Human fibroblasts from normal subjects and from patients with major depression are cultured and their β-adrenoreceptor-cyclic AMP-protein kinase A (PKA) system characterized. The results indicate that the β-adrenoceptor-mediated activation of PKA in the 900 g supernatant fraction of human fibroblasts is mediated via β-adrenoceptors. The activation of PKA by isoproterenol is very rapid with maximal stimulation occurring at 5 seconds. The time course of PKA activation by isoproterenol in fibroblasts from patients with major depression is identical to that in fibroblasts from normal subjects but the magnitude of activation is significantly reduced in fibroblasts from patients with major depression. Dose-response curves on cyclic AMP mediated activation of PKA confirmed the previously reported reduction in activation of PKA in patients with major depression but demonstrated that this reduction occurs without a change in the EC50 values of cyclic AMP (approximately 20 nm/L). The blunted β-adrenoceptor-linked PKA responses in patients with major depression occur without a change in the expression of the PKA catalytic subunit Cα. The studies suggest that the β-adrenoceptor-coupled adenylate cyclase PKA system in human fibroblasts may represent a valid model to explore possible abnormalities in the fine tuning of the β-adrenergic transduction cascade in patients with affective disorders.