Elsevier

Brain Research

Volume 757, Issue 1, 16 May 1997, Pages 60-68
Brain Research

Research report
Brain α-adrenoceptors in depressed suicides

https://doi.org/10.1016/S0006-8993(97)00138-8Get rights and content

Abstract

α1-Adrenoceptors and α2-adrenoceptors were measured by radioligand binding to homogenates of brain samples obtained at post-mortem from suicides with a retrospective diagnosis of depression, and age and gender-matched controls. Suicides were subdivided into those who had been free of antidepressant drugs for at least three months, and those in whom prescription of antidepressant drugs was clearly documented. The number of α1-adrenoceptors (or α1A+α1D-adrenoceptors) did not differ significantly between antidepressant-free or antidepressant-treated suicides and controls. In antidepressant-free suicides, the number of α2-adrenoceptors was significantly higher in temporal cortex (Ba 21/22). α2A-Adrenoceptors did not differ significantly from controls in this brain region, suggesting the involvement of other α2-adrenoceptor subtypes. In antidepressant-treated suicides, significantly lower numbers of α2-adrenoceptors were found in occipital cortex and hippocampus (and for α2A-adrenoceptors in caudate and amygdala) compared to controls.

Introduction

Since the mid 1960s the biological basis of depression has been dominated by the monoamine hypothesis, focusing in particular on the involvement of 5-hydroxytryptamine (5-HT) and noradrenaline. Since the overwhelming success of the selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, research has focused on serotonin, and noradrenaline has been relatively neglected.

There are several lines of evidence supporting an important involvement of noradrenaline and noradrenergic receptors in depression. Research into β-adrenoceptors has been predominant, initiated by the early observation of their consistent down-regulation following monoamine oxidase inhibitors, tricyclic antidepressants and electroconvulsive shock (ECS) 5, 7, 41, 50. There is, however, evidence implicating abnormalities in α-adrenoceptor function in depression. The most substantial evidence is for subsensitivity of α2-adrenoceptors based on a blunted growth hormone response to the α2-adrenoceptor agonist clonidine in depressed patients compared to controls 1, 12, 28, 33.

Platelet α2-adrenoceptors have been extensively studied as a model of their central counterparts. Some studies have demonstrated enhanced α2-adrenoceptor-mediated aggregation and higher numbers of α2-adrenoceptors in antidepressant-free depressed patients compared to controls 19, 39. However, the majority of studies have found no differences in these measures 16, 29, 30, 51, 52.

Radioligand binding studies of α2-adrenoceptors in rat brain following chronic antidepressant treatment have produced varied results 4, 14, 27, 42, 47, 48, which in part may be related to duration of antidepressant treatment [6]. Barturen and Garcia-Sevilla [6]demonstrated a reduction in α2-adrenoceptor binding in cortex and other regions following 7 and 14 days of desipramine administration, but binding had returned to baseline levels by 21 days. Rat brain α1-adrenoceptor binding has consistently been shown to be unchanged following chronic antidepressant administration 24, 26, 37, 38, 49, although increased binding has been reported in rat frontal cortex following chronic ECS 9, 24, 49.

Several studies have examined α-adrenoceptors in brain tissue obtained at post-mortem in relation to suicide and depression. Significantly higher numbers of α2-adrenoceptors have been reported in cortex and other regions in depressed suicides 20, 34, 36, 40. Studies of α1-adrenoceptors are less consistent 3, 22.

In recent years heterogeneity of α1- and α2-adrenoceptors has been delineated. α1-Adrenoceptors have been subdivided into α1A-, α1B- and α1D-adrenoceptors [25]. Prazosin has identical affinities for each subtype and thus [3H]prazosin can be used to label the total α1-adrenoceptor population. α1A- and α1D-Adrenoceptors have a broadly similar pharmacology, with WB4101 having high affinity for both subtypes and a lower affinity for α1B-adrenoceptors [31]. The distribution of α1-adrenoceptor subtypes in human brain has not, however, been well documented.

Four subtypes of α2-adrenoceptor have been identified, termed α2A, α2B, α2C and α2D[10]. The α2D-adrenoceptor is considered a species homologue of the human α2A-adrenoceptor. [3H]Rauwolscine has high affinity for the α2A, α2B and α2C subtypes. The high affinity of oxymetazoline for α2A-adrenoceptors allows this subtype to be distinguished from α2B- and α2C-adrenoceptors. The α2A-adrenoceptor subtype predominates in most areas of human brain, apart from the basal ganglia [17].

In the present study we have measured α1-adrenoceptors and α2-adrenoceptors by saturation binding using the selective antagonist ligands [3H]prazosin and [3H]rauwolscine in post-mortem brain tissue from suicides and controls. The use of agonist radioligands to label α2-adrenoceptors is problematical because additional non-adrenergic imidazoline receptors are also labelled. These sites have been reported to be altered in depression 18, 35, 43, 45. [3H]Rauwolscine does not label imidazoline receptors. In addition we have concurrently measured α1A+α1D-adrenoceptors (defined by WB4101) and α2A-adrenoceptors (defined by oxymetazoline). The study was limited to those suicides in whom there was sufficient evidence to establish a firm retrospective diagnosis of depression. We have studied separately those suicides who were free of antidepressant drugs for at least three months prior to death, and those in whom prescription of antidepressant drugs was clearly documented, and also analysed separately suicides dying by violent and non-violent means.

Section snippets

Subject selection

Deaths recorded as suicide at Coroners' inquest were subjected to retrospective diagnosis by a psychiatrist (C.L.E.K.) using hospital and Coroners' records and interviews with the subject's General Practitioner. Thirty-nine subjects in whom there was sufficient documentary evidence to establish a retrospective diagnosis of depression according to the criteria of Beskow et al. [8]were selected for study. Information on previous and current drug treatment was sought and blood samples obtained at

Regional distribution of α1A+α1D-adrenoceptors and α2A-adrenoceptors

Preliminary experiments were performed to determine the distribution of α1A-adrenoceptors and α2A-adrenoceptors in ten brain areas from five male subjects dying by myocardial infarction. The age of the subjects was 57±5 years (mean±S.E.M.; range 50–68) and post-mortem delay 51±18 hours (mean±S.E.M.; range 23–70). Results are expressed as a percentage of the total number of α1- and α2-adrenoceptors assayed concurrently (Table 2). The proportion of α1A+α1D-adrenoceptors ranged from 41 to 72%. The

Discussion

The present study appears to be the first to report the results of saturation binding of α1-adrenoceptors in brain homogenates from depressed suicides and controls. In antidepressant-free suicides, we found no differences or trends in the number or affinity of α1-adrenoceptors compared to controls. We have also examined α1A-adrenoceptor binding together with the more recently described α1D-adrenoceptor (both of which have high affinity for WB4101). These subtypes constitute between 40 and 70%

Acknowledgements

We gratefully acknowledge financial support from the Sir Jules Thorn Charitable Trust.

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