Serotonin Transporter Gene Expression Research Articles

Establishing an OCD Model in BALB/c Mice Using RU24969: A Molecular and Behavioural Study of Optimal Dose Selection.

Obsessive-compulsive disorder (OCD) is a disabling disease characterized by distressing obsessions and repetitive compulsions. The etiology of OCD is poorly known, and mouse modeling allows to clarify the genetic and neurochemical basis of this disorder and to investigate potential treatments. This study evaluates the impact of the 5-HT1B agonist RU24969 on the induction of OCD-like behaviours in female BALB/c mice (n = 30), distributed across five groups receiving varying doses of RU24969. Behavioural assessments, including marble test, tail suspension test, sucrose preference test, forced swim test, and nestlet shredding test, were conducted. Gene expression and protein quantitation of Gabra1 and serotonin transporter in mouse brain were also performed. Marble-burying behaviour increased significantly at high doses of RU24969 (15-20 mg/kg). The forced swimming test consistently showed elevated values at the same high concentrations, compared to the control. Altered reward-seeking behaviour was indicated by the sucrose preference test, notably at 15 and 20 mg/kg doses of RU24969. Nestlet shredding results did not show statistical significance among the tested animal groups. Gene expression analysis revealed reduced Gabra1 expression with increasing doses of RU, while serotonin transporter was not related to varying doses of RU24969. Western blotting corroborated these trends. The results underscore complex interactions between the serotonin system, GABAergic signaling, and OCD-relevant behaviours and suggest the use of intraperitoneal injection of 15 mg/kg of RU24969 to induce OCD-like behaviour in BALB/c mouse models.

Colitis-Induced Small Intestinal Hypomotility Is Dependent on Enteroendocrine Cell Loss in Mice

The abdominal discomfort experienced by patients with colitis may be attributable in part to the presence of small intestinal dysmotility, yet mechanisms linking colonic inflammation with small-bowel motility remain largely unexplored. We hypothesize that colitis results in small intestinal hypomotility owing to a loss of enteroendocrine cells (EECs) within the small intestine that can be rescued using serotonergic-modulating agents. Male C57BL/6J mice, as well as mice that overexpress (EECOVER) or lack (EECDEL) NeuroD1+ enteroendocrine cells, were exposed to dextran sulfate sodium (DSS) colitis (2.5% or 5% for 7 days) and small intestinal motility was assessed by 70-kilodalton fluorescein isothiocyanate-dextran fluorescence transit. EEC number and differentiation were evaluated by immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, and quantitative reverse-transcriptase polymerase chain reaction. Mice were treated with the 5-hydroxytryptamine receptor 4 agonist prucalopride (5 mg/kg orally, daily) to restore serotonin signaling. DSS-induced colitis was associated with a significant small-bowel hypomotility that developed in the absence of significant inflammation in the small intestine and was associated with a significant reduction in EEC density. EEC loss occurred in conjunction with alterations in the expression of key serotonin synthesis and transporter genes, including Tph1, Ddc, and Slc6a4. Importantly, mice overexpressing EECs revealed improved small intestinal motility, whereas mice lacking EECs had worse intestinal motility when exposed to DSS. Finally, treatment of DSS-exposed mice with the 5-hydroxytryptamine receptor 4 agonist prucalopride restored small intestinal motility and attenuated colitis. Experimental DSS colitis induces significant small-bowel dysmotility in mice owing to enteroendocrine loss that can be reversed by genetic modulation of EEC or administering serotonin analogs, suggesting novel therapeutic approaches for patients with symptomatic colitis.

Effects of wheel-running on anxiety and depression-relevant behaviours in the MCAO mouse model of stroke: moderation of brain-derived neurotrophic factor and serotonin receptor gene expression

Stroke continues to be a major cause of mortality globally. Post-stroke treatment is complicated by the heterogenous nature of pathology and the emergence of secondary psychological symptoms are an additional challenge to the recovery process. Poststroke depression (PSD) is a common co-morbidity and is a major impediment to recovery. While selective serotonin reuptake inhibitors (SSRIs) have proven to be clinically efficacious in treating PSD, the pathogenic processes that underlie the manifestation of depressive mood post-stroke remains unclear. Furthermore, the use of SSRIs is associated with risks of intracerebral haemorrhage, so alternative treatment options need to be continuously explored. Exercise has been demonstrated to be beneficial for improving mood in humans and preclinical models of neurological conditions. Little is known of the mood-related benefits of physical exercise post-stroke. Using the middle cerebral artery occlusion (MCAO) mouse model of cerebral ischaemia, we investigated whether behavioural deficits emerge post-MCAO and could be rescued by voluntary wheel-running. We report that MCAO induced hypo-locomotion and anhedonia-related behaviours, with some improvements conferred by wheel-running. Serotonin transporter gene expression was increased in the MCAO hippocampus and frontal cortex, but this increase remained despite wheel-running. Wheel-running associated up-regulation of BDNF gene expression was unaffected in MCAO mice, reflecting conservation of key neuroplasticity molecular pathways. Taken together, our results highlight the need for further research into serotonergic modulation of the affective symptoms of stroke.

Relationship between placental serotonin transporter gene (SLC6A4) expression, maternal metabolic state, and infant birthweight

Relationship between placental serotonin transporter gene (SLC6A4) expression, maternal metabolic state, and infant birthweight

Influence of 5-HTTLPR polymorphism on postpartum depressive and posttraumatic symptoms.

Postpartum depression (PPD) is a multifactor disorder caused by psychological, social, and also biological factors. 5-HTTLPR polymorphism in the promoter region of serotonin transporter gene seems to influence PPD onset. In this study, we examined the effect of 5-HTTLPR polymorphism on prenatal and postnatal symptoms of depression and posttraumatic stress in women. A longitudinal design with three points - time 1 (32-40 weeks gestation); time 2 (2 or 3 weeks after birth), and time 3 (3 months after birth) - was made. A total of 141 women were recruited during childbirth preparation courses. At time 1, women completed the Beck Depression Inventory (BDI) and the Los Angeles Symptoms Checklist (LASC). At time 2, they fulfilled BDI and Edinburgh Postnatal Depression Scale (EDPS), LASC and the Perinatal Posttraumatic stress disorder (PTSD) Questionnaire (PPQ); midwives and nurses collected biological test tubes by blood sampling for the genetic analysis. At time 3, the women were reassessed for BDI, LASC, EDPS, and PPQs. Analysis of variance and moderation analysis were used to correlate genotype and psychological investigations. Results showed that, compared with LL/LS genotypes, SS genotype moderated cognitive depressive symptoms onset at T2 and T3. Moreover, this genotype correlated, directly or indirectly, with PTSD postpartum aspects (re-experience, avoidance, and hyperarousal). Findings revealed that a lower expression of serotonin transporter gene, associated with SS genotype, seems to render women more vulnerable to depressive and PTSD symptoms after childbirth.

Impacts of caffeine on resistant chicken's performance and cardiovascular gene expression.

We previously reported a study on 288 broiler (Gallus gallus) chicks who received caffeine in water between days 3 and 42, at levels of 0, 6.25, 12.5, 25, 50 and 100mg/kg body weight (BW)/day. In the previous report, we found that caffeine caused pulmonary hypertension (PH)-associated mortality in a significant minority (20%-30%) of birds, including right ventricular hypertrophy and ascites. We have also shown a significant upregulation of the serotonin transporter (SERT), troponin T2, adenosine A1 receptor (ADORA1) and phosphodiesterase 5A (PDE5) in chicken suffering from PH. Here, we examine the resistant (survived) chicks from the first study that had not died due to acute heart failure and did not have clinical signs of pulmonary hypertension. Our goal was to determine whether birds who lacked overt signs of disease had subclinical manifestations, including similar changes in gene expression, growth rates and altered systemic haemodynamics. We found that growth was significantly increased by caffeine consumption (p<0.01) at low doses; however, dosage over 50mg/BW/d had remarkable adverse effects on growth (p<0.01). Blood pressure, troponin T2 and PDE5 gene expression were not significantly altered by caffeine administration (p>0.05). However, SERT gene expression linearly increased with increasing caffeine dosage (p<0.01). The impact of caffeine on ADORA1 gene expression was dose dependent and nonlinear. In conclusion, despite the significant effects of caffeine on birds' growth, no significant negative effects of caffeine were observed on the cardiovascular function of resistant chickens. This work provides valuable information for further study on different dosage of caffeine in an animal model.

Withanone Ameliorates Stress Symptoms in Caenorhabditis Elegans by Acting through Serotonin Receptors.

Depression is responsible for 800 000 deaths worldwide, a number that will rise significantly due to the COVID-19 pandemic. Affordable novel drugs with less severe side effects are urgently required. We investigated the effect of withanone (WN) from Withania somnifera on the serotonin system of wild-type and knockout Caenorhabditis elegans strains using in silico, in vitro, and in vivo methods. WN or fluoxetine (as positive control drug) was administered to wild-type (N2) and knockout C. elegans strains (AQ866, DA1814, DA2100, DA2109, and MT9772) to determine their effect on oxidative stress (Trolox, H2DCFDA, and juglone assays) on osmotic stress and heat stress and lifespan. Quantitative real-time RT-PCR was applied to investigate the effect of WN or fluoxetine on the expression of serotonin receptors (ser-1, ser-4, ser-7) and serotonin transporter (mod-5). The binding affinity of WN to serotonin receptors and transporter was analyzed in silico using AutoDock 4.2.6. WN scavenged ROS in wild-type and knockout C. elegans and prolonged their lifespan. WN upregulated the expression of serotonin receptor and transporter genes. In silico analyses revealed high binding affinities of WN to Ser-1, Ser-4, Ser-7, and Mod-5. Further studies are needed to prove whether the results from C. elegans are transferrable to mammals and human beings. WN ameliorated depressive-associated stress symptoms by activating the serotonin system. WN may serve as potential candidate in developing new drugs to treat depression.

The Effect of Exercise on Reducing Tumor Necrosis Factor Alpha Levels and Attenuating Serotonin Transporter Gene Expression: A Research Protocol

Introduction: The intricate relation between depression and inflammation has become a prevalent topic of discussion among the scientific community. Pro-inflammatory cytokines exert depressogenic effects by crossing the blood brain barrier and disrupting serotonin (5-hydroxytryptamine, 5-HT) homeostasis through serotonin transporters (SERTs). SERTs induce 5-HT reuptake, causing 5-HT deficiency. This study demonstrates that (1) exercise decreases levels of the pro-inflammatory cytokine, Tumor Necrosis Factor alpha (TNF-α), and (2) a decline in TNF-α attenuates SERT activity through the proposed mechanism of activating the p38 mitogen-activated protein kinase (MAPK) pathway in the hippocampus. Methods: 32 Sprague-Dawley rats are randomly divided into four groups. Rats not exercising serve as control. Exercising rats, exposed to 6 weeks of treadmill exercise, receive either vehicle intracerebroventricular injection, intracerebroventricular injection of TNF-α antibody Infliximab, or intracerebroventricular injection of MAPK inhibitor SB203580. Control rats also receive vehicle intracerebroventricular injection. 24 hours post-injection, blood is collected, and serum is separated for an ELISA test to assess TNF-α levels. To measure SERT gene expression, RNA is isolated from hippocampal tissue and PCR is performed. Results: Exercising rats are anticipated to show reduced TNF-α levels compared to control, confirming exercise decreases pro-inflammatory cytokines. Exercising rats should also show decreased SERT gene expression, as exercise attenuates TNF-α mediated stimulation of SERTs. SERT expression is expected to be similar in rats injected with Infliximab and SB203580, suggesting that TNF-α exerts its effect through the p38 MAPK pathway. Discussion: Moderate intensity exercise reduces TNF-α levels, which limits 5-HT uptake by attenuating the expression of the SERT gene, thus mitigating depressive symptoms. It is also postulated that TNF-α modulates levels of SERT expression through the p38 MAPK pathway, as rats injected with SB203580 have shown to have similar gene expression as rats injected with Infliximab. Conclusion: Understanding the negative correlation between exercise and depression provides insight into viable treatment alternatives for depression. Exercise may be used alone or in conjunction with current treatments to prevent or minimize symptoms of mood disorders. Further investigation may reveal the effects of other cytokines on extracellular 5-HT levels, and their consequent influence on depression and its symptoms.

Induction of stress resistance and extension of lifespan in Chaenorhabditis elegans serotonin-receptor knockout strains by withanolide A

IntroductionApproximately 300 million people worldwide suffer from depression. The COVID-19 crisis may dramatically increase these numbers. Severe side effects and resistance development limit the use of standard antidepressants. The steroidal lactone withanolide A (WA) from Withania somnifera may be a promising alternative. Caenorhabditis elegans was used as model to explore WA's anti-depressive and anti-stress potential. MethodsC. elegans wildtype (N2) and deficient strains (AQ866, DA1814, DA2100, DA2109 and MT9772) were used to assess oxidative, osmotic or heat stress as measured by generation of reactive oxygen species (ROS), determination of lifespan, and mRNA expression of serotonin receptor (ser-1, ser-4, ser-7) and serotonin transporter genes (mod-5). The protective effect of WA was compared to fluoxetine as clinically established antidepressant. Additionally, WA's effect on lifespan was determined. Furthermore, the binding affinities and pKi values of WA, fluoxetine and serotonin as natural ligand to Ser-1, Ser-4, Ser-7, Mod-5 and their human orthologues proteins were calculated by molecular docking. ResultsBaseline oxidative stress was higher in deficient than wildtype worms. WA and fluoxetine reduced ROS levels in all strains except MT9772. WA and fluoxetine prolonged survival times in wildtype and mutants under osmotic stress. WA but not fluoxetine increased lifespan of all heat-stressed C. elegans strains except DA2100. Furthermore, WA but not fluoxetine extended lifespan in all non-stressed C. elegans strains. WA also induced mRNA expression of serotonin receptors and transporters in wildtype and mutants. WA bound with higher affinity and lower pKi values to all C. elegans and human serotonin receptors and transporters than serotonin, indicating that WA may competitively displaced serotonin from the binding pockets of these proteins. ConclusionWA reduced stress and increased lifespan by ROS scavenging and interference with the serotonin system. Hence, WA may serve as promising candidate to treat depression.

Comparing the mRNA levels in the brain stem of stressed rats with Tianeptine and Sertraline administration

Since the discovery that antidepressants work in part by potentiating the actions of 5-HT within the serotonergic system the effects these drugs elicit on the serotonin transporter (SERT) protein have been an area of active research. The aim of the present study is to understand the mechanism of action of tianeptine and sertraline in relation to its effects on the expression of SERT gene and SERT protein in the brain stem of stressed rats. Albino Wistar rats were divided into two groups (n=12) i.e. saline and drug. Each group was further divided into two equal groups, stressed (Forced Swim Test-FST) and unstressed. Tianeptine and sertraline were administered to rats orally for 4 weeks prior to subjecting them to forced swim test and decapitation. Tianeptine increased the expression of SERT gene though the protein is reduced in the brain stem in stress. On the contrary sertraline decreased the expression of SERT gene but increased the protein in the brain stem. The increase in swimming time in FST by both the drugs indicates stress alleviating effects. It can be concluded that Tianeptine prevents stress induced changes through its effect on the serotonergic system, including SERT mRNA and protein. Sertraline complies to the reuptake inhibition property by reducing SERT gene expression. Results are discussed specifically, how changes in SERT expression following chronic antidepressant treatment may contribute to the therapeutic benefits of antidepressants. Keywords: Antidepressants; Serotonin transporters; Stress; Serotonergic system; SERT gene expression

Trait Anxiety Mediated by Amygdala Serotonin Transporter in the Common Marmoset.

High trait anxiety is associated with altered activity across emotion regulation circuitry and a higher risk of developing anxiety disorders and depression. This circuitry is extensively modulated by serotonin. Here, to understand why some people may be more vulnerable to developing affective disorders, we investigated whether serotonin-related gene expression across the brain's emotion regulation circuitry may underlie individual differences in trait anxiety using the common marmoset (Callithrix jacchus, mixed sexes) as a model. First, we assessed the association of region-specific expression of the serotonin transporter (SLC6A4) and serotonin receptor (HTR1A, HTR2A, HTR2C) genes with anxiety-like behavior; and second, we investigated their causal role in two key features of the high trait anxious phenotype: high responsivity to anxiety-provoking stimuli and an exaggerated conditioned threat response. While the expression of the serotonin receptors did not show a significant relationship with anxiety-like behavior in any of the targeted brain regions, serotonin transporter expression, specifically within the right ventrolateral prefrontal cortex (vlPFC) and most strongly in the right amygdala, was associated positively with anxiety-like behavior. The causal relationship between amygdala serotonin levels and an animal's sensitivity to threat was confirmed via direct amygdala infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram. Both anxiety-like behaviors, and conditioned threat-induced responses were reduced by the blockade of serotonin reuptake in the amygdala. Together, these findings provide evidence that high amygdala serotonin transporter expression contributes to the high trait anxious phenotype and suggest that reduction of threat reactivity by SSRIs may be mediated by their actions in the amygdala.SIGNIFICANCE STATEMENT Findings here contribute to our understanding of how the serotonin system underlies an individual's expression of threat-elicited negative emotions such as anxiety and fear within nonhuman primates. Exploration of serotonergic gene expression across brain regions implicated in emotion regulation revealed that serotonin transporter gene expression in the ventrolateral prefrontal cortex (vlPFC) and most strongly in the amygdala, but none of the serotonin receptor genes, were predictive of interindividual differences in anxiety-like behavior. Targeting of amygdala serotonin reuptake with selective serotonin reuptake inhibitors (SSRIs) confirmed the causal relationship between amygdala serotonin transporter and an animal's sensitivity to threat by reversing expression of two key features of the high trait-like anxiety phenotype: high responsivity to anxiety-provoking uncertain threat and responsivity to certain conditioned threat.

Chronic SJW pretreatment in the regulation of Cerebral Serotonergic and Behavioral Activity

Background: Saint John’s wort (SJW) is known for the medicinal powers of its leaves that are composed of a myriad of chemical components having diverse effects on various conditions like mild to moderately severe depressive disorders. Present study is carried out to explore the presynaptic adaptive measures resulting by the treatment with SJW prior to subjection of rats to forced swim test (FST). Method: Adult Albino Wistar rats were divided into 2 groups (Saline and drug administered rats, n=12 each). Each group was further divided into stressed and unstressed groups (n=6). SJW (500mg/kg/ml) was orally administered to the drug group for 28 days while saline was administered to the other group for the same period. Results: Behavioral analysis of FST shows an increase in swimming time and a decrease in floating time of rats pretreated with SJW. Serotonin transporter (SERT) gene expression is decreased by SJW in both stressed and unstressed groups. SERT protein is increased by SJW in the unstressed group but decreased in the stressed group as compared to the saline administered group. Conclusion: It can be concluded that SJW is affective in containing serotonergic hyperactivity simultaneously alleviating depression by mechanisms probably different to the serotonergic system.

Associations between the STin2VNTR Serotonin Transporter Gene Polymorphism and Background EEG in Younger and Older Adults

Spontaneous electrical brain activity is considered as a state of tonic activation or inhibition, which is the physiological basis for normal brain function and pathology. Projections of the serotonergic system are widely widespread in the cerebral cortex and affect both the processes of neuroplasticity and the formation of fundamental neural networks that determine the brain activity at rest. The STin2VNTR gene appears to be an allele-dependent enhancer of the expression of the serotonin transporter gene. This study was conducted to identify the associations of STin2VNTR polymorphism with the characteristics of background EEG in healthy older (51 men (64.5 ± 7.13 years of age) and 48 women (63.56 ± 5.4 years)) and younger (86 men (22.5 ± 3.5 years) and 110 women (21.17 ± 2.7 years)) adults. The endophenotypes of brain electrical activity associated with the STin2VNTR polymorphism of the serotonin transporter gene are characterized by specific patterns of α3 power asymmetry in parietal–occipital regions of the brain hemispheres and differ in younger and older subjects. In the younger age group, the 12'/12' genotype carriers had significantly higher values of the asymmetry index of the α3 power (right > left) in the parietal–occipital regions as compared with other genotypes. The presence of allele 12 in the genotype positively correlates with the value of asymmetry index of the α3 rhythm. In young carriers of allele 12 (10'/12' and 12'/12'), lateral differences were statistically significant. In the older age group, the 10'/10' genotype carriers had the lowest values of asymmetry index; only the carriers of this genotype had statistically significant lateral differences due to higher rhythm power in the parietal–occipital region of the right hemisphere as compared to the left one. Lateral differences due to high α-rhythm power values in the posterior region of the right hemisphere may be considered as electrophysiological endophenotype and may be associated with predisposition to the possible occurrence of schizoid disorders in young carriers of the 12'/12' genotype.

Serotonergic Regulation and Cognition after Stroke: The Role of Antidepressant Treatment and Genetic Variation

Introduction: Serotonin affects several brain functions including cognition. The serotonin transporter (SERT) regulates brain serotonin levels through reuptake into neurons. The gene encoding this transporter, the SERT gene, has several functional polymorphisms affecting the number of transporters and thereby the serotonin levels. SERT gene expression may be important for cognition and selective serotonin reuptake inhibitors (SSRI) may improve cognition post stroke. We therefore examined the association between SERT genotypes, cognitive function and early treatment with the SSRI citalopram among non-depressed Caucasian stroke patients. Patients and Methods: SERT gene polymorphisms in 270 non-depressed first-ever acute ischemic stroke patients randomized to citalopram, n = 130, or placebo, n = 140, were investigated. Patients were genotyped for a length polymorphism (L = long and S = short allele) and a single nucleotide polymorphism (A/G substitution) dividing the L-allele into L_A and L_G. According to these genotypes, patients were further grouped according to low (S/S, L_G/S and L_G/L_G), medium (S/L_A and L_G/L_A), or high functional gene expression (L_AL_A). Cognition was measured by the Symbol Digit Modalities Test (SDMT) at 1 and 6 months. Mean SDMT scores according to genotype and randomization groups were compared using multiple logistic regression adjusting for age, stroke severity, premorbid functional status, and vascular risk factors including smoking, hypertension, and diabetes. Results: Stratified by genotype groups, there were no statistically significant differences in SDMT scores between randomization groups. Placebo-treated patients with low SERT expression genotypes, however, tended to have lower mean SDMT scores (at 1 month: 30.2, SD 10.8) compared to citalopram-treated patients (33.6, SD 13.7). Within the placebo group, the low genotype expression patients had significantly lower adjusted mean SDMT scores at 1 month compared to the high genotype expression patients (adjusted mean difference of –6 points, CI –12.0 to –0.05). We found similar results at 6 months, although not statistically significant. The genotype expression was not associated with SDMT scores among citalopram-treated patients. Conclusion: There was no difference in cognition between citalopram and placebo-treated patients according to the genotype group. Our results indicate, however, that low expression SERT genotype may contribute to reduced cognitive function post stroke as placebo-treated patients with low SERT expression tended to score lower on the SDMT. The significant difference in SDMT scores between low and high expression patients was present only in the placebo-treated group, thereby warranting further exploration of the potential effect of early citalopram treatment on cognitive functioning. Our results are preliminary and need replication in larger-scale studies.

Anxiety Disorders: Sex Differences in Serotonin and Tryptophan Metabolism

Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety. A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and EMBASE databases from inception until December 31, 2017. This review shows that sex may interact with many serotonin functions thereby modulating anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations and metabolism. Sex-steroids modulate the expression of serotonin transporter genes, creating a difference in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sexrelated differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease (IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced in women than men, and therefore, females may show increased levels of anxiogenic TRYCAT following immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females and parturients and are associated with increased anxiety levels in the postnatal period. The results of this review underscore the necessity of studying the associations between serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune system through the production of anxiogenic TRYCATs.

Serotonin transporter gene expression predicts the worsening of suicidal ideation and suicide attempts along a long-term follow-up of a Major Depressive Episode

The quest for biomarkers in suicidal behaviors has been elusive so far, despite their potential utility in clinical practice. One of the most robust biological findings in suicidal behaviors is the alteration of the serotonin transporter function in suicidal individuals. Our main objective was to investigate the predictive value of the serotonin transporter gene expression (SLC6A4) for suicidal ideation and as secondary, for suicide attempts in individuals with a major depressive episode (MDE). A 30-week prospective study was conducted on 148 patients with a MDE and 100 healthy controls including 4 evaluation times (0, 2, 8 and 30 weeks). Blood samples and clinical data were collected and SLC6A4 mRNA levels were measured from peripheral blood mononuclear cells using RT-qPCR. We first demonstrated the stability and reproducibility of SLC6A4 mRNA expression measures over time in healthy controls (F=0.658; p=0.579; η2=0.008; ICC=0.91, 95% CI [0.87–0.94]). Baseline SLC6A4 expression level (OR=0.563 [0.340–0.932], p=0.026) as well as early changes in SLC6A4 expression between baseline and the 2nd week (β=0.200, p=0.042) predicted the worsening of suicidal ideation (WSI) in the following 8 weeks. Moreover, changes in SLC6A4 expression between the 2nd and 8th weeks predicted the occurrence of a suicide attempt within 30 weeks (OR=10.976 [1.438–83.768], p=0.021). Altogether, the baseline level and the changes in SLC6A4 mRNA expression during a MDE might predict the WSI and the occurrence of suicidal attempts and could be a useful biomarker in clinical practice.

Upregulation of SERT and ADORA1 in broilers with acute right ventricular failure

Pulmonary hypertension (PH), remains a challenging disease with a large impact on both humans and meat-type chickens. PH is characterized by the onset of idiopathic pulmonary arterial hypertension leading to right ventricular failure. In this experiment relative gene expression of adenosine A1 receptor (ADORA1), serotonin transporter (SERT), phosphodiesterase 5A (PDE5) and troponin T2 were compared in hearts from broilers with acute right ventricular failure and from healthy birds. There were major increases in adenosine A1 receptor (177%) and serotonin transporter (475%), and more modest but significant increases in PDE5 (146%) and troponin T2 (140%) gene expressions in broilers with right ventricular failure compared to healthy birds (P<0.01). This novel report shows that pulmonary hypertension related gene expression in broilers is similar to that in humans. This molecular similarity between PH in broilers and human patients suggests, first, that they will make a suitable animal model for study PH in humans, but also that the literature on PH in humans may be profitably applied to the study of PH in broilers.

Neonatal fluoxetine exposure modulates serotonergic neurotransmission and disturb inhibitory action of serotonin on food intake

The neurotransmitter serotonin (5-HT) acts as an important regulator of the critical neurodevelopmental processes and thus alterations in 5-HT signaling early promotes permanent structural and functional changes in brain. The selective serotonin reuptake inhibitors (SSRIs), as fluoxetine and citalopram, blocking serotonin transporter (SERT) at the presynaptic neuron, which regulates extracellular 5-HT levels. Evidence suggests that the exposure to SSRIs in the neurodevelopmental period may alters 5-HT signaling sensitivity on food intake control. The aim of the present study was to evaluate the effects of neonatal exposure to fluoxetine on molecular and cellular components of the serotonergic system and food intake control in young animals. Methods: The animals were divided according to experimental manipulation, Fluoxetine Group (FG): male pups received application of fluoxetine (10 mg/kg, 10 μL/g) and Saline Group (SG): male pups received saline application (0.9% NaCl, 10 μL/g), both throughout lactation (PND1–PND21). They evaluated body weight, food intake, SERT gene and protein expression, serotonin content in the hypothalamus. The neonatal exposure to fluoxetine promoted reduction in body weight, disturb the serotonin hypophagic response, and increase the serotonin and SERT hypothalamic in young animals. We conclude that the changes of components of the serotonergic system by neonatal exposure to fluoxetine may be responsible for disturb the inhibitory action of serotonin on food intake.

Looking Beyond the 5-HTTLPR Polymorphism: Genetic and Epigenetic Layers of Regulation Affecting the Serotonin Transporter Gene Expression.

Serotonin (5-HT) is a neurotransmitter that regulates fundamental aspects of brain development, physiology and behaviour. The serotonin transporter (5-HTT) is deputized to the reuptake of 5-HT from the intersynaptic space in the presynaptic neurons. 5-HTT governs duration and magnitude of 5-HT biological actions, acting as a master regulator of the fine-tuning of 5-HT signalling. Genetic variation at SLC6A4 gene locus, encoding 5-HTT, contributes to alteration in 5-HT reuptake. The 5-HTTLPR/rs25531/rs25532 polymorphisms located in the promoter region of SLC6A4 gene have been associated with stress-related psychopathology and functional brain phenotypes. Besides, further DNA variations in functional regulative elements located at 5' and 3' termini of the SLC6A4 gene influence transcriptional and post-transcriptional steps. Recently, epigenetic processes including SLC6A4 promoter methylation and transcript silencing by microRNA were shown to be involved in the aetiology of affective disorders. Furthermore, gene-environment interactions such as early life stress often encompass epigenetic changes, which can stably mark the genome in response to environmental stimuli potentially altering gene expression across lifespan. Therefore, it seems well established that functional variations in the SLC6A4 gene expression can no longer be ascribed to the modulating 5-HTTLPR promoter polymorphism but need to be integrated with the contribution arising from other interactive elements and epigenetic mechanisms. In this review, we discuss genetic and epigenetic layers of regulation affecting SLC6A4 gene expression. An overview of human and cellular studies investigating the impact of these regulatory processes on SLC6A4 gene expression is provided.

Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer's Disease.

Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer's disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.