Abstract: Background Alterations in brain density and signaling associated with monoamine receptors are believed to play a role in depressive disorders. This study evaluates the functional status of ?2A-adrenoceptors in postmortem frontal cortex of depressed subjects. Methods G-protein activation and inhibition of adenylyl cyclase (AC) activity induced by the ?2-adrenoceptor agonist UK14304 were measured in triplicate in samples from 15 suicide victims with an antemortem diagnosis of major depression and 15 matched control subjects. Results Basal [35S] guanosine ? thio-phosphate (GTP?S) binding and cyclic adenosine monophosphate accumulation did not differ between groups. In depressed victims, an increase in [35S] GTP?S binding potency (EC50 = .58 ?mol/L vs. EC50 = 3.31 ?mol/L; p < .01; depressed vs. control) and a significant reduction in the maximal inhibition of AC activity (Imax = 27 ± 4% vs. Imax = 47 ± 5%; p < .01) were observed after incubation with the ?2-adrenoceptor agonist UK14304. No differences were found between antidepressant-free and antidepressant-treated subjects. A significant relationship between EC50 values for [35S] GTP?S and Imax values for AC assay was found (n = 30; r = ?.43; p < .05). Conclusions The dual regulation of ?2A-adrenoceptor signaling pathways raises the possibility that factors affecting the G-protein cycle and/or selective access of G?i/o?protein to AC might be relevant to receptor abnormalities in depression, providing further support for the involvement of ?2A-adrenoceptors in the pathogenesis of depression.

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