The dopamine (DA) efflux in the medial prefrontal cortex (mPFC) can be modulated by the interaction between afferent norepinephrine (NE) and somatodendritic DA in the ventral tegmental area (VTA). However, it is unclear how locally administered amphetamine (AMPH) or cocaine in the VTA results in discrepant response of DA efflux in the mPFC. In this study, intra-VTA infusion of AMPH (1000 μM) or cocaine (200 μM) in anesthetized rats was employed to study the concurrent profile of extracellular DA level in the VTA and mPFC. In addition, the extracellular NE levels during the intra-VTA infusion of these two psychostimulants were analyzed to compare their effects on prefrontal DA efflux. During the intra-VTA infusion of AMPH, both extracellular DA and NE increased significantly in the VTA (270 ± 12% and 819 ± 40%, respectively). Meanwhile, the DA efflux in the mPFC elevated significantly. During the intra-VTA infusion of cocaine, the extracellular DA and NE in the VTA also increased (271 ± 21% and 150 ± 15%, respectively). However, the DA efflux decreased significantly in the mPFC. Noteworthy, the increase of extracellular NE in the VTA was much more robust via AMPH infusion, as compared with cocaine. It is suggested that AMPH and cocaine enhance the extracellular NE concentrations in the VTA in different magnitudes, which in turn contribute to discrepant profiles of distal DA efflux in the mPFC.