A diffuse reduction of 5-HTT binding in the PFC of individuals with major depression may reflect a widespread impairment of serotonergic function consistent with the range of psychopathologic features in major depression. The localized reduction in 5-HTT binding in the ventral PFC of suicides may reflect reduced serotonin input to that brain region, underlying the predisposition to act on suicidal thoughts. The 5-HTTLPR genotype was not related to the level of 5-HTT binding and does not explain why 5-HTT binding is lower in major depression or suicide. Arch Gen Psychiatry. 2000;57:729-738

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...

Major depressive disorder (MDD) and suicide are associated with deficient serotonergic neurotransmission. Tryptophan hydroxylase (TPH) is the rate-limiting biosynthetic enzyme for serotonin. Previously, we reported elevated levels of TPH protein in the dorsal raphe nucleus (DRN) of depressed suicides and now examine expression of neuronal TPH2 mRNA in a cohort of matched controls and depressed suicides (n ¼ 11 pairs). DRN TPH2 mRNA was measured by densitometric analysis of autoradiograms from in situ hybridization histochemistry experiments. TPH2 mRNA is confirmed as the raphe-specific isoform of TPH in human brain, and is expressed in neurons throughout the anteroposterior extent of the DRN and median raphe nucleus (MRN). TPH2 mRNA expression correlates with TPH protein distribution in the DRN, and has a negative correlation with age. In drug-free suicides, TPH2 expression is 33% higher in the DRN and 17% higher in the MRN as compared to matched nonpsychiatric controls. Higher levels of TPH2 mRNA were found throughout the entire extent of the rostrocaudal axis of the DRN, and were not specific to any single subnucleus. Higher TPH2 mRNA expression may explain more TPH protein observed in depressed suicides and reflect a homeostatic response to deficient brain serotonergic transmission.

Endogenous and exogenous cannabinoids (CBs) acting through the CB 1 receptors have been implicated in the regulation of several behavioral and neuroendocrine functions. Modulation of endocannabinoidergic system by ethanol in mouse brain, and the association of suicide and mood disorders with alcoholism suggest possible involvement of the cannabinoidergic system in the pathophysiology of depression and suicide. Therefore, the present study was undertaken to examine the levels of CB 1 receptors and mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who had died by suicides (depressed suicides, DS).

Although serotonin receptor and cytoarchitectonic alterations are reported in prefrontal cortex (PFC) in suicide and depression, no study has considered binding relative to neuron density. Therefore, we measured neuron density and SERT, 5-HT1A and 5-HT2A binding in matched suicides and controls. Suicides and normal controls (N=15 matched pairs) were psychiatrically characterized. Neuron density and binding were determined in dorsal (BA9) and ventral (BA47) PFC by stereology and quantitative autoradiography in near-adjacent sections. Binding index was defined as the ratio of receptor binding to neuron density. Suicides had lower neuron density in the gyrus of both areas. The binding index was lower for the serotonin transporter in BA47 but not in BA9; the 5-HT1A binding index was higher in BA9 but not in BA47, while the 5-HT2A binding index was not different between groups. SERT binding was lower in suicides in BA47 but not BA9, while 5-HT1A binding was higher in BA9 but not BA47. SERT binding negatively correlated with 5-HT1A binding in BA47 in suicides. Neuron density decreased with age. 5-HT1A binding index was higher in females than males. We found lower neuron density and lower SERT binding index in both PFC regions in suicides. More 5-HT1A binding with less SERT binding and the negative correlation in depressed suicides suggests post-synaptic receptor upregulation, and it is independent of the difference in neuron density. Thus, abnormalities in both cortical neurons and in their serotonergic innervation are present in suicides and future studies need to determine whether cortical changes reflect the trophic effect of altered serotonin innervation.