Association of serotonin receptor gene polymorphisms with anorexia nervosa: a systematic review and meta-analysis.

PURPOSE: Several studies have investigated the association between anorexia nervosa and polymorphisms of genes regulating serotonin neurotransmission, with a focus on the rs6311 polymorphism of 5-HTR2A. However, inconsistent results of these studies and conflicting conclusions of existing meta-analyses complicate the understanding of a possible association. We have updated these results and evaluated the involvement of other serotonin receptor gene polymorphisms in anorexia nervosa. METHODS: Adhering to PRISMA guidelines, we have searched studies on anorexia nervosa and serotonin-regulating genes published from 1997 to 2022, selected those concerning receptor genes and meta-analyzed the results from twenty candidate gene studies on the 5-HTR2A rs6311 polymorphism and the 5-HTR2C rs6318 polymorphism. RESULTS: Present analyses reveal an association for the 5-HTR2A rs6311 polymorphism, with G and A alleles, across eighteen studies (2049 patients, 2877 controls; A vs. G allele, Odds Ratio = 1.24; 95% Confidence Interval = 1.06-1.47; p = 0.009). However, after geographic subgrouping, an association emerged only in a Southern European area, involving five studies (722 patients, 773 controls; A vs. G allele, Odds Ratio = 1.82; 95% Confidence Interval = 1.41-2.37; p < 0.00001). No association was observed for the 5-HTR2C rs6318 polymorphism across three studies. CONCLUSIONS: To date, the involvement in the pathophysiology of anorexia nervosa of the 5-HTR2A rs6311 polymorphism appears limited to a specific genetic and/or environmental context, while that of the 5-HTR2C rs6318 polymorphism seems excluded. Genome-wide association studies and epigenetic studies will likely offer deeper insights of genetic and environmental factors possibly contributing to the disorder. LEVEL OF EVIDENCE: III Evidence obtained from well-designed cohort or case-control analytic studies. Clinical trial registration PROSPERO registration number: CRD42021246122.

Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT2C receptor in the mouse brain.

BACKGROUND: Serotonin (5-HT) 5-HT2C receptor mRNA editing (at five sites, A-E), implicated in neuropsychiatric disorders, including clinical depression, remains unexplored during alcohol abstinence-often accompanied by depressive symptoms. METHODS: We used deep sequencing to investigate 5-HT2C receptor editing in mice during early ethanol deprivation following prolonged alcohol exposure and mice lacking tryptophan hydroxylase (TPH)2, a key enzyme in central 5-HT production. We also examined Tph2 expression in ethanol-deprived animals using quantitative real-time PCR (qPCR). RESULTS: Cessation from chronic 10% ethanol exposure in a two-bottle choice paradigm enhanced immobility time and decreased latency in the forced swim test (FST), indicating a depression-like phenotype. In the hippocampus, ethanol-deprived "high ethanol-drinking" mice displayed reduced Tph2 expression, elevated 5-HT2C receptor editing efficiency, and decreased frequency of the D mRNA variant, encoding the less-edited INV protein isoform. Tph2-/- mice showed attenuated receptor editing in the hippocampus and elevated frequency of non-edited None and D variants. In the prefrontal cortex, Tph2 deficiency increased receptor mRNA editing at site D and reduced the frequency of AB transcript, predicting a reduction in the corresponding partially edited VNI isoform. CONCLUSIONS: Our findings reveal differential effects of 5-HT depletion and ethanol cessation on 5-HT2C receptor editing. Central 5-HT depletion attenuated editing in the prefrontal cortex and the hippocampus, whereas ethanol deprivation, coinciding with reduced Tph2 expression in the hippocampus, enhanced receptor editing efficiency specifically in this brain region. This study highlights the interplay between 5-HT synthesis, ethanol cessation, and 5-HT2C receptor editing, providing potential mechanism underlying increased ethanol consumption and deprivation.

Association of Serotonin Receptor Gene Polymorphisms with Regulatory and Adaptive Capacities of Medical Students.

Molecular genetic analysis of polymorphic variants of serotonin receptor genes (HTR2C and HTR2A) was performed in 89 healthy medical students and regulatory and adaptive capacities were determined by cardiorespiratory synchronism. The relationship of serotonin receptor gene polymorphisms and the regulatory and adaptive capabilities of the body were revealed. The highly active *G allele and *G/*G genotype of the serotonin receptor HTR2C gene and the heterozygous *A/*G genotype of the serotonin receptor HTR2A gene are associated with "good" regulatory and adaptive capacities. The low-active *C allele of the serotonin receptor HTR2C gene is associated with "low" regulatory and adaptive capacities.

Platelet Serotonin (5-HT) Concentration, Platelet Monoamine Oxidase B (MAO-B) Activity and HTR2A, HTR2C, and MAOB Gene Polymorphisms in Asthma.

The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology.

[Potential PTSD therapeutics targeting 5-HT2C receptors].

Post-traumatic stress disorder (PTSD) is often treated by (1) selective serotonin reuptake inhibitors (SSRIs), (2) exposure therapy, or a combination of the two. However, while all treatments have some efficacy, they are not fully effective. It is necessary to elucidate the causes of inadequate efficacy and to direct the development of effective treatments. First, regarding (1), pharmacological studies have indicated that the 5-HT2C receptor is one of the receptor subtypes that interfere with the therapeutic effects of SSRIs. To compensate for nonselective effects in pharmacological manipulations, we replicated pharmacological results using mice deficient in the 5-HT2C receptor gene. However, since either pharmacological blockade or gene knockout of the 5-HT2C receptor could increase locomotor activity, the locomotor-enhancing effects make the interpretations of results difficult. Therefore, we used the conditioned lick suppression test to evaluate fear response using corrected values that consider the effects of differences in locomotor activity, thereby eliminating this possibility. Next, to address (2), we conducted fear conditioning by simultaneously presenting a composite of sound and environmental stimuli and then re-exposing the subjects to the sound and environmental stimuli separately. We found that the fear response to the sound stimuli quickly decreased, while the fear response to the environmental stimuli did not diminish even after repeated exposure. Thus, exposure therapy may exacerbate PTSD, depending on the method used. In this paper, we will introduce the above results and suggest directions for future PTSD research.

Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior.

Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT2CR) in weight regulation and behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity. Using the 5-HT2CR agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT2CR is involved in the regulation of human appetite, weight and behavior. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.

Constitutive 5-HT2C receptor knock-out facilitates fear extinction through altered activity of a dorsal raphe-bed nucleus of the stria terminalis pathway.

Serotonin 2C receptors (5-HT2CRs) are widely distributed throughout the brain and are strongly implicated in the pathophysiology of anxiety disorders such as post-traumatic stress disorder (PTSD). Although in recent years, a considerable amount of evidence supports 5-HT2CRs facilitating effect on anxiety behavior, the involvement in learned fear responses and fear extinction is rather unexplored. Here, we used a 5-HT2CR knock-out mouse line (2CKO) to gain new insights into the involvement of 5-HT2CRs in the neuronal fear circuitry. Using a cued fear conditioning paradigm, our results revealed that global loss of 5-HT2CRs exclusively accelerates fear extinction, without affecting fear acquisition and fear expression. To investigate the neuronal substrates underlying the extinction enhancing effect, we mapped the immediate-early gene product cFos, a marker for neuronal activity, in the dorsal raphe nucleus (DRN), amygdala and bed nucleus of the stria terminalis (BNST). Surprisingly, besides extinction-associated changes, our results revealed alterations in neuronal activity even under basal home cage conditions in specific subregions of the DRN and the BNST in 2CKO mice. Neuronal activity in the dorsal BNST was shifted in an extinction-supporting direction due to 5-HT2CR knock-out. Finally, the assessment of DRN-BNST connectivity using antero- and retrograde tracing techniques uncovered a discrete serotonergic pathway projecting from the most caudal subregion of the DRN (DRC) to the anterodorsal portion of the BNST (BNSTad). This serotonergic DRC-BNSTad pathway showed increased neuronal activity in 2CKO mice. Thus, our results provide new insights for the fear extinction network by revealing a specific serotonergic DRC-BNSTad pathway underlying a 5-HT2CR-sensitive mechanism with high significance in the treatment of PTSD.

Single nucleotide polymorphisms in 5-HT receptors in the etiology of premature ejaculation.

INTRODUCTION AND OBJECTIVES: Premature ejaculation (PE) is characterized by shorter intravaginal ejaculation latency time than it is acceptable for the patient or partner. It is thought that lifelong PE is a neurobiological dysfunction associated with genetic predisposition and with central serotonin neurotransmission dysfunction in receptors. To contribute to the understanding the genetic etiology of lifelong PE, it was planned to compare the 5-HT2C receptor gene rs3813929, rs518147, 5-HT1A receptor gene rs6295, 5-HT1B receptor gene rs11568817 of lifelong PE patients to healthy controls. MATERIALS AND METHODS: For this purpose, 100 patients with premature ejaculation and 100 healthy controls were included in the study. Blood samples for DNA extraction were obtained. Appropriate procedures were applied to the probes (rs3813929, rs518147, rs6295, rs11568817) suitable for the DNA studied. RESULTS: A statistically significant relationship was found between the rs11568817 polymorphism (p=0.019) in the 5-HT1B receptor gene and the rs518147 polymorphism (p=0.016) in the 5-HT2C receptor gene. Also, no statistically significant relationship was found between 5-HT1A receptor gene rs6295 polymorphism and 5-HT2C receptor gene rs3813929 polymorphism and lifelong PE. CONCLUSIONS: The relationship between rs3813929 and rs11568817 polymorphisms with lifelong PE was confirmed. Repeating the study in larger sample groups could be useful in determining the genetic etiology of PE.

Serotonin 5-HT2C receptor knockout in mice attenuates fear responses in contextual or cued but not compound context-cue fear conditioning.

Previous findings have proposed that drugs targeting 5-HT2C receptors could be promising candidates in the treatment of trauma- and stress-related disorders. However, the reduction of conditioned freezing observed in 5-HT2C receptor knock-out (KO) mice in previous studies could alternatively be accounted for by increased locomotor activity. To neutralize the confound of individual differences in locomotor activity, we measured a ratio of fear responses during versus before the presentation of a conditioned stimulus previously paired with a footshock (as a fear measure) by utilizing a conditioned licking suppression paradigm. We first confirmed that 5-HT2C receptor gene KO attenuated fear responses to distinct types of single conditioned stimuli (context or tone) independently of locomotor activity. We then assessed the effects of 5-HT2C receptor gene KO on compound fear responses by examining mice that were jointly conditioned to a context and a tone and later re-exposed separately to each. We found that separate re-exposure to individual components of a complex fear memory (i.e., context and tone) failed to elicit contextual fear extinction in both 5-HT2C receptor gene KO and wild-type mice, and also abolished differences between genotypes in tone-cued fear extinction. This study delineates a previously overlooked role of 5-HT2C receptors in conditioned fear responses, and invites caution in the future assessment of molecular targets and candidate therapies for the treatment of PTSD.

A zebrafish embryo screen utilizing gastrulation identifies the HTR2C inhibitor pizotifen as a suppressor of EMT-mediated metastasis.

Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in 5 hr. The screen tested 1280 FDA-approved drugs and identified pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacological and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt signaling. In contrast, HTR2C induced epithelial-to-mesenchymal transition through activation of Wnt signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs.

[Correlation of lifelong premature ejaculation with 5-HT system gene polymorphism].

Premature ejaculation is one of the common male sexual dysfunction diseases. Lifelong premature ejaculation (LPE), characterized by an early onset and a long course of disease, has a variety of negative effects on men. The pathogenesis of LPE has not been clarified, but it is believed to be related to the regulation of 5-HT and the 5-HT1a and 5-HT2c receptors from the perspective of the theory of 5-HT system neurotransmitter disorder. Current studies indicate that the 5-HT transporter gene-linked polymorphic region (5-HTTLPR), 5-HT1a receptor gene polymorphism and 5-HT2c receptor gene polymorphism may be associated with the development of and drug effect on LPE. This article reviews the current studies on the development of LPE, effects of medication and 5-HT system gene polymorphism, and discusses the correlation of 5-HT system gene polymorphism with the development of LPE and effects of medication.

Gαi/o-coupled Htr2c in the paraventricular nucleus of the hypothalamus antagonizes the anorectic effect of serotonin agents.

The anorexigenic effect of serotonergic compounds has largely been attributed to activation of serotonin 2C receptors (Htr2cs). Using mouse genetic models in which Htr2c can be selectively deleted or restored (in Htr2c-null mice), we investigate the role of Htr2c in forebrain Sim1 neurons. Unexpectedly, we find that Htr2c acts in these neurons to promote food intake and counteract the anorectic effect of serotonergic appetite suppressants. Furthermore, Htr2c marks a subset of Sim1 neurons in the paraventricular nucleus of the hypothalamus (PVH). Chemogenetic activation of these neurons in adult mice suppresses hunger, whereas their silencing promotes feeding. In support of an orexigenic role of PVH Htr2c, whole-cell patch-clamp experiments demonstrate that activation of Htr2c inhibits PVH neurons. Intriguingly, this inhibition is due to Gαi/o-dependent activation of ATP-sensitive K+ conductance, a mechanism of action not identified previously in the mammalian nervous system.

Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused by long-term fluoxetine exposure.

Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitor (SSRI) antidepressants correlates with body weight (BW) gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here, we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased BW by enhancing food intake in healthy mice at 2 different time points and through 2 distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through 5-hydroxytryptamine receptor 1a (Htr1a). Following a longer treatment period, Flx blunted 5-hydroxytryptamine receptor 2c (Htr2c) expression and signaling, decreased the phosphorylation of cAMP response element-binding protein (CREB) and STAT3, and dampened the production of pro-opiomelanocortin (POMC, the precursor of α-melanocyte stimulating hormone [α-MSH]) in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (Mc4r) by cotreating mice with Flx and lipocalin 2, an anorexigenic hormone signaling through this receptor, normalized feeding and BW. Flx and other SSRIs also inhibited CREB and STAT3 phosphorylation in a human neuronal cell line, suggesting that these noncanonical effects could also occur in individuals treated long term with SSRIs. By defining the molecular basis of long-term SSRI-associated weight gain, we propose a therapeutic strategy to counter this effect.

Monoaminergic Multilocus Genetic Variants Interact with Stressful Life Events in Predicting Changes in Adolescent Anxiety Symptoms: A One-year Longitudinal Study.

Research suggests that genetic variants linked to monoaminergic neurotransmitter function moderate the association between stress and anxiety symptoms, but examining gene-environment (G × E) interactions with individual genes limits power. As one of polygenetic approaches, the multilocus genetic profile score is derived theoretically from combining the effects of multiple candidate genes based on the "biological plausibility". Using this approach, the current study examined the interaction between monoaminergic multilocus genetic variants and stressful life events on the changes in adolescent anxiety symptoms across a one-year timespan. In a Chinese Han adolescent sample which was derived from three vocational high schools (N = 587; T1: Mage = 16.47 ± 1.53 years; 50.8%, girls), the monoaminergic multilocus genetic profile score was calculated using 5-HTR2C rs6318, TPH2 rs4570625 and DRD2 rs1800497 polymorphisms. Results showed that this monoaminergic multilocus genetic profile score interacted with stressful life events in predicting changes in anxiety symptoms. Consistent with the G×E hypothesis of differential susceptibility, adolescents with more monoaminergic plasticity alleles not only suffered more from high levels of stressful life events, which increased the risk for anxiety symptoms, but also benefited more from low levels of stressful life events, which decreased the risk for anxiety symptoms. There were no significant G × E interactions when individual polymorphisms were examined in isolation. The results highlight the importance of examining aggregated influences of multiple genes in G × E interactions underlying the longitudinal development of adolescent anxiety symptoms.

RNA editing of 5-HT2C R impairs insulin secretion of pancreatic beta cells via altered store-operated calcium entry.

Recent studies emphasize the importance of 5-HT2C receptor (5-HT2C R) signaling in the regulation of energy homeostasis. The 5-HT2C R is the only G-protein-coupled receptor known to undergo post-transcriptional adenosine to inosine (A-to-I) editing by adenosine deaminase acting on RNA (ADAR). 5-HT2C R has emerged as an important role in the modulation of pancreatic ß cell functions. This study investigated mechanisms behind the effects of palmitic acid (PA) on insulin secretion in different overexpressed 5-HT2C R edited isoforms in pancreatic MIN6 ß cells. Results showed that the expressions of 5HT2C R and ADAR2 were upregulated in the pancreatic islets of mice fed with high-fat diet (HFD) compared to control mice. PA treatment significantly induced the expressions of 5-HT2C R and ADAR2 in pancreatic MIN6 ß cells. PA treatment significantly induced the editing of 5-HT2C R in pancreatic MIN6 ß cells. There was no significant difference in cell viability between naïve cells and three overexpressed 5-HT2C R edited isoforms in pancreatic MIN6 ß cells. Overexpressed 5-HT2C R edited isoforms showed reduced glucose-stimulated insulin secretion (GSIS) compared with green fluorescent protein (GFP) expressed cells. Moreover, 5-HT2C R edited isoforms displayed reduced endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through inhibition of stromal interaction molecule 1 trafficking under PA treatment. Altogether, our results show that PA-mediated editing of 5-HT2C R modulates GSIS through alteration of ER calcium release and SOCE activation in pancreatic MIN6 ß cells.

Use of an electrophysiological technique for stepwise detection of trace agonist constituents of Hochuekkito in Xenopus oocytes injected with serotonin 2C receptor mRNA.

An electrophysiological bioassay was used to isolate the active compound from Hochuekkito (HET), which the current authors previously described as having potent agonist action against serotonin 2C receptors (5-HT2CR). Synthetic 5-HT2CR mRNA was injected into Xenopus oocytes to specifically express these receptors. Crude extracts and purified products were subjected to an electrophysiological bioassay using the voltage clamp method. HET stimulated a 5-HT2CR-induced current response, whereas Juzentaohoto (JTT), which has anti-depressive action similar to that of HET, did not. Current responses were not observed with an extract mixed with five types of herbal medicines common to HET and JTT but were detected with an extract with the five types of herbal medicines found in HET alone (Hoc5). When the responses to each of the five types of Hoc5 were examined, current responses were noted with Cimicifugae rhizoma (CR) and Citrus unshiu Markovich extracts. Since efficacy and the EC50 value were higher for CR, its constituents were separated using three-dimensional high-performance liquid chromatography and the current response at each of the isolated peaks was examined. One constituent displayed a strong response and was identified as a single substance with a molecular weight of 283.1393 based on liquid chromatography/mass spectrometry. These results will contribute to the isolation of 5-HT2CR-stimulating constituents in HET and the identification of trace constituents with agonist action.

MicroRNA-34a regulates 5-HT2C expression in dorsal raphe and contributes to the anti-depressant-like effect of fluoxetine.

Selective serotonin reuptake inhibitors (SSRIs) are designed to improve mood by raising extracellular serotonin levels through the blockade of the serotonin transporter. However, they exhibit a slow onset of action, suggesting the involvement of adaptive regulatory mechanisms. We hypothesized that the microRNA-34 family facilitates the therapeutic activity of SSRIs. We show that genetic deletion of these microRNAs in mice impairs the response to chronic, but not acute, fluoxetine treatment, with a specific effect on behavioral constructs that are related to depression, rather than anxiety. Moreover, using a pharmacological strategy, we found that an increased expression of the serotonin 2C (5-HT2C) receptor in the dorsal raphe region of the brain contributes to this phenotype. The onset of the therapeutic efficacy of SSRIs is paralleled by the desensitization of the 5-HT2C receptor in the dorsal raphe, and 5-HT2C is a putative target of microRNA-34. In this study, acute and chronic fluoxetine treatment differentially alters the expression of 5-HT2C and microRNA-34a in the dorsal raphe. Moreover, by in vitro luciferase assay, we demonstrated the repressive regulatory activity of microRNA-34a against 5-HT2C mRNA. Specific blockade of this interaction through local infusion of a target site blocker was sufficient to prevent the behavioral effects of chronic fluoxetine. Our results demonstrate a new miR-34a-mediated regulatory mechanism of 5-HT2C expression in the dorsal raphe and implicate it in eliciting the behavioral responses to chronic fluoxetine treatment.

Effect of 5-HT2C receptor gene polymorphism (HTR2C-759C/T) on metabolic adverse effects in Thai psychiatric patients treated with risperidone.

BACKGROUND: The use of Atypical antipsychotics (AAPs) is related to metabolic disturbances, which put psychiatric patients at risk for cardiovascular morbidity and mortality. Evidence is emerging of genetic risk factors. The HTR2C gene is an essential candidate in pharmacogenetic studies of antipsychotic-induced metabolic effects. Nevertheless, there were inconsistent results among studies. OBJECTIVE: To investigate the relationship between -759C/T, functional polymorphism of the HTR2C gene and metabolic adverse effects in Thai psychiatric patients treated with risperidone monotherapy. METHOD: In this cross-sectional study, 108 psychiatric patients treated with risperidone monotherapy for ≥3 months were recruited. Anthropometric measurements and laboratory tests were obtained upon enrollment and history of treatment was reviewed from medical records. Weight gain was defined as an increase ≥7% of baseline weight. Metabolic syndrome was evaluated according to the 2005 International Diabetes Federation (IDF) Asia criteria. The -759C/T, polymorphism was genotyped. The associations between -759C/T polymorphism and metabolic side effects were analyzed. Multiple logistic regression was used for determining potential confounders. RESULTS: Neither weight gain nor metabolic syndrome was significantly associated with -759C/T allelic and genotype variants of HTR2C. However, T allele of -759C/T polymorphism significantly associated with the hypertension. This association was not affected by possible confounding factors such as gender, risperidone dose, duration of treatment and family history of hypertension. CONCLUSION: Our findings suggest that psychiatric patients with T allele of -759C/T polymorphism may be at higher risk for hypertension. Further study with prospective design with larger patient groups are needed.

RNA editing of the 5-HT2C receptor in the central nucleus of the amygdala is involved in resilience behavior.

Post-traumatic-stress-disorder (PTSD) is a stress-related condition that may develop after exposure to a severe trauma-event. One of the core brain areas that is considered to be a key regulatory region of PTSD is the amygdala. Specifically, the central amygdala (CeA) is involved in emotion processing and associative fear learning memory, two main circuits involved in PTSD. Long term dysregulation of trauma-related emotional processing may be caused by neuroadaptations that affect gene expression. The adenosine-(A) to-inosine (I) RNA editing machinery is a post-transcriptional process that converts a genomic encoded A to I and is critical for normal brain function and development. Such editing has the potential to increase the transcriptome diversity, and disruption of this process has been linked to various central nervous system disorders. Here, we employed a unique animal model to examine the possibility that the RNA editing machinery is involved in PTSD. Detection of RNA editing specifically in the CeA revealed changes in the editing pattern of the 5-HT2C serotonin receptor (5-HT2CR) transcript accompanied by dynamic changes in the expression levels of the ADAR family enzymes (ADAR and ADARb1). Deamination by ADAR and ADARb1 enzymes induces conformational changes in the 5-HT2CR that decrease the G-protein-coupling activity, agonist affinity, and thus serotonin signaling. Significantly, a single intra-CeA administration of a 5-HT2CR pharmacological antagonist produced a robust alleviation of PTSD-like behaviors (that was maintained for three weeks) as well as single systemic treatment. This work may suggest the way to a new avenue in the understanding of PTSD regulation.