The purpose of this study was to examine the effects of stress and the role of locally infused anxiogenic-like neuropeptides galanin, CCK-8, vasopressin, substance P and neurokinin A, and anxiolytic-like peptides NPY, nociceptin/orphanin FQ, somatostatin and neurotensin, on modulation of noradrenaline (NA) and cAMP efflux monitored simultaneously by microdialysis in the medial prefronatal cortex of awake rats. Concentrations of cAMP were determined by a newly developed method based on derivatization of cAMP with 2-chloroacetaldehyde followed by HPLC with fluorescence detection. Local infusion of forskolin (10 and 30 μM) dose-dependently increased the cAMP levels to 417% and 1050% of the control group, respectively. Similarly, local infusion of NA (10 μM) increased the cAMP to the peak level of 168%. A 5-min tail pinch and a 10-min swim stress rapidly increased the NA and cAMP levels to 167% and 203% (NA) and 141% and 161% (cAMP), respectively. Infusion of galanin and CCK-8 (0.5 nmol, and 1.5 nmol/0.5 μl) dose-dependently increased NA to the peak levels of 191% and 179% and cAMP levels to 174% and 166%, respectively. The peak levels following infusions of vasopressin, substance P and neurokinin A were 91%, 135% and 86% for NA and 131%, 83% and 76% for cAMP, respectively. Infusions of anxiolytic-like peptides at highest concentrations significantly increased (NPY, 136%) or decreased (nociceptin, 71%; somatostatin, 86%) the NA levels, whereas neurotensin had no effect. The cAMP levels decreased to 86% (NPY, neurotensin), 78% (nociceptin), somatostatin infusion was without effect. The present findings confirmed a close correlation between the stress-induced increases in prefrontal cortical NA and cAMP levels, as well as, concurrent changes in NA and cAMP levels following infusions of galanin and CCK-8 (increased levels) and nociceptin/orphanin FQ (decreased levels). Infusions of other neuropeptides showed a more complex pattern of NA and cAMP responses.