Maintenance of Chronic Fatigue Syndrome (CFS) in Young CFS Patients Is Associated with the 5-HTTLPR and SNP rs25531 A > G Genotype

Earlier studies have shown that genetic variability in the SLC6A4 gene encoding the serotonin transporter (5-HTT) may be important for the re-uptake of serotonin (5-HT) in the central nervous system. In the present study we investigated how the 5-HTT genotype i.e. the short (S) versus long (L) 5-HTTLPR allele and the SNP rs25531 A > G affect the physical and psychosocial functioning in patients with chronic fatigue syndrome (CFS). All 120 patients were recruited from The Department of Paediatrics at Oslo University Hospital, Norway, a national referral center for young CFS patients (12–18 years). Main outcomes were number of steps per day obtained by an accelerometer and disability scored by the Functional Disability Inventory (FDI). Patients with the 5-HTT SS or SL_G genotype had a significantly lower number of steps per day than patients with the 5-HTT L_AL_G, SL_A or L_AL_A genotype. Patients with the 5-HTT SS or SL_G genotype also had a significantly higher FDI score than patients with the 5-HTT L_AL_G, SL_A or L_AL_A genotype. Thus, CFS patients with the 5-HTT SS or SL_G genotype had worse 30 weeks outcome than CFS patients with the 5-HTT L_AL_G, SL_A or L_AL_A genotype. The present study suggests that the 5-HTT genotype may be a factor that contributes to maintenance of CFS.     

Polymorphism of the Serotonin 2A Receptor Gene (5HTR2A) and Personality Traits

The individual variation of temperament features (such as anxiety, neuroticism, harm avoidance) is determined, among other things, by allele polymorphism of genes involved in serotonin metabolism and has earlier been associated with the insertion/deletion polymorphism of the serotonin transporter gene. Polymorphic alleles of the serotonin 2A receptor gene (5HTR2A) were tested for association with personality traits assessed in several tests. The T102C and A1438G polymorphisms were associated with variation in emotionality, activity, and sociability, which are integral characteristics of temperament. With each polymorphism, differences were significant only between heterozygotes and homozygotes. Carriers of T102C genotype A1/A2 displayed a lower level of anxiety-related traits, a higher score on the Hypomania scale, and a lower score on the Social Introversion scale and were assumed to have higher activity and sociability. Carriers of A1438G genotype A/G differed from homozygotes G/G in having a lower level of social introversion and a lower score on the No Close Friends scale, which testified to higher sociability of heterozygotes. Thus, the polymorphic alleles of 5HTR2A proved to be associated with personality traits in mentally healthy people.     

Genetic variation of the 5-HT2A receptor gene and bipolar affective disorder

Abnormalities of the serotonergic system have classically been associated with the origin of affective disorders through the biochemical action of therapeutic agents and their role in affective and perceptual states. In the present study, we hypothesized that genetic variation in the 5-hydroxytryptamine (serotonin) type 2A (5-HT_2A ) receptor gene (HTR2A) might have an effect on the aetiology of bipolar affective disorder. Four different polymorphisms in the HTR2A gene were studied in 88 patients with bipolar affective disorder and 113 healthy controls, all of Spanish origin. No significant association was observed between any of the four polymorphisms at the HTR2A locus, whether tested individually or as haplotypes, and bipolar affective disorder. The lack of association suggests that HTR2A is not a major risk factor for bipolar affective disorder. Received: 4 December 1996 / Accepted: 15 April 1997     

5‐HTTLPR genotype potentiates the effects of war zone stressors on the emergence of PTSD,depressive and anxiety symptoms in soldiers deployed to iraq

Exposure to war zone stressors is common, yet only a minority of soldiers experience clinically meaningful disturbance in psychological function. Identification of biomarkers that predict vulnerability to war zone stressors is critical for developing more effective treatment and prevention strategies not only in soldiers but also in civilians who are exposed to trauma. We investigated the role of the serotonin transporter linked polymorphic region (5‐HTTLPR) genotype in predicting the emergence of post‐traumatic stress disorder (PTSD), depressive and anxiety symptoms as a function of war zone stressors. A prospective cohort of 133 U.S. Army soldiers with no prior history of deployment to a war zone, who were scheduled to deploy to Iraq, was recruited. Multilevel regression models were used to investigate associations between 5‐HTTLPR genotype, level of war zone stressors, and reported symptoms of PTSD, depression and anxiety while deployed to Iraq. Level of war zone stressors was associated with symptoms of PTSD, depression and anxiety. Consistent with its effects on stress responsiveness, 5‐HTTLPR genotype moderated the relationship between level of war zone stressors and symptoms of emotional disturbance. Specifically, soldiers carrying one or two low functioning alleles (S or L_G) reported heightened symptoms of PTSD, depression and anxiety in response to increased levels of exposure to war zone stressors, relative to soldiers homozygous for the high functioning allele (L_A). These data suggest that 5‐HTTLPR genotype moderates individual sensitivity to war zone stressors and the expression of emotional disturbance including PTSD symptoms. Replication of this association along with identification of other genetic moderators of risk can inform the development of biomarkers that can predict relative resilience vs. vulnerability to stress.     

Insular and Hippocampal Gray Matter Volume Reductions in Patients with Major Depressive Disorder

Background

Major depressive disorder is a serious psychiatric illness with a highly variable and heterogeneous clinical course. Due to the lack of consistent data from previous studies, the study of morphometric changes in major depressive disorder is still a major point of research requiring additional studies. The aim of the study presented here was to characterize and quantify regional gray matter abnormalities in a large sample of clinically well-characterized patients with major depressive disorder.

Methods

For this study one-hundred thirty two patients with major depressive disorder and 132 age- and gender-matched healthy control participants were included, 35 with their first episode and 97 with recurrent depression. To analyse gray matter abnormalities, voxel-based morphometry (VBM8) was employed on T1 weighted MRI data. We performed whole-brain analyses as well as a region-of-interest approach on the hippocampal formation, anterior cingulate cortex and amygdala, correlating the number of depressive episodes.

Results

Compared to healthy control persons, patients showed a strong gray-matter reduction in the right anterior insula. In addition, region-of-interest analyses revealed significant gray-matter reductions in the hippocampal formation. The observed alterations were more severe in patients with recurrent depressive episodes than in patients with a first episode. The number of depressive episodes was negatively correlated with gray-matter volume in the right hippocampus and right amygdala.

Conclusions

The anterior insula gray matter structure appears to be strongly affected in major depressive disorder and might play an important role in the neurobiology of depression. The hippocampal and amygdala volume loss cumulating with the number of episodes might be explained either by repeated neurotoxic stress or alternatively by higher relapse rates in patients showing hippocampal atrophy.     

Design, synthesis, and pharmacological evaluation of azetedine and pyrrolidine derivatives as dual norepinephrine reuptake inhibitors and 5-HT(1A) partial agonists

Compounds with combined norepinephrine reuptake inhibitor (NRI) and serotonin 1A (5-HT_1A) partial agonist pharmacology may offer a new therapeutic approach for treating symptoms of neuropsychiatric disorders including ADHD, depression, and anxiety. Herein we describe the design and optimization of novel chemical matter that exhibits favorable dual NRI and 5-HT_1A partial agonist activity. Lead compounds in this series were found to be devoid of activity at the dopamine transporter and were shown to be brain penetrant with high receptor occupancy.     

Involvement of 5-HT<Subscript>2A</Subscript> receptors in genetic mechanisms of autoregulation of brain 5-HT system

The brain serotonin (5-HT) system has been implicated in the pathophysiology of anxiety, depression, drug addiction, and schizophrenia. 5-HT_2A receptors are involved in the mechanisms of stressinduced psychopathology and impulsive behavior. In this work, we investigated the role of 5-HT_2A receptors in the autoregulation of the brain 5-HT system. Chronic treatment with DOI, a 5-HT_2A receptor agonist (1.0 mg/kg, i.p./14 days), produced a considerable decrease in the number of 5-HT_2A receptor-mediated head twitches in AKR/J mice, indicating the desensitization of 5-HT_2A receptors. Chronic DOI treatment did not affect the expression of the 5-HT_2A receptor gene in the midbrain, hippocampus and frontal cortex. At the same time, an increase in the expression of the gene encoding a key enzyme of 5-HT synthesis, tryptophan hydroxylase-2 (TPH-2), accompanied with an increase in TPH-2 activity and 5-HT levels, and decreased expression of the serotonin transporter (5-HTT) gene were observed in the midbrain of DOI-treated mice. These results provide new evidence of receptor-gene cross-talk in the brain 5-HT system and implication 5-HT_2A receptors in the autoregulation of the brain 5-HT system.     

Genetic determinants of aggression and impulsivity in humans

Human aggression/impulsivity-related traits have a complex background that is greatly influenced by genetic and non-genetic factors. The relationship between aggression and anxiety is regulated by highly conserved brain regions including amygdala, which controls neural circuits triggering defensive, aggressive, or avoidant behavioral models. The dysfunction of neural circuits responsible for emotional control was shown to represent an etiological factor of violent behavior. In addition to the amygdala, these circuits also involve the anterior cingulated cortex and regions of the prefrontal cortex. Excessive reactivity in the amygdala coupled with inadequate prefrontal regulation serves to increase the likelihood of aggressive behavior. Developmental alterations in prefrontal-subcortical circuitry as well as neuromodulatory and hormonal abnormality appear to play a role. Imbalance in testosterone/serotonin and testosterone/cortisol ratios (e.g., increased testosterone levels and reduced cortisol levels) increases the propensity toward aggression because of reduced activation of the neural circuitry of impulse control and self-regulation. Serotonin facilitates prefrontal inhibition, and thus insufficient serotonergic activity can enhance aggression. Genetic predisposition to aggression appears to be deeply affected by the polymorphic genetic variants of the serotoninergic system that influences serotonin levels in the central and peripheral nervous system, biological effects of this hormone, and rate of serotonin production, synaptic release and degradation. Among these variants, functional polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) may be of particular importance due to the relationship between these polymorphic variants and anatomical changes in the limbic system of aggressive people. Furthermore, functional variants of MAOA and 5-HTT are capable of mediating the influence of environmental factors on aggression-related traits. In this review, we consider genetic determinants of human aggression, with special emphasis on genes involved in serotonin and dopamine metabolism and function.     

Culture–gene coevolution of individualism–collectivism and the serotonin transporter gene

Culture–gene coevolutionary theory posits that cultural values have evolved, are adaptive and influence the social and physical environments under which genetic selection operates. Here, we examined the association between cultural values of individualism–collectivism and allelic frequency of the serotonin transporter functional polymorphism (5-HTTLPR) as well as the role this culture–gene association may play in explaining global variability in prevalence of pathogens and affective disorders. We found evidence that collectivistic cultures were significantly more likely to comprise individuals carrying the short (S) allele of the 5-HTTLPR across 29 nations. Results further show that historical pathogen prevalence predicts cultural variability in individualism–collectivism owing to genetic selection of the S allele. Additionally, cultural values and frequency of S allele carriers negatively predict global prevalence of anxiety and mood disorder. Finally, mediation analyses further indicate that increased frequency of S allele carriers predicted decreased anxiety and mood disorder prevalence owing to increased collectivistic cultural values. Taken together, our findings suggest culture–gene coevolution between allelic frequency of 5-HTTLPR and cultural values of individualism–collectivism and support the notion that cultural values buffer genetically susceptible populations from increased prevalence of affective disorders. Implications of the current findings for understanding culture–gene coevolution of human brain and behaviour as well as how this coevolutionary process may contribute to global variation in pathogen prevalence and epidemiology of affective disorders, such as anxiety and depression, are discussed.     

Predictors for self‐directed aggression in Italian prisoners include externalizing behaviors,childhood trauma and the serotonin transporter gene polymorphism 5‐HTTLPR

Suicidal behavior and self‐mutilation can be regarded as the expression of self‐directed aggression and both are common in prison populations. We investigated the influence of externalizing behaviors, depressive symptoms, childhood trauma, 5‐HTTLPR variants on self‐directed aggression (N = 145) in a group of 702 male Italian prisoners. Participants were comprehensively evaluated, including for psychiatric disorders, impulsive traits, lifetime aggressive behavior [Brown‐Goodwin Lifetime History of Aggression (BGHA)], hostility, violent behavior during incarceration, depressive symptomatology [Hamilton Depression Rating Scale (HDRS)], childhood trauma [Childhood Trauma Questionnaire (CTQ)]. Logistic regression analysis showed false discovery rate corrected independent main effects of externalizing behaviors: BGHA (P = 0.001), violent behavior in jail (P = 0.007), extraversion (P = 0.015); HDRS (P = 0.0004), Axis I disorders (P = 0.015), CTQ (P = 0.004) and 5‐HTTLPR genotype (P = 0.02). Carriers of 5‐HTTLPR high (L_AL_A), intermediate (L_AL_G, SL_A) activity variants were more likely to have exhibited self‐directed aggression relative to the low activity (L_GL_G, SL_G, SS) variant: high/low: odds ratio (OR) = 2.3, 95% confidence interval (CI) 1.27–4.68, P = 0.007; intermediate/low: OR = 1.96, 95% CI 1.09–3.68, P = 0.025. The CTQ main effect was driven by physical abuse. There was no interactive effect of 5‐HTTLPR and CTQ. Secondary logistic regression analyses in (1) all suicide attempters (N = 88) and (2) all self‐mutilators (N = 104), compared with controls showed that in both groups, childhood trauma (P = 0.008–0.01), depression (P = 0.0004–0.001) were strong predictors. BGHA, violent behavior in jail predicted self‐mutilation (P = 0.002) but not suicide attempts (P = 0.1). This study was able to distinguish differing influences on self‐directed aggression between groups of closely related predictor variables within the externalizing behavioral domain. 5‐HTTLPR had an independent, variant dosage effect.     

Hypersensitivity in Borderline Personality Disorder during Mindreading

Background

One of the core symptoms of borderline personality disorder (BPD) is the instability in interpersonal relationships. This might be related to existent differences in mindreading between BPD patients and healthy individuals.

Methods

We examined the behavioural and neurophysiological (fMRI) responses of BPD patients and healthy controls (HC) during performance of the ‘Reading the Mind in the Eyes’ test (RMET).

Results

Mental state discrimination was significantly better and faster for affective eye gazes in BPD patients than in HC. At the neurophysiological level, this was manifested in a stronger activation of the amygdala and greater activity of the medial frontal gyrus, the left temporal pole and the middle temporal gyrus during affective eye gazes. In contrast, HC subjects showed a greater activation in the insula and the superior temporal gyri.

Conclusion

These findings indicate that BPD patients are highly vigilant to social stimuli, maybe because they resonate intuitively with mental states of others.     

Evaluation of anti-depressant effects of phthalazinone-based triple-acting small molecules against 5-HT2A, 5-HT2C,and the serotonin transporter

Development of highly effective, safe, and fast-acting anti-depressants is urgently required for the treatment of major depressive disorder. It has been suggested that targeting 5-HT_2A and 5-HT_2C in addition to inhibition of serotonin reuptake may be beneficial in generating anti-depressant agents with better pharmacology and less adverse effects. We have developed phthalazinone-based compounds that potently bind to 5-HT_2A, 5-HT_2C, and the serotonin transporter. The representative compounds 11j and 11l displayed strong binding affinities against these targets, and showed favorable toxicity profiles as determined by hERG binding and CYP inhibition assays. Furthermore, these compounds presented promising anti-depressant effects comparable to fluoxetine and also synergistic effects with fluoxetine in forced swimming test, which implicates these compounds can be developed to help the treatment of major depressive disorder.     

A strong association of axillary osmidrosis with the wet earwax type determined by genotyping of the ABCC11 gene

Background

Lactase non-persistence is a condition where lactase activity is decreased in the intestinal wall after weaning. In European derived populations a single nucleotide polymorphism (SNP) C/T_-13910 residing 13.9 kb upstream from the lactase gene has been shown to define lactase activity, and several other single nucleotide polymorphisms (G/C_-14010 T/G_-13915, C/G_-13907 and T/C_-13913) in the same region have been identified in African and Middle East populations.

Results

The T_-13910 allele most common in European populations was present in 21.8% mixed ancestry (N = 62) individuals and it was absent in the Xhosa (N = 109) and Ghana (N = 196) subjects. Five other substitutions were also found in the region covering the previously reported variants in African and Middle East populations. These included the G/C_-14010 variant common in Kenyan and Tanzanian populations, which was present in 12.8% of Xhosa population and in 8.1% of mixed ancestry subjects. Two novel substitutions (C/T_-14091 and A/C_-14176) and one previously reported substitution G/A_-13937 (rs4988234) were less common and present only in the Xhosa population. One novel substitution G/A_-14107 was present in the Xhosa and Ghanaian populations. None of the other previously reported variants were identified.

Conclusion

Identification of the G/C_-14010 variant in the Xhosa population, further confirms their genetic relatedness to other nomadic populations members that belong to the Bantu linguistic group in Tanzania and Kenya. Further studies are needed to confirm the possible relationship of the novel substitutions to the lactase persistence trait.     

Regulating Prefrontal Cortex Activation: An Emerging Role for the 5-HT2A Serotonin Receptor in the Modulation of Emotion-Based Actions?

The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)_2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT_2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions.     

Polymorphism of the Serotonin System Genes in Some Finno-Ugric Populations

Polymorphic sites in the genes encoding monoamine oxidase A (MAO-A), serotonin transporter (hSERT) and 5-HT_2A receptor were typed in Khant and Komi ethnic groups with the purpose of revealing possible inerpopulation differences in genotype and allele frequencies. No statistically significant differences in the hSERT and 5-HT_2A gene frequencies were detected. At the same time, the populations examined had statistically significantly different MAO-A genotype and allele frequencies. These results obtained indicate the prevalence of the site gain alleles of theEcoRV and Fnu4HI RFLP loci at the MAO-A gene in Komis and the of the corresponding site loss alleles in Khants.     

Dissociation of neural representation of intensity and affective valuation in human gustation

We used a 2 x 2 factorial design to dissociate regions responding to taste intensity and taste affective valence. Two intensities each of a pleasant and unpleasant taste were presented to subjects during event-related fMRI scanning. The cerebellum, pons, middle insula, and amygdala responded to intensity irrespective of valence. In contrast, valence-specific responses were observed in anterior insula/operculum extending into the orbitofrontal cortex (OFC). The right caudolateral OFC responded preferentially to pleasant compared to unpleasant taste, irrespective of intensity, and the left dorsal anterior insula/operculuar region responded preferentially to unpleasant compared to pleasant tastes equated for intensity. Responses best characterized as an interaction between intensity and pleasantness were also observed in several limbic regions. These findings demonstrate a functional segregation within the human gustatory system. They also show that amygdala activity may be driven by stimulus intensity irrespective of valence, casting doubt upon the notion that the amygdala responds preferentially to negative stimuli.     

Association of several polymorphic loci of serotoninergic genes with unipolar depression

Serotoninergic system is one of the major brain neurotransmitter systems that is involved in the development of depressive spectrum disorders. Regulatory genes of this system are the principle candidate genes predisposing to unipolar depression. Using PCR-RFLP analysis, we have conducted a study of polymorphic loci of several genes of this system: C1019G of serotonin receptor 1A gene, (HTR1A); A-1438G of serotonin receptor 2A gene, (HTR2A); G861C of serotonin receptor 1B gene, (HTR1B); Stin2VNTR and 5-HTTLPR of serotonin transporter gene (SLC6A4) in patients with unipolar depression from Tatar and Russian population. The results of the study suggest that genotype 10/10 of the SLC6A4 gene as well as genotype G/G and allele G of the HTR2A gene can predispose to increased risk of unipolar depression development in ethnic Russians. In contrast, genotype 12/10 of the SLC6A4 gene is a marker of low risk of the disease in both groups.     

Alpha-ethyltryptamines as dual dopamine–serotonin releasers

The dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporter releasing activity and serotonin-2A (5-HT_2A) receptor agonist activity of a series of substituted tryptamines are reported. Three compounds, 7b, (+)-7d and 7f, were found to be potent dual DA/5-HT releasers and were >10-fold less potent as NE releasers. Additionally, these compounds had different activity profiles at the 5-HT_2A receptor. The unique combination of dual DA/5-HT releasing activity and 5-HT_2A receptor activity suggests that these compounds could represent a new class of neurotransmitter releasers with therapeutic potential.