Serotonin 1A Receptors, Serotonin Transporter Binding and Serotonin Transporter mRNA Expression in the Brainstem of Depressed Suicide Victims

Abstract

Suicide and depression are associated with reduced serotonergic neurotransmission. In suicides, there is a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HTReduced serotonergic function in the brain of suicide victims is suggested based on findings of lower brainstem levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), as well as fewer serotonin transporter (SERT) binding sites and more post-synaptic 5-HT 1A receptors in prefrontal cortex in suicide victims (see Mann et al. 2000 for review). In suicide victims, the changes in SERT and 5-HT 1A binding are NO . 6 Serotonin Transporter in the DRN of Suicides 893 localized to the ventral PFC (Arango et al. 1995), an area involved in behavioral inhibition (Damasio et al. 1994) and, therefore, the potential location of a diathesis for suicidal behavior. Studies in depressed suicide attempters compared to psychiatric controls have found lower cerebrospinal levels of 5-HIAA (Mann and Malone 1997). In vivo studies have employed pharmacological challenges that activate brain serotonin receptors invoking release of prolactin that can be measured in the blood Malone et al. 1996) or a change in regional glucose metabolism in the brain that can be measured by positron emission tomography (Malone et al. 2000). Results of these studies indicate blunted responses to 5-HT and support the notion of serotonin deficiency in depressed suicidal patients. Importantly, the relationship of serotonin hypofunction to suicidal acts is independent of psychiatric diagnosis (Mann et al. 1989;Stanley et al. 2000;Coccaro et al. 1989).The most widely reported serotonergic abnormality in major depression involves fewer platelet serotonin transporter sites (Owens and Nemeroff 1994). In vivo imaging (Malison et al. 1998;Willeit et al. 2000) and postmortem brain studies (Perry et al. 1983;Arango et al. 1995;Mann et al. 2000) conducted in depressed patients suggest that less SERT binding is more widespread in the brain compared with suicides, and includes the brainstem. One potential cause for fewer SERT sites, in the prefrontal cortex and elsewhere, would be a reduction in SERT gene expression. SERT mRNA is expressed in 5-HT neurons in the brainstem.We previously reported (Austin et al. 1994) the first anatomical visualization of human brain serotonin transporter gene expression and described the localization of the SERT mRNA to the serotonergic neurons of the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN). In rodents, non-human primates, and presumably humans, it is the dorsal and median raphe nuclei that provide the serotonergic innervation of the entire forebrain (Wilson and Molliver 1991a,b;Bobillier et al. 1975Bobillier et al. , 1976Sakai et al. 1977).In the DRN, the 5-HT 1A receptor is a somatodendritic inhibitory autoreceptor on 5-HT neurons (Vergé et al. 1985;Middlemiss and Fozard 1983). 5-HT released locally acts on the autoreceptor to inhibit further release of the 5-HT transmitter (Wang and Aghajanian 1977). Altered autoinhib...

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.…”

“…One case with schizoid personality disorder was suspected to have major depression, but failed to meet DSM criteria. Brain collection, neuropathology, toxicology, and tissue-sectioning protocols are described elsewhere (Arango et al, 2001). Postmortem interval, defined as the time of death to time of freezing the brain tissue, averaged 16.6 h. Brain pH was measured from cerebellar tissue and was 6.4470.12 in controls and 6.6370.08 in suicides (p40.05).…”

“…Tissue sections for in situ hybridization assay were collected approximately every millimeter throughout the rostrocaudal extent of the DRN, corresponding to 16-20 sections per case. Sets of adjacent sections from each case, assayed for TPH protein with biotinylated-PH8 (Boldrini et al, 2005) and [ 3 H]8-OH-DPAT (a 5-HT 1A receptor agonist (Arango et al, 2001), were used to identify boundaries of the raphe nuclei and to further delineate DRN subnuclei for the analysis of TPH2 mRNA in in situ hybridization autoradiograms.…”

“…Neuroendocrine studies find blunted serotoninmediated prolactin release related to aggressive and suicidal behavior (see Dulchin et al, 2001;Malone et al, 1996;Weiss and Coccaro, 1997). Furthermore, in postmortem serotonin receptor-binding studies, presynaptic alterations are identified in the brainstem (Arango et al, 2001) and pre-and postsynaptic alterations are described in the prefrontal cortex (Arango et al, 1995;Hrdina et al, 1993;Mann et al, 2000;Pandey et al, 2002).…”

Parametric and Regional Maps of Free Serotonin 5HT1A Receptor Sites in Human Brain as Function of Age in Healthy Humans

“…In vitro autoradiography reveals presynaptic serotonin 5HT 1A receptors on the soma of serotonergic neurons in the raphé nuclei, where they regulate the firing of these neurons (Arango et al, 2001;Hall et al, 1997). Most binding sites are located postsynaptically on the axon hillock or soma of cortical pyramidal neurons (Amargos-Bosch et al, 2004;Azmitia et al, 1996).…”