Serotonin transporter-mediated molecular axis regulates regional retinal ganglion cell vulnerability and axon regeneration after nerve injury.

Molecular insights into the selective vulnerability of retinal ganglion cells (RGCs) in optic neuropathies and after ocular trauma can lead to the development of novel therapeutic strategies aimed at preserving RGCs. However, little is known about what molecular contexts determine RGC susceptibility. In this study, we show the molecular mechanisms underlying the regional differential vulnerability of RGCs after optic nerve injury. We identified RGCs in the mouse peripheral ventrotemporal (VT) retina as the earliest population of RGCs susceptible to optic nerve injury. Mechanistically, the serotonin transporter (SERT) is upregulated on VT axons after injury. Utilizing SERT-deficient mice, loss of SERT attenuated VT RGC death and led to robust retinal axon regeneration. Integrin ß3, a factor mediating SERT-induced functions in other systems, is also upregulated in RGCs and axons after injury, and loss of integrin ß3 led to VT RGC protection and axon regeneration. Finally, RNA sequencing analyses revealed that loss of SERT significantly altered molecular signatures in the VT retina after optic nerve injury, including expression of the transmembrane protein, Gpnmb. GPNMB is rapidly downregulated in wild-type, but not SERT- or integrin ß3-deficient VT RGCs after injury, and maintaining expression of GPNMB in RGCs via AAV2 viruses even after injury promoted VT RGC survival and axon regeneration. Taken together, our findings demonstrate that the SERT-integrin ß3-GPNMB molecular axis mediates selective RGC vulnerability and axon regeneration after optic nerve injury.

Female serotonin transporter-knockout rat: A potential model of irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease. Although visceral hypersensitivity (VH) and disturbed gastrointestinal motility are typical pathophysiological features of IBS, the pathological mechanisms underlying this disease remain unclear. Serotonin system abnormalities are considered to play an important role in the pathomechanisms of IBS. Here, we hypothesize that similar alterations, including VH and colonic motility, induced by serotonin transporter (SERT) knockout result from altered serotonin signaling. We sought to determine the molecular mechanism underlying VH and colonic dysmotility induced by SERT knockout. We found that female SERT (slc6a4)-knockout (KO; ie, slc6a4-/- ) rats exhibited lower pain pressure thresholds (PPTs) than wild-type (WT; ie, slc6a4+/+ ) rats in response to colorectal distension (CRD). Significantly increased fecal pellet output and reduced concentration of serum tryptophan were observed in the female SERT KO rats. The concentrations of 5-hydroxytryptamine (5-HT) in platelet-rich plasma (PRP) and serum in SERT KO rats were lower than those in WT rats, but the numbers of enterochromaffin cells (ECs) and the concentrations of 5-HT in colon of SERT KO rats were higher than those of WT rats. Finally, increased expression levels of 5-HT1B receptors, 5-HT2C receptors, 5-HT3A receptors, 5-HT3B receptors, 5-HT6 receptors, 5-HT7 receptors, and glycosylated dopamine transporters (DATs) were found in the female SERT KO rats. We concluded that alterations in the serotonin system induced by the knockout of slc6a4 might result in VH and accelerated gastrointestinal motility in female SERT KO rats, which can be used as an animal model of IBS.

Evidence that ITGB3 promoter variants increase serotonin blood levels by regulating platelet serotonin transporter trafficking.

Elevated serotonin (5-HT) blood levels, the first biomarker identified in autism research, has been consistently found in 20-30% of patients with Autism Spectrum Disorder (ASD). Hyperserotonemia is mainly due to greater 5-HT uptake into platelets, mediated by the 5-HT transporter (SERT) located at the platelet plasma membrane. The protein complex involved in platelet SERT trafficking and externalization includes integrin ß3, the beta subunit of the platelet membrane adhesive GP IIb/IIIa. Integrin ß3 is encoded by the ITGB3 gene, previously identified as a quantitative trait locus (QTL) for 5-HT blood levels in ASD at single nucleotide polymorphism (SNP) rs2317385. The present study aims to identify the functional ITGB3 gene variants contributing to hyperserotonemia. ITGB3 gene sequencing in 20 individuals selected on the basis of rs2317385 genotypes defined four haplotypes encompassing six SNPs located in the ITGB3 gene promoter region, all in linkage disequilibrium with rs2317385. Luciferase assays in two hematopoietic cell lines, K-562 and HEL 92.1.7, demonstrate that ITGB3 gene promoter activity is enhanced by the presence of the C allele at rs55827077 specifically during differentiation into megakaryocytes (P < 0.01), with modulatory effects by flanking SNPs. This same allele is strongly associated with (a) higher 5-HT blood levels in 176 autistic individuals (P < 0.001), (b) greater platelet integrin ß3 protein expression (P < 0.05) and (c) enhanced SERT trafficking from the cytosol toward the platelet plasma membrane (P = 4.05 × 10-11). Our results support rs55827077 as the functional ITGB3 gene promoter variant contributing to elevated 5-HT blood levels in ASD and define a mechanistic chain of events linking ITGB3 to hyperserotonemia.

Syntaxin 3 interacts with serotonin transporter and regulates its function.

Herein, we investigated the functional association of the serotonin transporter (SERT) with syntaxin-3 (STX3). We first overexpressed SERT and STX3 in various cells and examined their interaction, localization, and functional association. Immunoprecipitation studies revealed that STX3 interacted with SERT when expressed in COS-7 cells. Immunocytochemical studies revealed that SERT and STX3 were colocalized in the endoplasmic reticulum (ER) and Golgi apparatus. STX3 overexpression significantly reduced the uptake activity of SERT by attenuating its plasma membrane expression, suggesting that overexpressed STX3 anchors SERT in the ER and Golgi apparatus. STX3 knockdown did not affect the uptake activity of SERT but altered its glycosylation state. To elucidate the association of STX3 with SERT under physiological conditions, rather than overexpressing cells, we investigated this interaction in polarized Caco-2 cells, which endogenously express both proteins. Immunocytochemical studies revealed that SERT and STX3 were localized in microvilli-like structures at the apical plasma membrane. STX3 knockdown marginally but significantly decreased the serotonin uptake activity of Caco-2 cells, suggesting that STX3 positively regulates SERT function in Caco-2 cells, as opposed to SERT regulation by STX3 in overexpressing cells. Collectively, STX3 may colocalize with SERT during SERT membrane trafficking and regulate SERT function in an STX3-expressing lesion-dependent manner.

SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior.

Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during perinatal periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. Here, we show that during an early postnatal period in mice (P0-P10), Slc6a4/SERT is transiently expressed in a subset of layer 5-6 pyramidal neurons of the prefrontal cortex (PFC). PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets, including the serotonin (5-HT) and GABA neurons of the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Complete or cortex-specific ablation of SERT increases the number of functional PFC glutamate synapses on both 5-HT and GABA neurons in the DRN. This PFC-to-DRN hyperinnervation is replicated by early-life exposure to the SSRI, fluoxetine (from P2 to P14), that also causes anxiety/depressive-like symptoms. We show that pharmacogenetic manipulation of PFC-SERT+ neuron activity bidirectionally modulates these symptoms, suggesting that PFC hypofunctionality has a causal role in these altered responses to stress. Overall, our data identify specific PFC descending circuits that are targets of antidepressant drugs during development. We demonstrate that developmental expression of SERT in this subset of PFC neurons controls synaptic maturation of PFC-to-DRN circuits, and that remodeling of these circuits in early life modulates behavioral responses to stress in adulthood.

SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus-deleted mutant via a Sigma-1 receptor-independent mechanism.

The serotonin transporter (SERT) is functionally regulated via membrane trafficking. Our previous studies have demonstrated that the SERT C-terminal deletion mutant (SERTΔCT) showed a robust decrease in its membrane trafficking and was retained in the endoplasmic reticulum (ER), suggesting that SERTΔCT is an unfolded protein that may cause ER stress. The Sigma-1 receptor (SigR1) has been reported to attenuate ER stress via its chaperone activity. In this study, we investigated the effects of SKF-10047, a prototype SigR1 agonist, on the membrane trafficking and uptake activity of SERT and SERTΔCT expressed in COS-7 cells. Twenty-four hours of SKF-10047 treatment (>200 µM) accelerated SERT membrane trafficking and robustly upregulated SERTΔCT activity. Interestingly, these effects of SKF-10047 on SERT functions were also found in cells in which SigR1 expression was knocked down by shRNA, suggesting that SKF-10047 exerted these effects on SERT via a mechanism independent of SigR1. A cDNA array study identified several candidate genes involved in the mechanism of action of SKF-10047. Among them, Syntaxin3, a member of the SNARE complex, was significantly upregulated by 48 h of SKF-10047 treatment. These results suggest that SKF-10047 is a candidate for ER stress relief.

Appetitive to aversive counter-conditioning as intervention to reduce reinstatement of reward-seeking behavior: the role of the serotonin transporter.

Counter-conditioning can be a valid strategy to reduce reinstatement of reward-seeking behavior. However, this has not been tested in laboratory animals with extended cocaine-taking backgrounds nor is it well understood, which individual differences may contribute to its effects. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on the effectiveness of counter-conditioning after extended access to cocaine self-administration. To this end, 5-HTT+/+ and 5-HTT-/- rats underwent a touch screen-based approach to test if reward-induced reinstatement of responding to a previously counter-conditioned cue is reduced, compared with a non-counter-conditioned cue, in a within-subject manner. We observed an overall extinction deficit of cocaine-seeking behavior in 5-HTT-/- rats and a resistance to punishment during the counter-conditioning session. Furthermore, we observed a significant decrease in reinstatement to cocaine and sucrose associated cues after counter-conditioning but only in 5-HTT+/+ rats. In short, we conclude that the paradigm we used was able to produce effects of counter-conditioning of sucrose seeking behavior in line with what is described in literature, and we demonstrate that it can be effective even after long-term exposure to cocaine, in a genotype-dependent manner.

[Genetics of Posttraumatic Stress Disorder (PTSD)]. / Genetische Grundlagen der Posttraumatischen Belastungsstörung (PTBS).

Post-traumatic stress disorder (PTSD) is a mental disorder following a severe traumatic experience and is characterized by high rates of comorbidity with related psychiatric disorders. However, even for individuals experiencing the same trauma, there is considerable inter-individual variability in the risk of PTSD, and this is largely thought to be determined by biological processes, such as genetic predisposition and epigenetic mechanism. In this review we will summarize recent research on genetics of PTSD, primarily focusing on candidate gene-association studies, targeting on functional genetic variants in the monoaminergic system and the hypothalamic-pituitary-adrenal (HPA) axis. In addition, results from recent genome-wide association studies (GWAS) will be reported and we will highlight the interplay of genetic factors with environmental factors, based on evidence from gene-environment interaction analysis and studies on the epigenetic regulation of PTSD. Finally, we will provide a brief outlook towards the potential and perspectives of pharmaco-genetic studies.

SLC6 Transporter Folding Diseases and Pharmacochaperoning.

The human genome encodes 19 genes of the solute carrier 6 (SLC6) family; non-synonymous changes in the coding sequence give rise to mutated transporters, which are misfolded and thus cause diseases in the affected individuals. Prominent examples include mutations in the transporters for dopamine (DAT, SLC6A3), for creatine (CT1, SLC6A8), and for glycine (GlyT2, SLC6A5), which result in infantile dystonia, mental retardation, and hyperekplexia, respectively. Thus, there is an obvious unmet medical need to identify compounds, which can remedy the folding deficit. The pharmacological correction of folding defects was originally explored in mutants of the serotonin transporter (SERT, SLC6A4), which were created to study the COPII-dependent export from the endoplasmic reticulum. This led to the serendipitous discovery of the pharmacochaperoning action of ibogaine. Ibogaine and its metabolite noribogaine also rescue several disease-relevant mutants of DAT. Because the pharmacology of DAT and SERT is exceptionally rich, it is not surprising that additional compounds have been identified, which rescue folding-deficient mutants. These compounds are not only of interest for restoring DAT function in the affected children. They are also likely to serve as useful tools to interrogate the folding trajectory of the transporter. This is likely to initiate a virtuous cycle: if the principles underlying folding of SLC6 transporters are understood, the design of pharmacochaperones ought to be facilitated.

The Role of Microbiota in Depression - a brief review.

The microbiota-gut-brain axis is a bidirectional homeostatic route of communication between both of the organs direct via receptors of the CNS or via epigenetic mechanisms of divers metabolites e.g. SCFA, GABA, ß-hydroxybutyrate. Thus, a modulation of gut microbiota via nutrition, lifestyle etc. might be effective for emotional status and depressive disorders. The dietary composition has an influence on gut microbiota composition, microbial metabolite profile and the according consequences on emotional status and depression within a system biologic approach. There are changes in gut microbiota composition and gut microbial profile (butyrate, GABA, ß-hydroxybutyrate) effecting epigenetic regulation (histone acetylation, DNA methylation) and gene expression of receptors and mediators (SLC6A4, BDNF, GABA, GPRs) involved in depressive disorders.

Involvement of the Serotonin Transporter Gene in Accurate Subcortical Speech Encoding.

A flourishing line of evidence has highlighted the encoding of speech sounds in the subcortical auditory system as being shaped by acoustic, linguistic, and musical experience and training. And while the heritability of auditory speech as well as nonspeech processing has been suggested, the genetic determinants of subcortical speech processing have not yet been uncovered. Here, we postulated that the serotonin transporter-linked polymorphic region (5-HTTLPR), a common functional polymorphism located in the promoter region of the serotonin transporter gene (SLC6A4), is implicated in speech encoding in the human subcortical auditory pathway. Serotonin has been shown as essential for modulating the brain response to sound both cortically and subcortically, yet the genetic factors regulating this modulation regarding speech sounds have not been disclosed. We recorded the frequency following response, a biomarker of the neural tracking of speech sounds in the subcortical auditory pathway, and cortical evoked potentials in 58 participants elicited to the syllable /ba/, which was presented >2000 times. Participants with low serotonin transporter expression had higher signal-to-noise ratios as well as a higher pitch strength representation of the periodic part of the syllable than participants with medium to high expression, possibly by tuning synaptic activity to the stimulus features and hence a more efficient suppression of noise. These results imply the 5-HTTLPR in subcortical auditory speech encoding and add an important, genetically determined layer to the factors shaping the human subcortical response to speech sounds. SIGNIFICANCE STATEMENT: The accurate encoding of speech sounds in the subcortical auditory nervous system is of paramount relevance for human communication, and it has been shown to be altered in different disorders of speech and auditory processing. Importantly, this encoding is plastic and can therefore be enhanced by language and music experience. Whether genetic factors play a role in speech encoding at the subcortical level remains unresolved. Here we show that a common polymorphism in the serotonin transporter gene relates to an accurate and robust neural tracking of speech stimuli in the subcortical auditory pathway. This indicates that serotonin transporter expression, eventually in combination with other polymorphisms, delimits the extent to which lifetime experience shapes the subcortical encoding of speech.

Serotonin transporter polymorphism moderates the effects of caregiver intrusiveness on ADHD symptoms among institutionalized preschoolers.

Research consistently chronicles a variety of mental health difficulties that plague institutionally reared children, including attention-deficit/hyperactivity disorder (ADHD), even if not all institutionalized children evince such problems. In seeking to extend work in this area, this research on gene × environment (GXE) interplay investigated whether the effect of the quality of institutional care-most notably, caregiver intrusiveness-on ADHD symptoms is moderated by the serotonin transporter (5-HTTLPR) polymorphism. One hundred and twenty-seven institutionalized preschoolers were evaluated using the Child Behavior Checklist. Caregiver-rated attention problems and hyperactivity were unrelated to both 5-HTTLPR polymorphism and caregiver intrusiveness. A significant GXE effect, independent of age at placement or duration of institutionalization, emerged, however, consistent with the differential-susceptibility hypothesis: s/s homozygotes manifest the most and least ADHD symptoms when they experienced, respectively, more and less intrusive caregiving. These results provide new insight into the reasons why some institutionalized children, but not others, exhibit ADHD symptoms.

Role for telomerase in pulmonary hypertension.

BACKGROUND: Cells exhibiting dysregulated growth may express telomerase reverse transcriptase (TERT), the dual function of which consists of maintaining telomere length, in association with the RNA template molecule TERC, and controlling cell growth. Here, we investigated lung TERT in human and experimental pulmonary hypertension (PH) and its role in controlling pulmonary artery smooth muscle cell (PA-SMC) proliferation. METHODS AND RESULTS: Marked TERT expression or activity was found in lungs from patients with idiopathic PH and from mice with PH induced by hypoxia or serotonin-transporter overexpression (SM22-5HTT(+) mice), chiefly within PA-SMCs. In cultured mouse PA-SMCs, TERT was expressed on growth stimulation by serum. The TERT inhibitor imetelstat and the TERT activator TA65 abrogated and stimulated PA-SMC growth, respectively. PA-SMCs from PH mice showed a heightened proliferative phenotype associated with increased TERT expression, which was suppressed by imetelstat treatment. TERC(-/-) mice at generation 2 and TERT(-/-) mice at generations 2, 3, and 4 developed less severe PH than did wild-type mice exposed to chronic hypoxia, with less distal pulmonary artery muscularization and fewer Ki67-stained proliferating PA-SMCs. Telomere length differed between TERC(-/-) and TERT(-/-) mice, whereas PH severity was similar in the 2 strains and across generations. Chronic imetelstat treatment reduced hypoxia-induced PH in wild-type mice or partially reversed established PH in SM22-5HTT(+) mice while simultaneously decreasing TERT expression. Opposite effects occurred in mice treated with TA65. CONCLUSIONS: Telomerase exerts telomere-independent effects on PA-SMC growth in PH and may constitute a treatment target for PH.

Metabotropic glutamate receptor 5 knockout promotes motor and biochemical alterations in a mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein, which promotes progressive neuronal cell loss, neurological symptoms and death. In the present study, we show that blockade of mGluR5 with MTEP promotes increased locomotor activity in both control (Hdh(Q20/Q20)) and mutant HD (Hdh(Q111/Q111)) mice. Although acute injection of MTEP increases locomotor activity in both control and mutant HD mice, locomotor activity is increased in only control mice, not mutant HD mice, following the genetic deletion of mGluR5. Interestingly, treatment of mGluR5 knockout mice with either D1 or D2 dopamine antagonists eliminates the increased locomotor activity of mGluR5 knockout mice. Amphetamine treatment increases locomotor activity in control mice, but not mGluR5 null mutant HD mice. However, the loss of mGluR5 expression improves rotarod performance and decreases the number of huntingtin intranuclear inclusions in mutant HD mice. These adaptations may be due to mutant huntingtin-dependent alterations in gene expression, as microarray studies have identified several genes that are altered in mutant, but not wild-type HD mice lacking mGluR5 expression. qPCR experiments confirm that the mRNA transcript levels of dynein heavy chain, dynactin 3 and dynein light chain-6 are altered following the genetic deletion of mGluR5 in mutant HD mice, as compared with wild-type mutant HD mice. Thus, our data suggest that mutant huntingtin protein and mGluR5 exhibit a functional interaction that may be important for HD-mediated alterations in locomotor behavior and the development of intranuclear inclusions.

Citation bias and selective focus on positive findings in the literature on the serotonin transporter gene (5-HTTLPR), life stress and depression.

BACKGROUND: Caspi et al.'s 2003 report that 5-HTTLPR genotype moderates the influence of life stress on depression has been highly influential but remains contentious. We examined whether the evidence base for the 5-HTTLPR-stress interaction has been distorted by citation bias and a selective focus on positive findings. METHOD: A total of 73 primary studies were coded for study outcomes and focus on positive findings in the abstract. Citation rates were compared between studies with positive and negative results, both within this network of primary studies and in Web of Science. In addition, the impact of focus on citation rates was examined. RESULTS: In all, 24 (33%) studies were coded as positive, but these received 48% of within-network and 68% of Web of Science citations. The 38 (52%) negative studies received 42 and 23% of citations, respectively, while the 11 (15%) unclear studies received 10 and 9%. Of the negative studies, the 16 studies without a positive focus (42%) received 47% of within-network citations and 32% of Web of Science citations, while the 13 (34%) studies with a positive focus received 39 and 51%, respectively, and the nine (24%) studies with a partially positive focus received 14 and 17%. CONCLUSIONS: Negative studies received fewer citations than positive studies. Furthermore, over half of the negative studies had a (partially) positive focus, and Web of Science citation rates were higher for these studies. Thus, discussion of the 5-HTTLPR-stress interaction is more positive than warranted. This study exemplifies how evidence-base-distorting mechanisms undermine the authenticity of research findings.

Genetic Modification of the Relationship between Parental Rejection and Adolescent Alcohol Use.

AIMS: Parenting practices are associated with adolescents' alcohol consumption, however not all youth respond similarly to challenging family situations and harsh environments. This study examines the relationship between perceived parental rejection and adolescent alcohol use, and specifically evaluates whether youth who possess greater genetic sensitivity to their environment are more susceptible to negative parental relationships. METHODS: Analyzing data from the National Longitudinal Study of Adolescent Health, we estimated a series of regression models predicting alcohol use during adolescence. A multiplicative interaction term between parental rejection and a genetic index was constructed to evaluate this potential gene-environment interaction. RESULTS: Results from logistic regression analyses show a statistically significant gene-environment interaction predicting alcohol use. The relationship between parental rejection and alcohol use was moderated by the genetic index, indicating that adolescents possessing more 'risk alleles' for five candidate genes were affected more by stressful parental relationships. CONCLUSIONS: Feelings of parental rejection appear to influence the alcohol use decisions of youth, but they do not do so equally for all. Higher scores on the constructed genetic sensitivity measure are related to increased susceptibility to negative parental relationships.

Cardiovascular afferents cause the release of 5-HT in the nucleus tractus solitarii; this release is regulated by the low- (PMAT) not the high-affinity transporter (SERT).

The nucleus tractus solitarii (NTS) integrates inputs from cardiovascular afferents and thus is crucial for cardiovascular homeostasis. These afferents primarily release glutamate, although 5-HT has also been shown to play a role in their actions. Using fast-cyclic voltammetry, an increase in 5-HT concentrations (range 12-50 nm) could be detected in the NTS in anaesthetized rats in response to electrical stimulation of the vagus and activation of cardiopulmonary, chemo- and baroreceptor reflexes. This 5-HT signal was not potentiated by the serotonin transporter (SERT) or the noradrenaline transporter (NET) inhibitors citalopram and desipramine (1 mg kg(-1) ). However, decynium-22 (600 µg kg(-1) ), an organic cation 3 transporter (OCT3)/plasma membrane monoamine transporter (PMAT) inhibitor, increased the 5-HT signal by 111 ± 21% from 29 ± 10 nm. The effectiveness of these inhibitors was tested against the removal time of 5-HT and noradrenaline applied by microinjection to the NTS. Citalopram and decynium-22 attenuated the removal of 5-HT but not noradrenaline, whereas desipramine had the reverse action. The OCT3 inhibitor corticosterone (10 mg kg(-1) ) had no effect. Blockade of glutamate receptors with topical kynurenate (10-50 nm) reduced the vagally evoked 5-HT signal by 50%, indicating that this release was from at least two sources. It is concluded that vagally evoked 5-HT release is under the regulation of the high-capacity, low-affinity transporter PMAT, not the low-capacity, high-affinity transporter SERT. This is the first demonstration that PMAT may be playing a physiological role in the regulation of 5-HT transmission and this could indicate that 5-HT is acting, in part, as a volume transmitter within the NTS.

Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model.

Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx.

Lower [3H]Citalopram binding in brain areas related to social cognition in alcoholics.

AIMS: In the present study, putative alterations in the serotonin transporter density were evaluated in anterior and posterior insula, posterior cingulate cortex, dorsolateral and dorsomedial prefrontal cortex, hippocampus, parahippocampal gyrus and dorsal raphe nucleus in Cloninger type 1 (n = 9) and type 2 (n = 8) alcoholics and non-alcoholic controls (n = 10). METHODS: Human whole-hemisphere autoradiography was used to measure [3H]citalopram binding to serotonin transporters in eight brain areas in all post-mortem brains. RESULTS: Significant differences were observed in the mean [3H]citalopram binding between the study groups, with antisocial type 2 alcoholics showing the lowest binding. Differences between the study groups were prominent in the posterior insula and posterior cingulate cortex, where both alcoholic groups had low [3H]citalopram binding, and in the parahippocampal gyrus where only antisocial type 2 alcoholics had low [3H]citalopram binding when compared with non-alcoholic controls. CONCLUSION: Although these data are preliminary, and from relatively small diagnostic groups, these results show that alcoholics may have lower serotonergic tone in the brain, thus decreasing social cognition and increasing alcohol-cue reactivity.

Serotonin transporter genotype affects serotonin 5-HT1A binding in primates.

Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. The relationship of a functional variation of the serotonin transporter promoter gene (5-HTTLPR) on serotonin transporter binding using in vivo imaging techniques have yielded inconsistent findings when comparing variants for short (s) and long (l) alleles. However, a significant 5-HTTLPR effect on receptor binding at the 5-HT(1A) receptor site has been reported in humans, suggesting the 5-HTTLPR polymorphism may play a role in serotonin (5-HT) function. Rhesus monkeys possess a 5-HTTLPR length polymorphism similar to humans and serve as an excellent model for studying the effects of this orthologous genetic variation on behaviors and neurochemical functions related to the 5-HT system. In this study, PET imaging of [(18)F]mefway was performed on 58 rhesus monkeys (33 l/l, 25 s-carriers) to examine the relation between 5-HT(1A) receptor-specific binding and 5-HTTLPR genotypes. Significantly lower 5-HT(1A) binding was found in s-carrier subjects throughout both cortical brain regions and the raphe nuclei. These results demonstrate that the underlying 5-HT neurochemical system is influenced by this functional polymorphism and illustrate the strong potential for extending the nonhuman primate model into investigating the role of this genetic variant on behavior and gene-environment interactions.