α2-Adrenoceptor Functionality in Postmortem Frontal Cortex of Depressed Suicide Victims

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 alpha(2A)-adrenoceptors in postmortem frontal cortex of depressed subjects. Methods: G-protein activation and inhibition of adenylyl cyclase (AC) activity induced by the alpha(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 [S-35] guanosine gamma thio-phosphate (GTP gamma S) binding and cyclic adenosine monophosphate accumulation did not differ between groups. In depressed victims, an increase in [S-35] GTR gamma S binding potency (EC50 = .58 mu mol/L vs. EC50 = 3.31 mu mol/L; p < .01; depressed vs. control) and a significant reduction in the maximal inhibition of AC activity (I-max = 27 +/- 4% vs. I-max = 47 +/- 5%; p < .01) were observed after incubation with the alpha(2)-adrenoceptor agonist UK14304. No differences were found between antidepressant-free and antidepressant-treated subjects. A significant relationship between EC50 values for [S-35] GTP gamma S and I-max values for AC assay was found (n = 30; r = -.43; p < .05). Conclusions: The dual regulation of alpha(2A)-adrenoceptor signaling pathways raises the possibility that factors affecting the G-protein cycle and/or selective access of G alpha(i/o)-protein to AC might be relevant to receptor abnormalities in depression, providing further support for the involvement of alpha(2A)-adrenoceptors in the pathogenesis of depression.