The present study investigated whether chronic methamphetamine (METH) would suppress METH-induced mRNA expression of immediate early genes (IEGs) in the rat brain. Rats were given METH or saline over two weeks. After an overnight withdrawal, saline-and METH-pretreated rats received an acute saline or METH challenge. The acute METH challenge increased expression of members of activator protein 1 (AP-1) and Nr4a IEG families in the nucleus accumbens (NAc) and midbrain of saline-pretreated rats. Chronic METH exposure attenuated the effects of acute METH challenge on AP-1 IEG expression in the NAc. However, chronic METH failed to attenuate acute METH-induced increases of Nr4a1 and Nr4a3 expression in the NAc. In contrast to observations in the NAc, chronic METH did not prevent acute METH-induced changes in IEG expression in the midbrain. These results suggest that these two brain regions that are implicated in neuroplastic effects of illicit substances might be differentially affected by psychostimulants.