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 α₂(A)-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 (I(max) = 27 ± 4% vs. I(max) = 47 ± 5%; p < .01) were observed after incubation with the α(2)-adrenoceptor agonist UK14304. No differences were found between antidepressant-free and antidepressant-treated subjects. A significant relationship between EC₅₀ values for [³⁵S] GTPγS and I(max) values for AC assay was found (n = 30; r = -.43; p < .05).


CONCLUSIONS
The dual regulation of α(2A)-adrenoceptor signaling pathways raises the possibility that factors affecting the G-protein cycle and/or selective access of Gα(i/o)-protein to AC might be relevant to receptor abnormalities in depression, providing further support for the involvement of α₂(A)-adrenoceptors in the pathogenesis of depression.
Valdizán
Elsa M
EM
Instituto de Biomedicina y Biotecnología de Cantabria, Department of Physiology and Pharmacology, University of Cantabria, Santander, Spain.
Díez-Alarcia
Rebeca
R
González-Maeso
Javier
J
Pilar-Cuéllar
Fuencisla
F
García-Sevilla
Jesús A
JA
Meana
J Javier
JJ
Pazos
Angel
A
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000068438:Brimonidine Tartrate; D003865:Major Depressive Disorder / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000819:agonists / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011810:Quinoxalines / Q000494:pharmacology; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D015398:Signal Transduction; D013405:Suicide / Q000523:psychology*
D000067956:Adenylyl Cyclase Inhibitors; D058647:Adrenergic alpha-2 Receptor Agonists; D000928:Antidepressive Agents; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D000068438:Brimonidine Tartrate; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases