α2-adrenoceptor functionality in postmortem frontal cortex of depressed suicide victims
El pdf del artículo es el manuscrito de autor.-- et al. ; [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 α2A-adrenoceptors in postmortem frontal cortex of depressed subjects. [Methods]: G-protein activation and inhibition of adenylyl cyclase (AC) activity induced by the α2-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 γ thio-phosphate (GTPγS) binding and cyclic adenosine monophosphate accumulation did not differ between groups. In depressed victims, an increase in [35S] GTPγS binding potency (EC50 = .58 μmol/L vs. EC50 = 3.31 μmol/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 α2-adrenoceptor agonist UK14304. No differences were found between antidepressant-free and antidepressant-treated subjects. A significant relationship between EC50 values for [35S] GTPγS and Imax values for AC assay was found (n=30; r=−.43; p<.05). [Conclusions]: The dual regulation of α2A-adrenoceptor signaling pathways raises the possibility that factors affecting the G-protein cycle and/or selective access of Gαi/o–protein to AC might be relevant to receptor abnormalities in depression, providing further support for the involvement of α2A-adrenoceptors in the pathogenesis of depression. ; This work was supported by grants from the Ministerio de Ciencia e Innovacion–Fondo Europeo de Desarrollo Regional (SAF 04/2784 and SAF 09/8460 to JJM; SAF 04/00941 and SAF07/61862 to AP, and SAF08/01311 and RETICS-Trastornos Adictivos to JAG-S), The Basque Government (IT199-07) and the Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Instituto de Salud Carlos III. The cooperation of the staff members of the Basque Institute of Legal Medicine and the Romand University Center of Legal Medicine at Geneva is acknowledged. ; Peer reviewed