It is unclear whether the functional changes found in panic disorder reflect disturbed physiology of particular neurotransmitters. One method of investigating altered neurotransmission is to assess regional brain activations in response to agonist challenges. D-Fenfluramine is a medication that induces neuronal release of serotonin. Using ¿15OH(2)O and positron emission tomography (PET), measurements of regional cerebral blood flow (rCBF) were done at t=-20, -5, +20 and +35 relative to the IV D-fenfluramine injection (t=0) in nine panic-disordered and 18 healthy subjects. Subjects were otherwise healthy, right-handed, non-smoking and not taking psychotropic medication. ¿15OH(2)O PET scans were assessed with Statistical Parametric Mapping using individual global cerebral blood flow as a covariate. Comparisons of the (baseline) first two scans between healthy and panic-disordered subjects showed a decreased rCBF in the left posterior parietal-superior temporal cortex in the patient group. Fenfluramine-induced increases as defined by the last two scans minus the first two scans were compared between groups and a significantly greater increase in the same left posterior parietal-superior temporal region was found in panic-disordered subjects. Consistent with this finding, differences between the last two scans (post-fenfluramine) of the healthy and panic-disordered subjects showed an increased rCBF in the left superior temporal cortex in panic-disordered subjects. Functional pathology in the left parietal-superior temporal cortex in panic disorder may be related to abnormal modulation by serotonin.