Increase in Serotonin-1A Autoreceptors in the Midbrain of Suicide Victims with Major Depression—Postmortem Evidence for Decreased Serotonin Activity

Abstract

It has been hypothesized that a deficit in serotonin may be a crucial determinant in the pathophysiology of major depression. Serotonin-1A receptors are located on serotonin cell bodies in the midbrain dorsal raphe (DR) nucleus, and the activation of these receptors inhibits the firing of serotonin neurons and diminishes the release of this neurotransmitter in the prefrontal cortex. Repeated treatment with some antidepressant medications desensitizes serotonin-1A receptors in the rat midbrain. The present study determined whether the binding of [, an agonist at serotonin-1A receptors, is altered in the midbrain of suicide victims with major depression. Radiolabeling of the serotonin-1A receptor in the DR varied significantly along the rostral-to-caudal extent of the human midbrain. The binding of [ 3 H]8-OH-DPAT to serotonin-1A receptors was increased significantly in the midbrain DR of suicide victims with major depression as compared with psychiatrically normal control subjects. In suicide victims with major depression, the increase in the binding of [ 3 H]8-OH-DPAT to serotonin-1A receptors was detected in the entire DR and specifically localized to the dorsal and ventrolateral subnuclei. Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.

Serotonin 1A Receptor Binding and Treatment Response in Late-Life Depression

“…Work by Sargent et al (2000) included both medication free and subjects on antidepressant medication. Contrary to the data from these studies, postmortem work by Stockmeier et al (1998) indicated elevated rather than depressed binding of [ 3 H]8-OH-DPAT in the midbrain of suicide victims with major depression.…”

“…Indeed, Stockmeier et al (1998) observed elevated autoreceptor number in the brains of suicide victims with major depression. Two in vivo studies of 5-HT 1A function in mid-life depression also contradicted the Stockmeier et al report.…”

“…ROIs were sampled on multiple consecutive MR images on which the structure was visualized (except for the occipital cortex, which was sampled on a single plane) and right and left regions were combined to reduce noise (Meltzer et al, 2001). Regions sampled included areas known to contain moderate to high 5-HT 1A receptor density and those implicated in depressive illness and the response to antidepressant therapy (Mayberg et al, 2000;Stockmeier et al, 1998). These included the hippocampus (HIP) and mesial temporal cortex (MTC, which encompassed the amygdalo-hippocampal complex and adjacent portions of the parahippocampal gyrus), lateral orbitofrontal cortex (LOF) (Brodmann area (BA) 47), pregenual anterior cingulate (PGC; BA 24/32), and subgenual cingulate (SGC; BA 25/32).…”

Neuronal Tryptophan Hydroxylase mRNA Expression in the Human Dorsal and Median Raphe Nuclei: Major Depression and Suicide

“…Furthermore, we have confirmed our finding of higher TPH immunoreactivity in a second cohort of suicides and controls using immunoautoradiography (Boldrini et al, 2005). Further evidence of disordered function in DRN neurons of suicide subjects includes altered 5-HT 1A autoreceptor binding (Arango et al, 2001;Stockmeier et al, 1998), and both less serotonin transporter binding and expression (Arango et al, 2001). The combination of postmortem studies reporting low serotonin/5-HIAA midbrain levels in suicide, and in vivo studies reporting low CSF 5-HIAA in suicide attempters (Placidi et al, 2000), combined with postmortem findings of greater DRN TPH-IR neuron density, more TPH protein, and fewer transporter sites, suggests upregulation of biosynthetic capacity and putative transporter internalization in response to less serotonin.…”

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

“…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.…”