs were determined 3 h after a challenge injection of either saline or 4 mg/kg METH at the three-week withdrawal point in rats which had previously been exposed to either saline or METH (4 mg/kg/day) for 2 weeks. After the saline challenge, the group chronically exposed to METH displayed significantly higher levels of Nurr1 mRNA in the PrL, S1 and VTA, and of NGFI-B mRNA in the PrL, M1, S1, striatum and AcbC than did the group chronically treated with saline. The groups chronically exposed to METH failed to increase Nurr1 mRNA in the VTA, and NGFI-B mRNA in the AcbC, when challenged with 4 mg/kg METH. These results suggest that Nurr1 and NGFI-B mRNA play differential roles upon exposure to METH.