5-HT2C Receptor Gene Research Articles

Potential PTSD therapeutics targeting 5-HT<sub>2C</sub> 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.

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

Introduction and objectivesPremature 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 methodsFor 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. ResultsA 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. ConclusionsThe 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.

Serotonin 5-HT2C Receptor Cys23Ser Single Nucleotide Polymorphism Associates with Receptor Function and Localization In Vitro

A non-synonymous single nucleotide polymorphism of the human serotonin 5-HT2C receptor (5-HT2CR) gene that converts a cysteine to a serine at amino acid codon 23 (Cys23Ser) appears to impact 5-HT2CR pharmacology at a cellular and systems level. We hypothesized that the Cys23Ser alters 5-HT2CR intracellular signaling via changes in subcellular localization in vitro. Using cell lines stably expressing the wild-type Cys23 or the Ser23 variant, we show that 5-HT evokes intracellular calcium release with decreased potency and peak response in the Ser23 versus the Cys23 cell lines. Biochemical analyses demonstrated lower Ser23 5-HT2CR plasma membrane localization versus the Cys23 5-HT2CR. Subcellular localization studies demonstrated O-linked glycosylation of the Ser23 variant, but not the wild-type Cys23, may be a post-translational mechanism which alters its localization within the Golgi apparatus. Further, both the Cys23 and Ser23 5-HT2CR are present in the recycling pathway with the Ser23 variant having decreased colocalization with the early endosome versus the Cys23 allele. Agonism of the 5-HT2CR causes the Ser23 variant to exit the recycling pathway with no effect on the Cys23 allele. Taken together, the Ser23 variant exhibits a distinct pharmacological and subcellular localization profile versus the wild-type Cys23 allele, which could impact aspects of receptor pharmacology in individuals expressing the Cys23Ser SNP.

Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders

Background: Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. Methods: Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss-Durkee Hostility Inventory and the Beck Depression Inventory. Results: No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. Conclusions: The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed.

Study of the prevalence of 5 HT-2C receptor gene polymorphisms in Egyptian patients with lifelong premature ejaculation.

We investigated the prevalence of 5HT2C receptor gene polymorphisms in Egyptian patients with lifelong premature ejaculation. A total of 350 participants were enrolled in a prospective study. Two hundred and forty-five cases with lifelong premature ejaculation joined this study, in addition to 105 controls. We instructed the partners of the cases to measure the IELT of the first intercourse only using a stopwatch for 1month. Genotyping was carried out at the end of the study. The results showed that the majority of the patients and controls were Cys/Cys. A highly significant statistical association was found between the studied gene polymorphisms and IELT among cases (p-values=.009). The study emphasised the potential role of 5HT2C receptor gene polymorphisms in patients with lifelong premature ejaculation.

Association of Polymorphisms within the Serotonin Receptor Genes 5-HTR1A, 5-HTR1B, 5-HTR2A and 5-HTR2C and Migraine Susceptibility in a Turkish Population.

ObjectiveMigraine, a highly prevelant headache disorder, is regarded as a polygenic multifactorial disease. Serotonin (5-HT) and their respective receptors have been implicated in the patogenesis.MethodsWe investigated the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor gene polymorphisms and their association with migraine in Turkish patients. The rs6295, rs1300060, rs1228814, rs6311, rs6313, rs6314, rs6318, rs3813929 (−759C/T) and rs518147 polymorphisms were analyzed in 135 patients with migraine and 139 healthy subjects, using a BioMark 96.96 dynamic array system.ResultsWe found no difference in the frequency of the analyzed eight out of nine polymorpisms between migraine and control groups. However, a significant association was found between the rs3813929 polymorphism in the promoter region of 5-HTR2C gene and migraine. Also, the allele of rs3813929 was more common in the migraine group.ConclusionThis result suggests that the 5-HTR2C rs3813929 polymorphism can be a genetic risk factor for migraine in a Turkish population.

Nonsynonymous HTR2C polymorphism predicts cortisol response to psychosocial stress II: Evidence from two samples

The 5-HT2C receptor is the primary serotonin receptor located in the corticotrophin releasing hormone (CRH) neurons of the hypothalamus. These neurons initiate the signaling cascade that culminates in cortisol release. Therefore, genetic variation in the 5-HT2C receptor gene (HTR2C) is a prime candidate for affecting cortisol reactivity to stress. Accordingly, we examined the association of a nonsynonymous polymorphism (Cys23Ser; rs6318) in HTR2C with stress reactivity in two Trier Social Stress Tests conducted at separate sites. In both Study 1 (N=128) and Study 2 (N=185), Cys23 homozygous females and hemizygous males had greater cortisol reactivity. There was no relation between this polymorphism and self-reported affective response (Studies 1 and 2) or cardiovascular reactivity (Study 2). Additionally, the short/short genotype of a polymorphism (5-HTTLPR) in the serotonin transporter gene was associated with greater cortisol reactivity in Study 1 as well as in Study 2 (previously reported). The Cys23Ser polymorphism and the 5-HTTLPR were independently associated with cortisol reactivity in both studies. These findings emphasize the important role of genetic variation in the serotonin system on regulating cortisol reactivity to social evaluative stress. Comparison of the present associations with those of prior studies underscores the likely importance of situational and psychological factors in determining the direction and magnitude of the association between genotype and phenotype.

Correlation study on susceptible genes of obsessive compulsive disorder of Han population in northeast China

Objective To explore the relationship between Monoamine oxidase A (MAOA) receptor gene, catechol-O- methyltransferase(COMT)receptor gene, dopamine D3 receptor(DRD3)gene and 5-HT2C receptor gene(5-HT2c) of Han population in northern China and obsessive compulsive disorder. Methods Polymerase chain reaction amplification determination of MAOA-T1460C, COMT-Val158Met, DRD3-Ser9Gly, 5-HT2c-C ys23Ser four loci receptor gene polymorphism in 164 patients with OCD patients including 103 core pedigrees of fragment length polymorphism, and association and linkage disequilibrium(TDT)analysis. Results There was no significant difference of MAOA-T1460C, COMT-Val158Met, DRD3-Ser9Gly, 5-HT2c-Cys23Ser four receptor gene in the patient group and the control group of genotype and allele distribution difference(P>0.05), four receptor gene loci were in accordance with the balance of the H-W, the MAOA-T1460C receptor gene in female patients group and control group, the early group and control group, which has forced thinking and difference of compulsive behavior group and the control group, only the obsessional group and the control group of genotype and allele distribution was statistically significant(P 0.05), and with the house group does not exist between the chain (P=0.0622); DRD3-Ser9Gly receptor gene in the control experiments were no significant difference(P>0.05), and with the family groups there is no chain(P=0.1101). Conclusion MAOA-T1460C receptor gene polymorphism and 5-HT2c-Cys23Ser receptor gene polymorphisms may be the susceptible gene of obsessive compulsive disorder. Key words: Obsessive-compulsive disorder; Gene; Monoamine oxidase A receptor; Catechol-O- methyl transferase receptor; Dopamine D3 receptor; 5-serotonin 2C receptor; Association study

The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation.

It has been postulated that the persistent short intravaginal ejaculation latency time (IELT) of men with lifelong premature ejaculation (LPE) is related to 5-hydroxytryptamine (HT)2C receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2C receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for Cys23Ser 5-HT2C receptor gene polymorphism. Allele frequencies and genotypes of Cys and Ser variants of 5-HT2C receptor gene polymorphism were determined. Association between Cys/Cys and Ser/Ser genotypes and the natural logarithm of the IELT in men with LPE were investigated. As a result, the geometric mean, median and natural mean IELT were 25.2, 27.0, 33.9 s, respectively. Of all men, 20.0%, 10.8%, 23.1% and 41.5% ejaculated within 10, 10–20, 20–30 and 30–60 s after vaginal penetration. Of the 64 men, the Cys/Cys and Ser/Ser genotype frequency for the Cys23Ser polymorphism of the 5-HT2C receptor gene was 81% and 19%, respectively. The geometric mean IELT of the wildtypes (Cys/Cys) is significantly lower (22.6 s; 95% CI 18.3–27.8 s) than in male homozygous mutants (Ser/Ser) (40.4 s; 95% CI 20.3–80.4 s) (P = 0.03). It is concluded that Cys23Ser 5-HT2C receptor gene polymorphism is associated with the IELT in men with LPE. Men with Cys/Cys genotype have shorter IELTs than men with Ser/Ser genotypes.

Preliminary Examination of Olanzapine and Diet Interactions On Metabolism in a Female Macaque.

Clinical data suggest that atypical antipsychotics such as olanzapine (OLZ) induce significant metabolic changes that are serious side effects of their primary use. Since controlled human studies are problematic and rodent data may be poorly translatable, we have initiated development of a macaque model of OLZ-induced metabolic disease. In this preliminary feasibility study, we examined some metabolic effects of OLZ in a female macaque in the context of a standard low-calorie/fat monkey chow diet followed by a high-fat/sugar Western-style diet (WSD). A female Japanese macaque was administered OLZ (1.25 mg/day) for 6 months, with dietary changes at 2-month intervals as follows: OLZ+Restricted chow, OLZ+Unrestricted chow, OLZ+WSD, and placebo+WSD. Weight was assessed weekly. Glucose tolerance tests (GTT) and Dexascans were performed at baseline and every 2 months. Omental (OM) and subcutaneous (SQ) adipose tissue biopsies were obtained at baseline, after OLZ+Unrestricted chow and after OLZ+WSD to evaluate adipocyte size, lipolysis and insulin-stimulated free fatty acid uptake (FFA). A separate trial was conducted on 2 monkeys with 5 days of OLZ- or no-treatment followed by RT-PCR on rostral and medial basal hypothalamus. Weight increased on OLZ+Restricted chow and stabilized on OLZ+Unrestricted chow. OLZ+WSD did not significantly change the weight plateau. Weight declined upon withdrawal of OLZ with continued WSD. Body fat increased from 14% at baseline to 22%, 30%, 28% and 19% at 2, 4, 6 and 8 mo, respectively, indicating that body fat was elevated on OLZ regardless of diet and declined upon OLZ removal. Glucose tolerance and the insulin response during GTT were normal with OLZ+Restricted chow or OLZ+Unrestricted chow. Addition of WSD with OLZ impaired glucose clearance during GTT. Insulin remained in the normal range, but first phase insulin secretion was reduced. After removal of OLZ, but continued WSD, glucose clearance returned to normal, but this was associated with hyperinsulinemia. Adipocyte diameter was increased in OM and SQ fat by OLZ+chow and OLZ+WSD to a similar extent. (p<0.01, 2-way ANOVA). In OM, isoproterenol-stimulated lipolysis occurred at baseline. In both depots, isoproterenol-stimulated lipolysis occurred with OLZ+chow, but it was significantly blunted by addition of WSD (ANOVA p<0.0001; posthoc p<0.05). Insulin increased FFA uptake at baseline. OLZ +chow or OLZ+WSD increased basal FFA uptake and insulin-induced FFA uptake was blunted in both depots (posthoc p<0.05). There was a marked decrease in POMC gene expression, and increased AgRP and NPY expression in the hypothalamus. There was also a clear increase in serotonin (5HT) 2C, melanocortin (MCR4), and Leptin (LepR) receptor gene expression. These data support the hypotheses that OLZ acts on peripheral tissues as well as in the CNS; that changes in hypothalamic gene expression occur very rapidly and precede increased fat accumulation; that adipose tissue exhibits insulin resistance prior to alterations in GTT; that addition of WSD to OLZ precipitates hyperglycemia without an obvious insulin response; and that removal of OLZ and continued WSD resulted in normalized glucose clearance and elevated insulin. These data suggest complex and early responses to OLZ that may be exacerbated by WSD.

Re: gene mapping of serotoninergic system polymorphisms provides insight on pathology and treatment of men with lifelong premature ejaculation

We appreciate and thank Drs Saitz and Serefoglu for their positive and sympathetic words on our article.1 Indeed, our genetic studies have shown that 5-HTTLPR polymorphism, 5-HT1A receptor gene polymorphism and 5-HT2C receptor gene polymorphism are associated with the duration of the intravaginal ejaculatory latency time in men with lifelong premature ejaculation. In line with the remarks,1 we hope that our stopwatch method will be used by other investigators to investigate the role of serotonergic gene polymorphisms on the duration of the intravaginal ejaculatory latency time. But lifelong premature ejaculation is not only characterized by persistent short intravaginal ejaculatory latency times, inability to delay ejaculation and negative personal consequences. Recently, lifelong premature ejaculation is characterized by an acute hypertonic state with facilitated ejaculation (ejaculatio praecox), together with either facilitated erections (erectio praecox) and/or facilitated penile detumescence (detumescentia praecox).2 Future research is required to answer the question whether this combination of symptoms is associated with polymorphisms of various serotonergic gene and other neurotransmitter gene systems.

759C/T Variants of the Serotonin (5-HT2C) Receptor Gene and Weight Gain in Children and Adolescents in Long-Term Risperidone Treatment.

BackgroundGreat inter-individual variability exists in the susceptibility to gain weight during antipsychotic treatment. Thus, we examined whether the −759C/T variants in the promoter region of the 5HT2C receptor gene were differentially associated with weight gain in children and adolescents in long-term risperidone treatment.MethodsMedically healthy 7 to 17 year-olds, treated with risperidone for ≥ six months, were enrolled. Anthropometric measurements, laboratory tests, and treatment history were obtained upon enrollment and from medical records. The effect of the genotype on the trajectory of age-sex-adjusted weight and body mass index (BMI) z scores before and after the onset of risperidone treatment was investigated.ResultsIn 124 subjects (90% males, mean age: 11.8 years) treated with risperidone for a mean of 2.8 years, weight and BMI z scores significantly increased after starting risperidone. This change was similar across the two genotype groups as were changes in several cardiometabolic variables.ConclusionIn contrast to other reports, the T allele failed to confer protection against excessive weight gain or cardiometabolic abnormalities in this group of children and adolescents chronically treated with risperidone.

Pharmacogenetic Aspects of Antipsychotic Drug-induced Weight Gain - A Critical Review

Treatment with several antipsychotic drugs can result in weight gain, which may lead to further morbidity such as type 2 diabetes and cardiovascular disease via the development of metabolic syndrome. These important and problematic metabolic consequences of antipsychotic drug treatment probably reflect a pharmacological disruption of the mechanisms involved in control of food intake and body weight. The extent of weight gain following antipsychotic drug treatment shows substantial variability between individuals, due in part to genetic factors. Common functional polymorphisms in many candidate genes implicated in the control of body weight and various aspects of energy and lipid metabolism have been investigated for association with weight gain in subjects receiving antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia. Perhaps the strongest and most replicated findings are the associations with promoter polymorphisms in the 5-HT2C receptor and leptin genes, although many other possible genetic risk factors, including polymorphisms in the fat mass and obesity associated (FTO) gene and genes for the alpha2A adrenoceptor and melanocortin4 receptor, have been reported. Genome-wide association studies (GWAS) have also addressed antipsychotic-induced weight gain and other indicators of metabolic disturbances. However there is as yet little consistency between these studies or between GWAS and classical candidate gene approaches. Identifying common genetic factors associated with drug-induced weight gain and its metabolic consequences may provide opportunities for personalized medicine in the predictive assessment of metabolic risk as well as indicating underlying physiological mechanisms.

Sa1396 Potential New Treatment to Alleviate Stress-Induced Anorexia

Background/Aim: Exposure to a novel environment causes anxiety and depressed reactions and is well-known to provoke various gastrointestinal symptoms like anorexia. However, the mechanism underlying this behavior is unclear and there has not been approached to that the anorexia. The present study aimed to clarify the role of corticotrophin-releasing factor (CRF) and serotonin (5-HT) receptors in mice exposed to novel environment stress and attempted to discover a new treatment method for improving gastrointestinal tract dysfunction caused by stress. Methods: Male C57BL/6J mice (6-week-old) were housed in groups (n = 5/cage) for one week and acclimated to their environment, following which they were fasted for 24 h. Next, they were moved to isolated cages to induce novel environment stress. We analyzed the expression of stressand appetite-related genes in the hypothalamus and gastric corpus after the exposure to the stress. In addition, we administered a CRF receptor antagonist and various 5-HT receptor antagonists to study their effects on the decreased food intake. Results: Mice exposed to novel environment stress demonstrated a significant increase in the expression of CRF, CRF1 receptor, urocortin, and urocortin 2 genes in the hypothalamus compared with the mice housed in groups. The expression of urocortin 3 and CRF2 receptor genes was unaffected. Moreover, the mice exposed to stress showed an increase or tended to have an increase in the hypothalamic expression of 5HT1a, 5-HT1b, and 5-HT2c receptor genes, and gastric expression of 5-HT2b receptor genes. Administration of the receptor antagonists for CRF1 (NBI27914), 5-HT1b (SB224289), 5-HT2b (SB215505 and SB204741), and 5-HT2c (SB242084) significantly inhibited the decreased food intake caused by novel environment stress. Furthermore, rikkunshito, which has an antagonist action on CRF1, 5-HT2c, and 5-HT2b receptors, clearly inhibited the decrease in food intake after exposure to the stress. Conclusion: The decrease in feeding behavior exposed to novel environment stress is primarily controlled by the signaling of the CRF1, 5-HT1b, 5-HT2b, and 5-HT2c receptors. Drugs that block the signal transmission of these receptors are expected to be appropriate for the potential treatment for anorexia caused by stress.

Cloning and expression of a zebrafish 5-HT2C receptor gene

The 5-HT2C receptor is one of 14 different serotonin (5-HT) receptors that control neural function and behavior. Here, we present the entire sequence of a zebrafish 5-HT2C receptor cDNA including the 3′ untranslated region and the previously unknown 5′ untranslated region. The cloned 5-HT2C receptor gene is located on chromosome 7, is approximately 202kbp long, and contains six exons. The coding region of the gene is 1557bp long and flanked by a 504bp 5′ UTR and a 1474bp 3′ UTR. The deduced protein sequence of 518 amino acids aligns with orthologs of other vertebrates and is 54% identical to the human and mouse 5-HT2C receptor protein sequences. The region of the cDNA that encodes the 2nd cytoplasmic loop of the protein shows a 66% identity with vertebrate orthologs and clearly identifies the gene as a 5-HT2C receptor gene. Coupling sites for beta-arrestin and calmodulin are conserved in zebrafish. In-situ hybridization shows that the receptor is expressed in the brain and spinal cord including areas such as the olfactory bulb, the dorsal thalamus, the posterior tuberculum, the hypothalamus and the medulla oblongata. Reverse Transcriptase-PCR experiments indicate that the receptor gene can also be active in other tissues such as skin, ovaries, and axial muscle of adult zebrafish. Expression of the 5-HT2C receptor during ontogeny was found as early as 2.5hpf. Five edited adenines in the region of the human, rat and mouse mRNA that encodes the 2nd cytoplasmic loop are conserved in the zebrafish transcript. However, RNA editing was not detected in the zebrafish. The results characterize the zebrafish 5-HT2C receptor gene and gene expression pattern for the first time. The similarities to mammalian 5-HT2C receptor genes suggest the use of zebrafish for the study of 5-HT2C receptor function in behavior, development and drug discovery.

Role of 5-HT2C receptor gene variants in antipsychotic-induced weight gain

Antipsychotic-induced weight gain is a serious side effect of antipsychotic medication that can lead to increased morbidity, mortality, and non-compliance in patients. Numerous single nucleotide polymorphisms have been studied for association with antipsychotic-induced weight gain in an attempt to find genetic predictors of this side effect. An ability to predict this side effect could lead to personalized treatment plans for predisposed individuals, which could significantly decrease the prevalence and severity of weight gain. Variations in the serotonin receptor 2c gene (HTR2C) have emerged as promising candidates for prediction of antipsychotic-induced weight gain. Specifically, the well-studied −759C/T promoter polymorphism has been associated with weight gain in diverse populations, although some studies have reported no association. This discrepancy is likely due to heterogeneity in study design with respect to ethnicity, treatment duration, and other variables. Notably, the association between HTR2C and antipsychotic-induced weight gain appears strongest in short-term studies on patients with limited or no previous antipsychotic treatment. Other, less extensively studied promoter polymorphisms (−697C/G, −997G/A, and −1165A/G) have also emerged as potential predictors of antipsychotic-induced weight gain. Conversely, the well-studied intronic polymorphism Cys23Ser does not appear to be associated. With further research on both HTR2C and other genetic and environmental predictors of antipsychotic-induced weight gain, a predictive test could one day be created to screen patients and provide preventative or alternative treatment for those who are predisposed to this serious side effect.

Association between HTR2C polymorphisms and metabolic syndrome in patients with schizophrenia treated with atypical antipsychotics

Background Previous research indicates that common single-nucleotide polymorphisms (SNPs) in the serotonin 5-HT2C receptor gene ( HTR2C) are associated with metabolic syndrome (MetS) related to antipsychotic treatment. This study analyzes a large sample of patients with schizophrenia treated with atypical antipsychotics to determine whether variation in the HTR2C is associated with MetS. Methods Six tag SNPs, capturing all common genetic variations in the HTR2C gene in the Han population, were genotyped in 456 Chinese schizophrenic inpatients treated with atypical antipsychotics (clozapine: 171, olanzapine: 91, and risperidone: 194). Results Single-marker based analysis shows that of the six HTR2C SNPs, the rs498177 SNP showed a significant association with MetS in female patients, and the C allele was associated with an increased risk of MetS (for genotype TT/TC/CC: MetS vs. non-MetS = 50%/27%/23% vs. 69%/28%/3%, and for allele T/C: MetS vs. non-MetS = 63%/37% vs. 83%/17%, p = 0.0007). Haplotype analysis shows that the A–C type of rs521018–rs498177 in the HTR2C gene significantly decreased the risk of MetS (corrected p = 0.0108) in female patients. Conclusions The results of this study support the role of HTR2C genetic variants in susceptibility to MetS in patients treated with atypical antipsychotics. However, this association is gender-dependent.

Functional Characteristics of Serotonin 5-HT2A and 5-HT2C Receptors in the Brain and the Expression of the 5-HT2A and 5-HT2C Receptor Genes in Aggressive and Non-Aggressive Rats

The functional activity of serotonin 5-HT(2A) and 5-HT(2C) receptors and the expression of the genes encoding them were studied in Norway rats bred for 60 generations for the presence and absence of high levels of stress-evoked aggression to humans. There were no significant differences in the levels of 5-HT(2A) receptor mRNA in the midbrain, frontal cortex, and hippocampus and the extents of head twitching evoked by the 5-HT(2A) agonist DOI in rats with and without genetically determined high levels of aggression. Administration of the selective 5-HT(2C) agonist MK-212 weakened reflex startle in response to an acoustic signal (the acoustic startle response) in non-aggressive animals but had no significant effects on the response in aggressive animals. Increases in the level of 5-HT(2C) receptor mRNA were seen in the frontal cortex and hippocampus in non-aggressive rats as compared with aggressive animals. Increases in the expression of the 5-HT(2C) receptor gene and the functional state of 5-HT(2C) receptors were seen in the brains of non-aggressive rats, without any changes in the 5-HT(2A) receptor mRNA level or receptor sensitivity; this is evidence for the involvement of 5-HT(2C) receptors in the mechanisms inhibiting fear-evoked aggressive behavior.

P03-367 - Sertindole in the treatment of tardive dyskinesia in a patient with genetically abnormal dopamine D3 receptors

ObjectiveTardive dyskinesia (TD) is a difficult-to-treat condition. The presence of genetically abnormal D2 and D3 dopamine receptors is associated with increased like hood of TD in patients with schizophrenia. We present a case of a patient with TD and genetically abnormal dopamine D3 receptors with chronic schizophrenia, treated successfully by sertindole.MethodsA 47-year old male with history of chronic chizophrenia was assessed clinically by means of SCID IV, PANSS and AIMS, and was genotyped for DRD3ser-gly and 5-HT2C receptor gene polymorphisms.ResultsThe patient suffered from an exacerbation of positive and negative psychotic symptoms and TD. He was also found to be DRD3ser-gly heterozygous. He had been suffering from TD for two years, developed by chronic administration of haloperidole and resperidone. A trial with quetiapine failed to ameliorate his TD and psychotic symptoms, whereas a successive trial with clozapine induced life-treating hematological side effects. After the administration of sertindole (16mh/day) his psychotic and TD symptoms remitted (PANSS:29, AIMS : 0). One year later his level of improvement was wholly preserved.ConclusionSertindole might be beneficial for the treatment of TD in patients who have genetically abnormal D3 receptors.