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ABSTRACT Background: In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans. Methods: The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age ± SD, 20.6 ± 2.4 years) was measured using positron emission tomography and [18F]fallypride. Each subject was scanned in two separate days in counterbalanced order: one with the MIST and one with the control task. Binding potential (BPND) maps of the whole brain were calculated for each scan, using a simplified reference tissue compartmental model. Then BPND was compared between subjects. Heart rate, galvanic skin response, and salivary cortisol level were measured during the scans. Results: The psychological stressor significantly decreased [18F]fallypride binding values in the dorsal part of the medial prefrontal cortex (dmPFC), corresponding to the rostal part of the cingulate motor zone. The greater the stress-induced decrease in [18F]fallypride binding in the dmPFC, the greater the stress-induced increases in heart rate. Conclusions: The present study provides evidence of stress-induced dopamine release in the mPFC in humans, in vivo. Synapse 67:821-830, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]