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Dwivedi Y, editor. The Neurobiological Basis of Suicide. Boca Raton (FL): CRC Press/Taylor & Francis; 2012.

2.1. INTRODUCTION

The serotonergic system has been shown to be affected in a number of psychiatric illnesses in the last 50 years. A large body of work has focused on serotonin (5-HT) deficits in major depressive disorder (MDD) and suicide. A great deal has been learned about the anatomy, development, and functional organization of the 5-HT system and the alterations in this system that are present within the suicide brain. Historically, evidence for the involvement of 5-HT in suicide stemmed from findings of low cerebral spinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) in depressed suicide attempters and in the brain stems of completed suicides (Åsberg 1976;Åsberg et al. 1976;Banki et al. 1984;Carlsson et al. 1980;Mann and Malone 1997;Placidi et al. 2001;Roy et al. 1986;Träskman et al. 1981). Suicide attempters also exhibit a blunted release of prolactin in response to administration of fenfluramine, a measure of 5-HT activity (Dulchin et al. 2001;Duval et al. 2001;Malone et al. 1996;Mann et al. 1995;Pandey 1997;Weiss and Coccaro 1997). These studies provided evidence for deficits in serotonergic neurotransmission in the brain stem or serotonergic targets in the forebrain of suicidal individuals. 5-HT is produced by neurons embedded in the midline raphe nuclei in the brain stem with widespread targets that appear to be topographically organized. In this chapter, we will discuss data that shed light into the contribution of these serotonergic neurons to brain diseases such as MDD and suicide.

2.2. ANATOMY OF THERAPHE NUCLEI

The raphe nuclei in the brain stem are a collection of cytoarchitectonically ill-defined aggregates of neurons that flank the midline and contain all the 5-HT-synthesizing neurons in the brain. The word raphe is derived from the Greek word “suture” and indicates a seam between two halves. In general, the rostral raphe nuclear group, which is contained in the mesencephalon and rostral pons, projects to the forebrain, while the caudal group, extending from the caudal pons to the caudal medulla, has projections to the spinal cord and medulla (Hornung 2003;Törk and Hornung 1990).

The rostral group of raphe nuclei consists of thecaudal linear nucleus (CLi),dorsal (DRN), andmedian (MRN) raphe nuclei. The CLi (Halliday and Törk 1986) is a nucleus of the ventral mesencephalic tegmentum that contains dopaminergic pigmented and substance P neurons as well as serotonergic neurons. The 5-HT neurons in the CLi are small to medium neurons with dendrites running parallel to the midline.

In nonhuman primates, serotonergic innervation of the cerebral cortex and much of the forebrain is derived from 5-HT-synthesizing neurons in the DRN and in the MRN of the brain stem. In the human, the DRN is a large group of neurons embedded in the ventral part of the central gray matter of caudal mesencephalon and rostral pons (Figure 2.1A). Based on topographic and cytoarchitectonic characteristics in Nissl-stained material, the DRN is subdivided into distinct subnuclei (Baker et al. 1990). These subdivisions correspond to those observed in tissue immunoreacted with anti-phenylalanine hydroxylase (anti-PH-8) sera (Hornung 2003;Törk 1990;Törk and Hornung 1990), which also revealed an additional component (the ventral subnucleus), not previously recognized in Nissl material. The subnuclei of the DRN are median (or interfascicular), ventrolateral, dorsal, lateral, and caudal. Themedian subnucleus is long and dense; its cells are oriented parallel to the midline and the processes extend within the medial longitudinal fasciculi. Its rostrocaudal extent goes from the anterior pole of the DRN to the rostral appearance of the median sulcus of the fourth ventricle. Caudal to this point, all DRN neurons are on either side of the floor of the fourth ventricle and none are on the midline. Theventrolateral subnucleus is made up of small, multipolar neurons extending caudally from the central gray to a position just dorsal to the trochlear nuclei and the medial longitudinal fasciculus.Olszewski and Baxter (1954) referred to this part of the DRN as nucleus supratrochlearis to indicate its appearance surrounding the nucleus of the trochlear nerve and extending dorsally and laterally. This subdivision has the highest density of PH-8-immunoreactive neurons, has no midline component, and extends further caudally than the median subnucleus in the rostral pons. A characteristic of this sub-nucleus in the nonhuman primate is that it contains the greatest density of neurons (Azmitia and Gannon 1986;Hornung and Fritschy 1988). Thedorsal subnucleus has loosely arranged medium-sized neurons dorsomedially flanking the dense ventrolateral subgroup. The two wings of this subnucleus are joined in the midline. Thecaudal subnucleus is made of two dense strips of PH-8-immunoreactive neurons lateral to the midline and dorsal to the medial longitudinal fasciculus. Its cells are small- to medium-sized and processes are oriented parallel to the floor of the fourth ventricle. Thelateral subdivision cannot be recognized in Nissl-stained material. It is very loosely organized and has the largest multipolar neurons of any of the DRN subdivisions. Neuronal processes extend across large fields in the central gray and axons are characteristically coiled close to the soma. Theventral subdivision is made up of round neurons located between the dorsal and ventrolateral subnucleus.

FIGURE 2.1

(A) A low-power (10×) photomicrograph of a rostral section of human brain stem DRN reacted for PH-8 (TPH2) by immunocytochemistry. (B) A higher power (40×) image of the rostral section shown in (A) demonstrating the specific expression(more...)

Although it has been known for many decades that there are massive projections from the raphe to the telencephalon (Brodal et al. 1960), at present it is not possible to verify the cortical targets of the various DRN nuclear subdivisions in the human. The projection from the DRN to cortical targets in the monkey exhibits a coarse rostrocaudal topographic relationship, as opposed to the MRN projections that are not separated rostrocaudally (Wilson and Molliver 1991a,b). The serotonergic projection to the prefrontal cortex (PFC) has a very heavy component arising from cells in the rostral part of the DRN. Regarding cortical innervation in the primate, the density is highest in layer 1, except in sensory areas where the highest density is in layer IV. The serotonergic target cells in the cortex are GAD-IR, indicating that they are GABAergic, inhibitory neurons.

The ascending dual serotonergic projection system described in the rat (Mamounas et al. 1991) has also been demonstrated in nonhuman primates (Wilson and Molliver 1991a,b) as arising from both the DRN and the MRN. The fine varicose axon system (D-fibers) originates in the DRN and branches profusely in the target area. It has been difficult to estimate the incidence of synaptic contacts from this system. The second system has large round varicosities (M-fibers), more divergent innervation and originates in the MRN. The fine, DRN nucleus system is more susceptible to degeneration by amphetamine derivatives, while the median raphe fiber system appears to be spared (Wilson et al. 1989). Both the DRN and the MRN project to the cortex and they differ in their distribution within the cortex (Kosofsky and Molliver 1987). Delineation of projections to and from DRN subnuclei has also been described in the rat. Using retrograde tracers into the dorsal subnucleus, afferent projections from the bed nucleus of the stria terminalis were found to be selectively labeled (Peyron et al. 1998). Efferent projections from the rat dorsal subnucleus have been shown to densely innervate the central amygdaloid nucleus and the dorsal hypothalamic area (Commons et al. 2003). Serotonergic innervation of the medial PFC and the nucleus accumbens originates almost exclusively from the dorsal subnucleus in rats (Van Bockstaele et al. 1993). All these regions are involved in regulation of stress-induced behavioral responses and anxiety-related behaviors.

Recent rodent studies have evaluated the role of specific DRN subnuclei in mediating 5-HT-related stress responses in behavioral paradigms. The lateral wing subregion of the mouse DRN is specifically involved in mediating the stress response in the forced swim test. Further, electrophysiological membrane studies of the serotonergic neurons of the lateral wing subregion show that these neurons have elevated intrinsic excitability compared to serotonergic neurons in the ventromedial subregion of the DRN (Crawford et al. 2010). This suggests that there are fundamental differences in serotonergic neuronal physiology that regulate stress-related behaviors and are regionally specific within the DRN.

2.3. 5-HT INDICES AND NEURON COUNTS IN THE DRN OF DEPRESSED SUICIDES

Brain serotonergic neurotransmission is regulated by a network of pre- and post-synaptic receptors and the 5-HT transporter (SERT). The available clinical and postmortem data suggest that reduced serotonergic input constitutes a critical element in the vulnerability to suicidal behavior, regardless of the associated psychiatric illness. Postmortem studies using SERT autoradiography with the specific 5-HT transporter ligand, cyanoimipramine, demonstrate reduced 5-HT transporter binding in the PFC of suicides (Arango et al. 1995, 2002;Laruelle et al. 1993;Mann et al. 2000) and raise the possibility that there is reduced serotonergic innervation. The functional capacity of serotonergic neurons may be reduced because of inadequate innervation of the target brain region or a reduction in the number of SERT sites synthesized. In 1999 (Underwood et al. 1999), we sought to estimate the total number and the morphometric characteristics of serotonergic neurons in the DRN from a group of suicides and nonpsychiatric controls. Tissue was sectioned, stained for Nissl, and processed with an antiserum (PH-8) (Cotton et al. 1988), which cross-reacts with tryptophan hydroxylase (referred to as TPH) (Figure 2.1A andB). All DRN neurons were identified, counted, and analyzed every 1000 μm. We found that suicide victims had 35% greater density and number of 5-HT neurons in the DRN compared to non-suicide controls (seeFigure 2.2). The total volume of the DRN did not differ in the two groups, suggesting that there is a difference in the absolute number in DRN neurons. Moreover, the mean density of serotonergic neurons is also significantly greater in the suicide victims.

FIGURE 2.2

A high-power photomicrograph of PH-8-immunoreacted sections of human brain stem from an age- and sex-matched control (a) and suicide (b). Note the increased density of TPH-immunoreactive neurons and neuropil in the suicide case compared to the control.(more...)

We used stereology to count Nissl-stained neurons in adjacent sections to those stained for TPH in 1999 (Underwood et al. 1999). The number of neurons was determined using the fractionator method (Gundersen et al. 1988;West 1993). Suicides did not differ from controls in the total number of Nissl-stained DRN neurons. However, the percent of DRN neurons that were also serotonergic, as measured in adjacent immunostained sections, was 79.9% in the suicides and 57.7% in the controls. The phenotype of the non-serotonergic DRN neurons is unknown in humans.

2.4. NEURONAL TRYPTOPHAN HYDROXYLASE IN SUICIDE

Recent studies have provided further evidence of 5-HT alterations involving the neuronal isoform of the rate-limiting serotonergic biosynthetic enzyme, TPH2 (Bach-Mizrachi et al. 2006,2008;Boldrini et al. 2005). TPH2 converts the amino acid tryptophan to 5-hydroxytryptophan (5-HTP) en route to subsequent decarboxylation into 5-hydroxytryptamine (5-HT, seeMockus and Vrana 1998 for review). TPH2 is a critical component in the determination of the amount of brain 5-HT synthesizedin vivo (Patel et al. 2004;Zhang et al. 2004). Deficits in TPH2 amount or catalytic activity may result in aberrant 5-HT production and subsequent behavioral changes. Until the discovery of TPH2 (Walther et al. 2003), quantitative studies ofTPH gene expression in brain had been hampered by the almost undetectable level of transcript expression in the raphe (Austin and O’Donnell 1999;Clark and Russo 1997). These studies were measuring peripheral TPH (TPH1), the nonneuronal isoform of the enzyme (Walther et al. 2003) predominantly expressed in the pineal gland and the gut and responsible for the production of melatonin.

TPH is a member of a superfamily of structurally and functionally related monoamine biosynthetic enzymes along with tyrosine hydroxylase and PH-8 (Mockus and Vrana 1998). The considerable amount of shared sequence homology between the enzymes conveyed similar functional regulatory and catalytic domains and provided the basis for the development of PH-8, an antibody for the immunocytochemical detection of this family of enzymes (Haan et al. 1987). TPH, tyrosine hydroxylase, and the other related enzymes are highly regulated by both transcription and posttranslational modification. Neuronal TPH is the product of a gene located on chromosome 12q15 (Walther et al. 2003;Zhang et al. 2004) and is present in quantities large enough to be detected in postmortem human brain usingin situ hybridization (Figure 2.1C). TPH2 mRNA expression is specific to all raphe nuclei tested thus far in rodents and primates (Bach-Mizrachi et al. 2006;Patel et al. 2004). In the earlier studies described previously, we found elevated TPH2 (PH-8 immunoreactivity) protein expression in MDD suicides (Underwood et al. 1999), a finding we replicated in a second cohort using PH-8 (TPH) immunoautoradiography (Boldrini et al. 2005). More TPH indicates an up-regulatory homeostatic response to impaired 5-HT release or less serotonergic autoreceptor activation. Alternatively, the 5-HT impairment in suicide may be due to hypofunctional 5-HT-synthesizing enzyme. While the change in PH-8 immunoautoradiography was not replicated by another laboratory using depressed suicides (Bonkale et al. 2004), greater PH-8 expression was found in the dorsal subnucleus of the DRN of depressed suicides who were also alcohol dependent (Bonkale et al. 2006). This inconsistency in immunoautoradiography may be reconciled by variation in methodologies between the two laboratories.Bonkale et al. (2004) sampled five representative rostral-most sections of the DRN, while our group sampled the anteroposterior length of the DRN at 1 mm intervals, thereby increasing the resolution in which changes in expression can be found.

With the discovery of the neuronal form of TPH in 2003 came the ability to detect and measure transcript levels of the 5-HT-producing enzyme in postmortem human brain tissue. We developed a riboprobe specific for TPH2 mRNA and found robust expression specific to the large multipolar neurons within the DRN and MRN. Consistent with our protein (immunocytochemical) findings, we discovered that TPH2 mRNA expression was elevated in depressed suicides compared to matched controls and further that the 5-HT-synthesizing neurons in suicide had higher transcriptional capacity (Bach-Mizrachi et al. 2006,2008). More TPH-immunoreactive neurons (Underwood et al. 1999), when taken together with more TPH protein (Boldrini et al. 2005;Underwood et al. 1999), and more TPH2 mRNA (Bach-Mizrachi et al. 2006) would favor higher 5-HT levels and yet most studies report lower 5-HT levels in suicides. Lower brain stem 5-HT levels in depressed suicides and lower CSF 5-HIAA suggest a compensatory mechanism in which the enzyme level may be increased but catalytic activity or release of 5-HT is impaired. To date, there is only one functional yet rare single nucleotide polymorphism (SNP) in the humanTPH2 gene that affects TPH2 catalytic activity (Zhang et al. 2005). While this SNP was shown to be associated with MDD in one population, the association was not found in any of the several other studies that attempted to replicate this finding (Glatt et al. 2005;Van Den et al. 2005;Zhou et al. 2005). While an undiscovered functional SNP in theTPH2 gene may still remain a reasonable explanation for deficits in TPH2 catalytic activity, it should be noted that TPH2 function is dependent on a number of factors including phosphorylation state (Winge et al. 2006), regulation by signal transduction pathways (Beaulieu et al. 2008), presence of cofactors and adapters (Winge et al. 2008), and potentially other regulatory TPH isoforms (Haghighi et al. 2008). These mechanisms likely regulate TPH2 catalytic activity by gauging brain 5-HT levels and therefore in suicides where 5-HT is low, the TPH2 enzyme produced in affected individuals may be of lower catalytic activity.

Previous studies have shown the presence of low levels of TPH2 transcript in the terminal fields of serotonergic neurons including the cortex, hippocampus, and amygdala (De Luca et al. 2005;Zill et al. 2007) using quantitative Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). However, abundant levels of TPH protein have been found in the PFC by western blot (Ono et al. 2002). The presence of TPH in serotonergic terminals suggests a potential mechanism for the regulation of 5-HT synthesis locally, at the synapse in terminal regions far from the site of origin in the raphe nuclei. Therefore, it is possible that inefficient axoplasmic flow of TPH to cortical terminal fields could lead to decreases in TPH protein at terminals and increased levels at cell bodies. This notion is proposed in one postmortem study of Alzheimer’s patients in which TPH activity and the serotonergic metabolite 5-HIAA were found to be increased in the DRN but decreased in terminal fields in the amygdala. These authors propose that high levels of toxic serotonergic metabolites in the raphe contribute to degeneration of serotonergic neurons seen in Alzheimer’s disease (Burke et al. 1990).

2.5. 5-HT RECEPTORS AND THE 5-HT TRANSPORTER IN SUICIDE

The 5-HT_1A receptor is a G protein-coupled receptor that is expressed at pre- and postsynaptic sites and plays a role in multiple physiological functions including mood regulation, neuroendocrine functions, thermoregulation, sexual behavior, and food intake (for review, seeRaymond et al. 2001). Dysfunction of the 5-HT_1A receptor has been implicated in the pathology of various psychiatric disorders including major depression, anxiety, and suicide (Blier et al. 1993;Mann 2003). In the DRN, the 5-HT_1A receptor functions as a somatodendritic inhibitory autoreceptor on 5-HT neurons (Middlemiss and Fozard 1983;Verge et al. 1985). Locally released 5-HT acts on the autoreceptor to inhibit further release (Wang and Aghajanian 1977). Greater autoinhibition of the 5-HT_1A receptor in the brain stem raphe nuclei may be a mechanism that contributes to reduced serotonergic neurotransmission in the PFC in the context of suicide and depression (Stockmeier et al. 1998).

In postmortem studies, 5-HT_1A autoreceptor levels have been shown to be elevated in the midbrain of suicides by some (Stockmeier et al. 1998), but not all (Arango et al. 2001), investigators. The apparently discrepant findings were reconciled by our recent work (Boldrini et al. 2008) that shows an increase in 5-HT_1A receptors in the rostral part of the dorsal raphe (DRN) in suicides and a decrease in the remaining 15 mm (∼75% of the DRN), for a net decrease in binding throughout the DRN (see 5-HT_1A receptor binding profile in the DRN inFigure 2.3).Stockmeier et al. (1998) examined the most rostral 5 mm of the DRN and, like in our study (Boldrini et al. 2008), found an increase in binding. Another determining factor may be found in the sex composition of the patient cohorts from which the various postmortem samples were obtained. For example, we find that females have significantly higher 5-HT_1A receptor binding than males (Arango et al. 2001), a finding replicated by our groupin vivo with positron emission tomography (PET) (Parsey et al. 2002).Goswami et al. (2010) reported that mRNA concentrations of the 5-HT_1D receptor as well as transcription regulators were significantly increased in DRN laser-captured neurons of female MDD subjects compared to female control subjects, while no differences were reported in male subjects from both groups.

FIGURE 2.3

(See color insert.) Pseudocolor receptor autoradiograms representing³H-8OH-DPAT binding, a 5-HT agonist, within the DRN and MRN along the rostrocaudal axis of the brain stem.

Some postmortem studies showed greater 5-HT_1A receptor binding in the ventrolateral PFC (Arango et al. 1995;Lowther et al. 1997), while other studies did not find any changes (Stockmeier et al. 1997). We also reported an increase in 5-HT_1A receptor binding across the ventral, lateral, orbital, and medial aspects of the hemisphere compared to the dorsal gyri and sulci in the PFC of depressed suicides compared to controls (Arango et al. 2002). We considered increased cortical 5-HT_1A receptor binding to be a compensatory mechanism in response to decreased 5-HT levels partly because binding to the 5-HT transporter and receptor is inversely correlated in the PFC.

The 5-HT_1A autoreceptor is speculated to be involved in the mechanisms underlying the delayed onset of therapeutic effects of selective serotonin reuptake inhibitors (SSRIs). SSRIs increase 5-HT levels present in the extracellular space and therefore increase activation of postsynaptic 5-HT receptors. However, the desired increase in presynaptic 5-HT release is not achieved until the somatodendritic 5-HT_1A autoreceptors in the raphe are desensitized, thereby releasing the inhibition on serotonergic firing. 5-HT_1A receptor-mediated serotonergic neurotransmission is a passive process dependent on intrasynaptic 5-HT availability and therefore the time it takes to desensitize the receptor contributes to the delayed onset of the therapeutic effects of SSRIs (reviewed inHensler 2006). One interpretation of the mechanism of SSRI action is that release of inhibition on serotonergic neurons by desensitization of the 5-HT_1A autoreceptor does result not only in increased serotonergic firing and subsequent increased release of 5-HT into the synapse but also inde novo synthesis of 5-HT by serotonergic neurons (Kim et al. 2002;Meller et al. 1990). This was demonstrated by one study in which long-term treatment of rats with the potent SSRI sertraline resulted in marked up-regulation of TPH transcript and protein expression. When tested in cell culture, this group showed that TPH activity and total 5-HT were increased in the presence of sertraline (Kim et al. 2002). The idea that sertraline stimulatesde novo synthesis of 5-HT is intriguing and has a potential therapeutic value.

In the rat, serotonergic neurons can be distinguished from non-serotonergic neurons by their electrophysiological properties (Kirby et al. 2003). In addition, double-label immunocytochemical experiments in rat with antibodies against 5-HT and 5-HT_1A receptor show that the modulatory 5-HT_1A receptor protein does not totally colocalize with all 5-HT-containing neurons in the raphe. In fact, in this species at least, a significant non-serotonergic population of cells exist thatalso express 5-HT_1A receptors (Kirby et al. 2003). Stimulation of the 5-HT_1A autoreceptor by 5-HT or an agonist results in the feedback inhibition of the serotonergic neuron, with subsequent suppression of 5-HT synthesis and turnover (Sibille and Hen 2001). However, the role of 5-HT_1A receptors on non-serotonergic cells is unclear. There is evidence that serotonergic and non-serotonergic neurons in the DRN may be affected by 5-HT_1A and 5-HT_2A receptors (Craven et al. 2001). Studies by the Beck laboratory (Beck et al. 2004;Kirby et al. 2003) have determined that both 5-HT and non-5-HT DRN neurons respond to 5-HT_1A receptor agonists. Furthermore, they were able to determine that DRN neurons, whether or not serotonergic, have similar characteristics traditionally associated with 5-HT neurons. In contrast, 5-HT and non-5-HT MRN neurons have very different characteristics (Beck et al. 2004). Presumably, stimulation of receptors on non-serotonergic neurons will act indirectly to modulate local 5-HT levels in the raphe nuclei.

The presumption that non-serotonergic neurons in the DRN and MRN have a regulatory role in controlling local 5-HT levels is further supported by the finding that the majority of neurons in this population, at least in rodents, are GABAergic (Stamp and Semba 1995). A GABAergic coexpression with 5-HT_1A receptors in humans would suggest a postsynaptic regulation of 5-HT in the raphe by GABA neurons. This may help explain the time delay in patient response to antidepressant drugs that block 5-HT_1A autoreceptors. However, it is not yet known whether there are GABAergic neurons in the human DRN that also express 5-HT_1A receptors.

Most, but not all, studies of postsynaptic serotonergic receptor binding studies in suicides report an increase in 5-HT_2A receptor binding in the PFC (reviewed inMann et al. 1996). Using [³H]ketanserin to measure 5-HT_2A receptor density in frontal cortex, some groups reported no difference between suicides and control subjects (Arranz et al. 1994;Cheetham et al. 1988;Crow et al. 1984;Lowther et al. 1994;Owen et al. 1983;Rosel et al. 2000) while others found an increase in the number of 5-HT_2A receptors in the PFC of suicide subjects (Gross-Isseroff et al. 1990;Hrdina et al. 1993;Turecki et al. 1999). Using other ligands to study 5-HT_2A binding sites, other groups have reported higher 5-HT_2A cortical receptor binding in suicide subjects (Arango et al. 1990;Arora and Meltzer 1989;Pandey et al. 2002;Stanley and Mann 1983). Differences in methodology and age and sex of cases studied may explain some of the discrepancies in the studies, but, nevertheless, most studies find an increase in 5-HT_2A postsynaptic receptor binding in the PFC. We recently reported a positive correlation of prefrontal cortical 5-HT_2A receptor binding sites and lifetime aggression scores in suicides (Oquendo et al. 2006). In another postmortem study, cases with depression had an increase in 5-HT_2A receptor abundance in Brodmann area 10, which was correlated with decreased Protein Kinase A (PKA) activity (Shelton et al. 2009), a finding consistent with previous studies demonstrating decreased PKA expression and activity in the PFC of teenage suicides compared to controls (Dwivedi et al. 2004). The postsynaptic 5-HT_2c receptor is also reported to be specifically elevated in the PFC of suicides compared to controls (Pandey et al. 2006) Taken together, these studies demonstrate the vulnerability of the serotonergic system in cortical targets that regulate mood and behavior in suicide.

Serotonergic neurotransmission between the DRN/MRN and the PFC is regulated by the presynaptic 5-HT transporter (SERT) and by pre- and postsynaptic serotonergic receptors. SERT regulates intrasynaptic 5-HT levels via reuptake into the presynaptic neuron. Using³H-cyanoimipramine and receptor autoradiography, we found reduced SERT binding in the ventral PFC in depressed suicides (Arango et al. 1995,2002), a finding replicated by immunocytochemical studies that showed a deficit in the length and density of 5-HT transporter-immunoreactive neurons (Austin et al. 2002). Lower SERT binding in the ventromedial PFC was related specifically to suicide independent of diagnosis, a finding consistent with the role of this region of the PFC (PFC) in regulating behavioral inhibition (Shallice and Burgess 1996). Lower SERT binding throughout the PFC was related to MDD, which was confirmed byin vivo PET studies showing lower SERT binding that was widespread throughout the PFC in patients with MDD (Parsey et al. 2006). In the brain stem,in situ hybridization was used to measure transporter mRNA expression (McLaughlin et al. 1996) and no difference was found in total SERT mRNA between suicides and controls (Arango et al. 2001;Little et al. 1997). However, MDD suicides had fewer SERT expressing neurons and these neurons had higher SERT transcriptional capacity (Arango et al. 2001). Taken together, less SERT binding in the PFC and fewer SERT expressing neurons in the brain stem support a compensatory homeostatic mechanism for deficits in 5-HT neurotransmission.

2.6. CONCLUSIONS

Postmortem human brain studies have made significant contributions to unraveling the neuroanatomical and biochemical profile of suicide. We and others have used the postmortem brain of suicides to understand the alterations present in the serotonergic system that underlie suicidal behaviors. In reviewing the current data from postmortem studies of suicides, it is clear that there are anatomically specific alterations in the serotonergic system that are specific to suicide and consistent with a homeostatic brain response both in source 5-HT synthesizing neurons in the raphe nuclei and in postsynaptic target neurons in the cortex, to deficits in serotonergic neurotransmission. While the data from postmortem studies are compelling and define the molecular profile of the brain in suicide, further studies are necessary to pinpoint whether these changes define causality for 5-HT deficits or are alternatively a normal brain response to a preexisting hyposerotonergic environment.

ACKNOWLEDGMENTS

We would like to thank the NIH, the American Foundation for Suicide Prevention, and the Diane Goldberg Foundation for supporting the research described in this chapter. We would also like to thank Suham A. Kassir, Mihran J. Bakalian, and Virginia Johnson for their help with the postmortem human brain studies.

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