Autoradiographic Demonstration of Increased α₂‐Adrenoceptor Agonist Binding Sites in the Hippocampus and Frontal Cortex of Depressed Suicide Victims

Abstract

To examine directly in the brain the status of α2‐adrenoceptors in major depression, the specific binding of the agonist [3H]UK 14304 was measured by quantitative receptor autoradiography in the hippocampus and frontal cortex of suicide victims (n = 17) with a retrospective diagnosis of depression (n = 7) or other psychiatric disorders (n = 10) as well as of matched control subjects (n = 9). In suicide victims, a significant increase in the number of α2‐adrenoceptors was found in the CA1 field (40%) and dentate gyrus (20%) of the hippocampus and in the external layers I (33%) and II (31%) of the frontal cortex, compared with that in matched controls. In depressed suicide victims, the increase in α2‐adrenoceptors in the CA1 field (57%) was significantly greater (24%, p < 0.05) than that observed in the group of suicide victims with other diagnoses (26%). In the same depressed suicide victims, the increase in cortical α2‐adrenoceptors was restricted to layer I (34%) and it was equivalent to that found in layer I (33%) of suicide victims with other diagnoses. The results indicate that suicide is associated with increases in the high‐affinity state of brain α2‐adrenoceptors and that there is a pronounced localized increase of this inhibitory receptor in the hippocampus of depressed suicide victims.

Genetic Predictors of Increase in Suicidal Ideation During Antidepressant Treatment in the GENDEP Project

“…Suicide victims have increased numbers of alpha-2A adrenergic receptors and mRNA expression in the hippocampus and frontal cortex (Escriba et al, 2004;Garcia-Sevilla et al, 1999;Gonzalez et al, 1994). Moreover, the ADRA2A receptor gene is located on chromosome 10q24-q26, a region that has been linked to SB in genome-wide linkage studies (Cheng et al, 2006).…”

Increased mRNA Expression of α2A-Adrenoceptors, Serotonin Receptors and μ-Opioid Receptors in the Brains of Suicide Victims

“…Previous studies, using specific antibodies, have demonstrated that the density of a 2A -adrenoceptor is increased in suicide subjects with major depression . In addition, other studies using radioligand agonists revealed an elevation in the density of a 2A -adrenoceptor (high-affinity state) in the post-mortem brains of suicide victims (Callado et al, 1998;De Paermentier et al, 1997;González et al, 1994;Meana et al, 1992;Meana and García-Sevilla, 1987). In addition, higher levels of G i proteins (García-Sevilla et al, 1996b, 1999 and lower levels of adenylyl cyclase activity (Reiach et al, 1999) were reported in the platelets of depressed subjects and post-mortem brains of suicide victims who previously suffered from depression.…”

“…serve as auto-or heteroreceptors, and control neurotransmitter release (Schlicker and Göthert, 1998;Starke, 1981). There is evidence that the density of some of these GPCR proteins, such as a 2 -adrenoceptors and 5-HT receptors, is altered in the brains of suicide victims and in the platelets of depressed patients (Callado et al, 1998;De Paermentier et al, 1997;García-Sevilla et al, 1986, 1999González et al, 1994;Meana et al, 1992;Meana and García-Sevilla, 1987;Mendelson, 2000;Ordway et al, 1994;Pandey et al, 1995;Sargent et al, 2000;Stockmeier et al, 1998). These alterations have been correlated with impaired neurotransmitter release that results from a 2 -adrenoceptor supersensitivity and/or serotonin receptor dysfunction.…”

Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of α2A-adrenoceptors

“…[8][9][10][11][12]14 A lack of differences in the agonist radioligand binding density of ␣ 2 -adrenoceptors has also been reported between subjects with major depression and controls. 45,46 The more rigorous diagnosis methodology (psychological autopsy vs searching of established medical records in the present study), the stricter inclusion and exclusion criteria, and the careful matching one-to-one reported herein could explain the apparent discrepancies between authors.…”

“…Among them, ␣ 2 -adrenoceptors, -opioid, GABA B and cholinergic muscarinic M 2 /M 4 receptors, by acting as autoreceptors or heteroreceptors, contribute to the inhibition of neurotransmitter release. [5][6][7] In depressed suicide victims, high densities of brain ␣ 2 -adrenoceptors have been found in terminal areas of NE and 5-HT pathways [8][9][10][11][12][13] and at the somatodendritic level of noradrenergic cells. 14 Many antidepressant treatments are able to modulate ␣ 2 -adrenoceptor density and/or function.…”