Localization of the Serotonin Transporter in the Dog Intestine and Comparison to the Rat and Human Intestines

Serotonin is crucial in gastrointestinal functions, including motility, sensitivity, secretion, and the inflammatory response. The serotonin transporter (SERT), responsible for serotonin reuptake and signaling termination, plays a prominent role in gastrointestinal physiology, representing a promising therapeutic target in digestive disorders. Serotonin transporter expression has been poorly investigated in veterinary medicine, under both healthy and pathological conditions, including canine chronic enteropathy, in which the serotonin metabolism seems to be altered. The aim of the present study was to determine the distribution of SERT immunoreactivity (SERT-IR) in the dog intestine and to compare the findings with those obtained in the rat and human intestines. Serotonin transporter-IR was observed in canine enterocytes, enteric neurons, lamina propria cells and the tunica muscularis. Data obtained in dogs were consistent with those obtained in rats and humans. Since the majority of the serotonin produced by the body is synthesized in the gastrointestinal tract, SERT-expressing cells may exert a role in the mechanism of serotonin reuptake.

A summary-statistics-based approach to examine the role of serotonin transporter promoter tandem repeat polymorphism in psychiatric phenotypes

In genetic studies of psychiatric disorders in the pre-genome-wide association study (GWAS) era, one of the most commonly studied loci is the serotonin transporter (SLC6A4) promoter polymorphism, a 43-base-pair insertion/deletion polymorphism in the promoter region (5-HTTLPR). The genetic association signals between 5-HTTLPR and psychiatric phenotypes, however, have been inconsistent across many studies. Since the polymorphism cannot be tested via available SNP arrays, we had previously proposed an efficient machine learning algorithm to predict the genotypes of 5-HTTLPR based on the genotypes of eight nearby SNPs, which requires access to individual-level genotype and phenotype data. To utilize the advantage of publicly available GWAS summary statistics obtained from studies with very large sample sizes, we develop a GWAS summary-statistics-based approach for testing the variable number of tandem repeat (VNTR) associations with various phenotypes. We first cross-verify the accuracy of the summary-statistics-based approach for 61 phenotypes in the UK Biobank. Since we observed a strong similarity between the predicted individual-level 5-HTTLPR genotype-based approach and the summary-statistics-based approach, we applied our method to the available neurobehavioral GWAS summary statistics data obtained from large-scale GWAS. We found no genome-wide significant evidence for association between 5-HTTLPR and any of the neurobehavioral traits. We did observe, however, genome-wide significant evidence for association between this locus and human adult height, BMI, and total cholesterol. Our summary-statistics-based approach provides a systematic way to examine the role of VNTRs and related types of genetic polymorphisms in disease risk and trait susceptibility of phenotypes for which large-scale GWAS summary statistics data are available.

The Impact of the Serotonin Transporter Gene Promoter DNA Methylation on Anorexia Nervosa：A Preliminary Longitudinal Study

BackgroudThe serotonin system has been reported to be involved in the pathogenesis of anorexia nervosa (AN). The promoter region of serotonin transporter gene (SLC6A4), also called 5-HTTLPR, responsible for serotonin reuptake, has received much attention, especially 5-HTTLPR methylation, which was associated with abnormal eating behaviors. The study was aimed to explore the association between 5-HTTLPR methylation and AN, as well as its predictive effect on therapeutic response.Methods91 AN patients and 87 healthy controls (HCs) were recruited. Only 30 patients completed the 12-week follow-up. 5-HTTLPR methylation levels and clinical symptoms were assessed at baseline for all participants, at the fourth and the twelfth week for follow-up patients. 5-HTTLPR methylation was measured by MassArray methods and clinical symptoms were mainly evaluated by the EDE-Q6.0 scale. ResultsAN patients had higher methylation at CpG 11, CpG 24.25, CpG 31.32 and CpG_mean than healthy controls (P=0.039, 0.042, 0.018, 0.001). Furthermore, it was the binge/purging subtype that revealed significant hypermethylation at CpG4 and CpG_mean (P=0.027, 0.031). However, it failed to discover significant differences between AN-R and AN-BP groups at all units. Besides, CpG 11 methylation level was positively correlated with EDEQ-6.0 total score in patients (r=0.226, P=0.047). The methylation level of CpG11, CpG26.27.28, CpG31.32, CpG33.34.35.36 and CpG_mean decreased after treatment, but not significantly. 5-HTTLPR methylation was not significantly different between the two groups after treatment.ConclusionsOur study provided preliminary evidence that 5-HTTLPR methylation played vital roles in AN pathogenesis. The characteristic of 5-HTTLPR among untreated AN patients was hypermethylation. However, whether it is the biomarker to distinguish the subtypes and therapeutic response of AN needs further investigation.

The Developmental Role of Serotonin: A Comparison of Short- and Long-term Blockade of the Serotonin Transporter on Behavioural Outcomes in Adulthood

<p>Serotonin is an important neurotransmitter that regulates a range of processes within the brain and is implicated in several psychiatric disorders. In addition, serotonin acts as a developmental signal during critical periods of prenatal development, influencing processes such as neuronal proliferation, migration, and synaptogenesis (Gaspar et al., 2003). The serotonin transporter (5- HTT) plays a key role in regulating extracellular serotonin levels and is the main target of selective-serotonin reuptake inhibitors (SSRIs), a class of drugs that have anti-anxiety and anti- depressive activity. SSRIs cause an acute increase in extracellular serotonin and are commonly prescribed as a treatment for depression and anxiety during pregnancy (Tran & Robb, 2015). Given that these drugs alter serotonin transmission and can pass to the developing fetus via the placenta, it is vital that the outcomes of prenatal SSRI exposure are investigated. In humans, a genetic variant of the gene that codes for the 5-HTT (SLC6A4) has been linked to increased risk for developing depression and anxiety (Caspi et al., 2003). The functional consequences of this genetic polymorphism are life-long alterations in 5-HTT activity, resulting in increased extracellular levels of serotonin (Nakamura et al., 2000). Given prenatal SSRI exposure results in a time-locked blockade of 5-HTT during critical periods of development, it follows that alterations in serotonin during development might similarly result in enhanced risk for depression and anxiety later in life. Outcomes in children prenatally exposed to SSRIs are difficult to study due to confounds of pre- existing maternal depression. Therefore, the current thesis presents two experiments that aimed to further investigate the role of altered extracellular serotonin levels during development in an animal model. Experiment one aimed to develop a method of voluntary oral administration of the SSRI fluoxetine to pregnant rat dams. This method was then applied in experiment two to create a time-locked blockade of 5-HTT during critical periods of development in an animal model of life-long 5-HTT blockade. The aim of experiment two was to directly assess the contribution of short- and long-term 5-HTT blockade on anxiety and depression phenotypes in adult male offspring. In addition, maternal behaviour was assessed to determine whether fluoxetine treatment had an influence on mother-pup interactions that could confound results. To test for anxiety and depression phenotypes, the novel affective disorder test (ADT) was used to assess anxiety behaviour and the deficits in anticipatory pleasure indicative of anhedonia. In the current study, fluoxetine treatment did not have an effect on litter outcomes or mother-pup interactions. Crucially, no significant group differences were found indicating that neither short- nor long- term blockade of 5-HTT resulted in increased anxiety- or depressive-like behaviours in the current experiment. However, limitations with methodological design limit the translatability of these results to the broader literature, and validation of the ADT is required before these results can be generalised beyond this thesis.</p>

The Developmental Role of Serotonin: A Comparison of Short- and Long-term Blockade of the Serotonin Transporter on Behavioural Outcomes in Adulthood

<p>Serotonin is an important neurotransmitter that regulates a range of processes within the brain and is implicated in several psychiatric disorders. In addition, serotonin acts as a developmental signal during critical periods of prenatal development, influencing processes such as neuronal proliferation, migration, and synaptogenesis (Gaspar et al., 2003). The serotonin transporter (5- HTT) plays a key role in regulating extracellular serotonin levels and is the main target of selective-serotonin reuptake inhibitors (SSRIs), a class of drugs that have anti-anxiety and anti- depressive activity. SSRIs cause an acute increase in extracellular serotonin and are commonly prescribed as a treatment for depression and anxiety during pregnancy (Tran & Robb, 2015). Given that these drugs alter serotonin transmission and can pass to the developing fetus via the placenta, it is vital that the outcomes of prenatal SSRI exposure are investigated. In humans, a genetic variant of the gene that codes for the 5-HTT (SLC6A4) has been linked to increased risk for developing depression and anxiety (Caspi et al., 2003). The functional consequences of this genetic polymorphism are life-long alterations in 5-HTT activity, resulting in increased extracellular levels of serotonin (Nakamura et al., 2000). Given prenatal SSRI exposure results in a time-locked blockade of 5-HTT during critical periods of development, it follows that alterations in serotonin during development might similarly result in enhanced risk for depression and anxiety later in life. Outcomes in children prenatally exposed to SSRIs are difficult to study due to confounds of pre- existing maternal depression. Therefore, the current thesis presents two experiments that aimed to further investigate the role of altered extracellular serotonin levels during development in an animal model. Experiment one aimed to develop a method of voluntary oral administration of the SSRI fluoxetine to pregnant rat dams. This method was then applied in experiment two to create a time-locked blockade of 5-HTT during critical periods of development in an animal model of life-long 5-HTT blockade. The aim of experiment two was to directly assess the contribution of short- and long-term 5-HTT blockade on anxiety and depression phenotypes in adult male offspring. In addition, maternal behaviour was assessed to determine whether fluoxetine treatment had an influence on mother-pup interactions that could confound results. To test for anxiety and depression phenotypes, the novel affective disorder test (ADT) was used to assess anxiety behaviour and the deficits in anticipatory pleasure indicative of anhedonia. In the current study, fluoxetine treatment did not have an effect on litter outcomes or mother-pup interactions. Crucially, no significant group differences were found indicating that neither short- nor long- term blockade of 5-HTT resulted in increased anxiety- or depressive-like behaviours in the current experiment. However, limitations with methodological design limit the translatability of these results to the broader literature, and validation of the ADT is required before these results can be generalised beyond this thesis.</p>

Serotonin Transporter Genetic Variation and Antidepressant Response and Tolerability: A Systematic Review and Meta-Analysis

Antidepressants are used to treat several psychiatric disorders; however, a large proportion of patients do not respond to their first antidepressant therapy and often experience adverse drug reactions (ADR). A common insertion–deletion polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter (SLC6A4) gene has been frequently investigated for its association with antidepressant outcomes. Here, we performed a systematic review and meta-analysis to assess 5-HTTLPR associations with antidepressants: (1) response in psychiatric disorders other than major depressive disorder (MDD) and (2) tolerability across all psychiatric disorders. Literature searches were performed up to January 2021, yielding 82 studies that met inclusion criteria, and 16 of these studies were included in the meta-analyses. Carriers of the 5-HTTLPR LL or LS genotypes were more likely to respond to antidepressant therapy, compared to the SS carriers in the total and European ancestry-only study populations. Long (L) allele carriers taking selective serotonin reuptake inhibitors (SSRIs) reported fewer ADRs relative to short/short (SS) carriers. European L carriers taking SSRIs had lower ADR rates than S carriers. These results suggest the 5-HTTLPR polymorphism may serve as a marker for antidepressant outcomes in psychiatric disorders and may be particularly relevant to SSRI treatment among individuals of European descent.