Preclinical models suggest that repeated high-dose methamphetamine (METH) exposures, administered in a “binge-like” pattern, acutely decrease norepinephrine (NE), and acutely and persistently decrease serotonin (5-hydroxytryptamine; 5HT) content in the frontal cortex. However, the impact of METH self-administration on this region is unknown. Because of the importance of the monoaminergic neurons in the frontal cortex to a variety of cognitive and addictive processes, effects of METH self-administration on cortical NE and 5HT content were assessed. Results revealed several novel findings. First, METH self-administration decreased cortical NE content as assessed 24 h after last exposure. Consistent with previous preclinical reports after a binge METH regimen, this decrease was reversed 8 days after the final METH exposure. Second, and in contrast to our previous reports involving the hippocampus or striatum, METH self-administration caused persistent decreases in 5HT content as assessed 8 days after the final METH exposure. Of note, the magnitude of this decrease (∼20%) was less than that observed typically after a binge METH treatment. Third, prior METH self-administration attenuated METH-induced serotonergic deficits as assessed 7 days, but not 1 h, following a neurotoxic METH regimen. No protection was observed when the binge exposure occurred 15 days after the last self-administration session. Taken together, these data demonstrate important and selective alterations in cortical serotonergic neuronal function subsequent to METH self-administration. These data provide a foundation to investigate complex questions involving “resistance” to the persistent deficits caused by neurotoxic METH exposure and frontal cortical function. Synapse 67:875–881, 2013. © 2013 Wiley Periodicals, Inc.