5-HTT Genotype Research Articles

The winner and loser effect, serotonin transporter genotype, and the display of offensive aggression

Aggressive behaviour results from a complex interplay between genetic and environmental factors. Key modulators of aggression include the serotonergic system on the molecular level and experience in prior aggressive contests as an environmental factor. The aim of this study was to elucidate the effects of fighting experience on the display of offensive aggressive behaviour in adult male mice varying in serotonin transporter (5-HTT) genotype. 5-HTT +/+, 5-HTT +/− and 5-HTT −/− mice were given either a winning or a losing experience on each of three consecutive days and were subsequently observed for their offensive aggressive behaviour as residents against a docile intruder from the C3H strain in a resident–intruder paradigm. The main findings were: There was no significant difference between the amount of offensive aggressive behaviour displayed by the genotypes. Winners showed more engagement with the intruder, attacked him faster and exhibited overall higher aggression scores than losers. There was no significant genotype × social experience interaction: winning and losing had a similar effect on offensive aggressive behaviour in all three 5-HTT genotypes.We conclude that social experience in terms of having been a winner or having been a loser rather than the 5-HTT genotype determines the behaviour towards a docile intruder.

Early adversity and serotonin transporter genotype interact with hippocampal glucocorticoid receptor mRNA expression, corticosterone, and behavior in adult male rats.

Despite its importance for development, relatively little is known about how allelic variation interacts with both pre- and postnatal stress. We examined the interaction between serotonin transporter (5-HTT) genotype, prenatal and postnatal stress on glucocorticoid receptor (GR) mRNA expression, corticosteroid stress responses, and behavior in adult male rats. Prenatal stress involved a daily restraint of pregnant dams from gestational Day 10-21. Postnatal stress involved raising pups after parturition either by their mothers (MR) or in the artificial rearing (AR) paradigm, with or without additional "licking-like" stroking stimulation. 5-HTT genotype, hippocampal GR mRNA level, corticosteroid stress response, and behaviors including startle response, prepulse inhibition (PPI), and locomotor activity were measured in adult male rat offspring. We found significant genotype by prenatal stress interactions for hippocampal GR mRNA levels and for the corticosterone stress responses in adulthood. In contrast, behavioral endpoints tended to be more clearly affected by an interaction between genotype and postnatal environment. These findings suggest that allelic variation in the 5-HTT gene interacts with the prenatal environment to affect the hypothalamic-pituitary-adrenal (HPA) axis physiology and the postnatal environment to affect behavior. These results are the first to indicate a role for genetic variation in the 5-HTT gene in physiology and behavior in the rat.

Serotonin transporter gene polymorphism implicates reduced orbito-frontal cortex in obsessive–compulsive disorder

Although a number of magnetic resonance imaging (MRI) and genetic studies have been performed on obsessive–compulsive disorder (OCD), only limited studies in which genetic and neuroanatomical variables are evaluated concurrently have been performed. Therefore, the aim of our present study is (to understand) better understanding how genetic variation in the promoter region of the 5-HTT gene (5-HTTLPR) is associated with key brain structures in OCD, orbito-frontal cortex (OFC), thalamus and anterior cingulate. 5-HTT genotypes (SS, SL, LL) were determined for 40 patients with OCD and the same number of healthy controls. MRI-derived volumes of the OFC, thalamus, and anterior cingulate were determined by reliable tracing techniques. Volumetric measurements were made with T1-weighted coronal MRI images, with 1.5-mm-thick slices, at 1.5 T, and were done blindly. In comparison with controls, OCD patients demonstrated volumes reduction in OFC, increased volumes of thalamus and total white matter volumes, but no difference in total brain volume, total gray matter volumes and anterior cingulate volumes. No significant difference was observed in allelic frequencies between the patients and controls. The stronger effects of 5-HTT polymorphism on brain morphology in OCD than those in controls were determined in the both OFC and thalamus. On the other hand, for the OCD patients, ANCOVA revealed a significant main effect of genotype for both the OFC and thalamus and a significant genotype-by-side interaction for the OFC, demonstrating that the short variants had a smaller right OFC than the long variants. In conclusion, we found a significant genotype-diagnosis interaction effects on key brain structures, with a stronger effects of 5-HTT polymorphism in OFC and thalamus of OCD patients, whereas no morphological changes related to the polymorphism were found in normal individuals.

Away game or home match: The influence of venue and serotonin transporter genotype on the display of offensive aggression

Aggression can be modulated by both genetic and environmental factors. Here, we analyse how the serotonin transporter (5-HTT) genotype and the environmental situation in which a contest takes place shape the display of offensive aggression. Therefore, male wildtype, heterozygous, and homozygous 5-HTT knockout mice, which are known to differ in inborn levels of anxiety, were confronted three times with a docile opponent in one of three environmental situations: own territory, opponent's territory or neutral area. The main findings were: The frequency of approaching the contestant in order to gather information about him depended significantly on the venue but not on the genotype with lowest frequencies in the opponent's territory. The decision how quickly to attack the opponent was significantly influenced by the 5-HTT genotype but not by the venue: Homozygous 5-HTT knockout mice showed longest latencies. The sum of offensive aggression was significantly influenced by the 5-HTT genotype, the environmental situation, and a genotype by environment interaction. It is likely that, due to their varying genetic predisposition for anxiety, mice of the three genotypes were differentially affected by the aversiveness of the respective venue and the opponent's behaviour, which influenced their decision to display offensive aggression. As a consequence, the amount of aggression shown by homozygous 5-HTT knockout mice was influenced by the venue and the opponent's behaviour, whereas heterozygotes reacted only to the venue. Strikingly, wildtypes behaved always the same way, irrespective of venue and opponent.

Body weight decreases induced by estradiol in female rhesus monkeys are dependent upon social status

Gonadal steroids regulate appetite and thus body weight. In addition, continuous exposure to stressors negatively influences appetite through circuits likely distinct from those of gonadal steroids. The occurrence of adverse metabolic consequences due to chronic exposure to psychosocial stressors is twice as frequent in women as men, implicating a role for ovarian hormones, estradiol (E2) and progesterone (P4), in modulating stress-induced changes in appetite. Using social subordination in female macaques as a model of social stress, the current study tested the hypothesis that subordinate females would lose more weight during E2 treatment and gain less weight during P4 administration than dominant females. Because polymorphisms in the gene encoding the serotonin transporter (5HTT; SCL6A4) are known to alter responsivity to stress, we hypothesized that weight loss during E2 administration would be greatest in females with the short variant (s-variant) allele of 5HTT. Dominant females were significantly heavier than subordinate animals throughout the study, a result consistent with previous accounts of food intake when animals are fed a low-fat, high-fiber diet. Females with the s-variant 5HTT genotype weighed significantly less than l/l animals. Dominant animals lost significantly more weight than subordinate animals during E2 treatment. Administration of P4 blocked the weight-reducing effects of E2 in all females, regardless of social status. These data provide evidence that social subordination modulates the influence of ovarian steroid hormones on body weight in female rhesus monkeys independent of 5HTT genotype. Given the prosocial effects of these steroids, future studies are necessary to determine whether status differences in E2-induced weight loss are due to diminished food intake and or increases in energy expenditure and how the change in energy availability during E2 treatments relates to a female's motivation to interact with conspecifics.

Relationships among 5-HTT genotype, life events and gender in the recognition of facial emotions

Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin-transporter (5-HTTLPR) modulates neural activation during the perceptual processing of emotional facial expressions. Furthermore, behavioral research has shown that attentional bias for negative information is increased in s allele carriers. We examined the interactions among 5-HTTLPR (including SNP rs25531), life events and gender on the detection of facial emotions. We found a main effect of genotype, as well as moderating effects of childhood emotional abuse (CEA) and recent life events (RLE). S homozygous participants recognized negative facial expressions at a lower intensity than the other genotype groups. This effect was more evident in female participants and in participants who had experienced life events. The 5-HTTLPR genotype affects facial emotional perception, a process which is linked to a neurobiological response to threat and vulnerability to emotional disorders.

Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks

Modulation of serotonin transporter (5-HTT) function causes changes in affective behavior, both in humans and rodents. Stressful life events likewise affect emotional behavior. In humans, a low-expressing genetic 5-htt variant, the s allele of the 5-htt linked promoter region, has been associated with increased risk for depression only where there was a history of stressful life events. To investigate this gene by environment interaction in mice, we compared the effects of inescapable shocks on the behavior of wild-type (5-htt+/+), heterozygote (5-htt+/-) and serotonin transporter deficient (5-htt-/-) mice. Inescapable shocks induce behavioral changes including a shock escape deficit, in a subsequent test when escape is possible. Confirming a gene by environment interaction, we found that stress increases escape latencies in a gene-dose dependent manner (5-htt-/->5-htt+/->5-htt +/+), where as there were no differences among the genotypes in the unstressed condition. The vulnerability to increased escape latency could not be accounted for by enhanced fear learning, as 5-htt-/- mice did not show heightened fear conditioning. The interaction of 5-htt genotype and stress appeared to produce a selective behavioral vulnerability, because no interaction of 5-htt genotype and stress was observed in other measures of anxiety and depression-linked behavior, including the open field, novelty suppressed feeding, and forced swim tests. We replicated prior findings that the 5-htt-/- displays heightened anxiety and depression-like behavior at baseline (unstressed condition). In conclusion, our data offer the possibility for future investigation of the neural basis underlying 5-htt genotype-by-stress interaction shown here.

Methylation at 5HTT Mediates the Impact of Child Sex Abuse on Women's Antisocial Behavior: An Examination of the Iowa Adoptee Sample

To examine epigenetic processes linking childhood sex abuse to symptoms of antisocial personality disorder (ASPD) in adulthood and to investigate the possibility that the link between childhood sex abuse and deoxyribonucleic acid methylation at the 5HTT promoter might represent a pathway of long-term impact on symptoms of ASPD. Deoxyribonucleic acid was prepared from lymphoblast cell lines derived from 155 female participants in the latest wave of the Iowa Adoptee Study. Methylation at 71 CpG residues was determined by quantitative mass spectroscopy, and the resulting values were averaged to produce an average CpG ratio for each participant. Simple associations and path analyses within an Mplus framework were examined to characterize the relationships among childhood sex abuse, overall level of methylation among women, and subsequent antisocial behavior in adulthood. Direct effects of biological parent psychopathology and 5HTT genotype were controlled. Replicating prior work, we found that a significant effect of childhood sex abuse on methylation of the 5HTT promoter region emerged for women. In addition, a significant effect of methylation at 5HTT on symptoms of ASPD emerged. Child sex abuse may create long-lasting changes in methylation of the promoter region of 5HTT in women. Furthermore, hypermethylation may be one mechanism linking childhood sex abuse to changes in risk for adult antisocial behavior in women. Better understanding of the methylome may prove critical in understanding the role of childhood environments on long-term psychiatric sequelae.

Developmental Origins of Chronic Physical Aggression and Epigenetics

Over the past half century, two theoretical models strongly inf luenced research on the development of human physical aggression: social learning and disease onset. According to these developmental perspectives, children learn to physically aggress from their environment, and the onset of the disease is triggered by the accumulated exposure to aggressive models in the environment such as family violence, neighborhood violence and media violence. Most of the evidence came from studies of school-aged children and adolescents. Recent longitudinal studies tracing developmental trajectories of physical aggression from early childhood onwards suggest an inversed developmental process. Frequency of physical aggression is at its peak during early childhood and, as they age, children learn socially acceptable behaviors from interactions with their environment [1,2]. A ‘disease’ status is eventually given to children who failed to learn socially acceptable behaviors. The mechanisms that lead to deficits in learning to use socially accepted behaviors appear to be strongly intergenerational, based on complex genetic and environmental contributions. Longitudinal studies initiated during the perinatal period suggest that several early life environmental factors are involved in triggering the mechanisms that lead to deficits in learning to use socially acceptable behaviors for solving problems. These include family characteristics (e.g., poverty and marital conflicts), maternal history of behavior problems (e.g., antisocial behavior, school failure, teen pregnancy and depression), maternal lifestyle during pregnancy (e.g., smoking) and maternal parenting practices (e.g., coercive discipline) [2]. These family and maternal characteristics can be used to identify at-risk pregnant women and offer them adequate support [3]. Genetic studies have also identified sequence differences in critical genes such as MOA, the serotonin transporter and others, which may play a role in the development and maintenance of chronic aggression. However, an increasing number of studies are demonstrating that phenotypic variations in behavior cannot be accounted for by just these genetic differences, and that the phenotype would best be accounted for by an interaction of genetic and environmental factors. Experiments with nonhuman primates that measured the impact of maternal deprivation on the behavior of monkeys with different 5-HTT genotypes illustrated how gene–environment interactions might provide a better explanation for certain behavioral phenotypes such as aggression than genetic differences per se [4,5]. These data suggest that social–environmental triggers are extremely important in defining the final phenotype and they can override a phenotype driven by sequence differences present in critical genes. This primate study is consistent with other studies in humans. Association studies in humans have suggested, for example, that violent behavior in humans was more frequent for males who were maltreated during childhood when they had a genotype conferring low MAO-A activity [6]. However, further studies indicate that these gene–environment statistical interactions may depend on age, severity of maltreatment and situational factors, and may apply to many other types of behavior problems [7–9]. A criticism of the approach to mental health that focuses on statistical interactions between one gene variant and one environmental factor is that it ignores the potential diverse statistical and bio–psycho–social interactions between multiple gene variants and varied environmental conditions that lead to a multitude of endophenotypes and phenotypes related to mental

Association of serotonin transporter promoter (5-HTTLPR) and intron 2 (VNTR-2) polymorphisms with treatment response in temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common epilepsy and about 30% of patients have poorly controlled seizures. Neurobiology underlying responsiveness to medical treatment in TLE patients is unclear and there are currently no biological tests to predict course of the disease. Animal and human studies repeatedly suggested serotonergic dysfunction in subjects with TLE. We investigated association of serotonin transporter (5-HTT) gene polymorphisms with medical treatment response in patients with TLE. We analyzed 5-HTT gene linked polymorphic region (5-HTTLPR) in promoter and variable number of tandem repeats in the second intron of the 5-HTT gene (VNTR-2) in 101 consecutive subjects with TLE. TLE patients with the combination of transcriptionally more efficient genotypes, i.e. 5-HTTLPR L/L and VNTR-2 12/12, had increased seizure refractoriness to antiepileptic medication therapy and shorter periods of seizure freedom, than subjects with other combinations of the 5-HTT genotypes. There were no other clinical or demographic differences among patient groups based on the 5-HTT genotypes. Combination of the 5-HTT genotypes linked with higher 5-HTT gene expression was found to be associated with worse response to optimal drug therapy. Further studies should determine potential role of this 5-HTT genotype polymorphism in epileptogenesis.

Central serotonin transporter levels are associated with stress hormone response and anxiety

Negative mood states are characterized by both stress hormone dysregulation and serotonergic dysfunction, reflected by altered thalamic serotonin transporter (5-HTT) levels. However, so far, no study examined the individual association between cortisol response and cerebral in vivo 5-HTT levels in patients suffering from negative mood states. The objective of this cross-sectional study was to assess the interrelation of cortisol response, thalamic 5-HTT levels, and anxiety in healthy subjects and two previously published samples of patients with unipolar major depression (UMD) and obsessive-compulsive disorder (OCD), controlling for age, gender, 5-HTT genotype, smoking, and seasonality. Regional 5-HTT levels and cortisol response to dexamethasone-corticotropin (Dex-CRH) challenge were assessed in consecutive samples of medication-free patients suffering from UMD (N = 10) and OCD (N = 10), and 20 healthy volunteers. The intervention used was combined Dex-CRH test and [(11)C]DASB positron emission tomography. The main outcome measures were: 5-HTT binding potential (BP(ND)) in a predefined thalamic ROI, cortisol response defined as the maximum cortisol increase in the combined Dex-CRH-test, and state of anxiety from the state-trait-anxiety inventory. Reduced thalamic 5-HTT BP(ND) was associated with increased cortisol response (r = -0.35, p < 0.05; in patients: r = -0.53, p < 0.01) and with increased state anxiety (r = -0.46, p < 0.01), surviving correction for age, gender, 5-HTT genotype, smoking, and seasonality (p < 0.05). The 5-HTT genotype, on the contrary, was not significantly associated with cortisol response (p = 0.19) or negative mood (p = 0.23). The association between stress hormone response, thalamic 5-HTT levels, and anxiety in patients suffering from negative mood states suggests an interaction between two major mechanisms implicated in negative mood states in humans.

5HTT genotype moderates the influence of early institutional deprivation on emotional problems in adolescence: evidence from the English and Romanian Adoptee (ERA) study

A common polymorphism in the serotonin transporter gene (SLC6A4, 5HTT) has been repeatedly shown to moderate the influence of childhood adversity and stressful life events on the development of psychopathology. Using data from the English and Romanian Adoptee Study, a prospective-longitudinal study of individuals (n = 125) exposed to severe early institutional deprivation (ID), we tested whether the effect of ID on adolescent emotional problems is moderated by 5HTT genotype and stressful life events in adolescence. Emotional problems were assessed using questionnaire data (age 11), and on the basis of the CAPA diagnostic interview (age 15). Additionally, the number of stressful life events was measured. There was a significant effect for genotype (p = .003) and a gene x environment interaction (p = .008) that was independent of age at testing. Carriers of the s/l and s/s genotype who experienced severe ID showed the highest emotional problem scores, while l/l homozygotes in the severe ID group showed the lowest overall levels. Furthermore, s/s carriers in the severe ID group who experienced a high number of stressful life events between 11 and 15 years had the largest increases in emotional problem scores, while a low number of stressful life events was associated with the largest decrease (4-way interaction: p = .05). The effects of severe early ID on emotional problems in adolescence are moderated by 5HTT genotype, and influenced by stressful life events in adolescence.

Utilization of 5HTT-gene polymorphism as a prognostic indicator in cancer.

TPS139 Background: Clinical studies show an association between depression and cancer outcomes as decreased desire for life- sustaining treatment and increased mortality. Neurotransmitters are capable of altering immune function whereas immune-derived mediators regulate neuroendocrine and autonomic outflow from the brain. Host cellular defenses against cancer involve immune-mediated mechanisms that can be influenced by neurotransmitter activity. Recent studies on polymorphism of the 5-HTT gene explain why some individuals develop psychological morbidities on exposure to stressful life events while others exposed to the same conditions do not. This offers a screening criterion for identifying patients at risk for psychological morbidity that might be detrimental to their treatment outcome and may be used as a prognostic indicator in which case, starting anticancer treatment of this group of patients with concurrent psychological intervention may improve their treatment outcomes. Aim: To study the role of 5HTT gene as a prognostic indicator in cancer and its utilization for clinical selection of patients for concurrent psychotherapy with anticancer treatment. Methods: A simultaneous two study program. Study I: a longitudinal observational study in which cancer outcomes are compared in two independent cohorts of cancer patients grouped by 5HTT genotype (patients with two long alleles versus those with at least one short allele). In Study II, patients with at least one short allele will be randomized into either an intervention arm receiving anticancer treatment accompanied by supportive psychiatric care program or control arm receiving standard care (anticancer treatment without psychotherapy). Outcomes: Primary outcome is progression-free survival. Secondary outcomes are response to treatment, functional and psychological status of the patient as expressed by Quality of Life measurement using FACT-G questionnaire and the Hospital Anxiety and Depression Scale, and overall survival. No significant financial relationships to disclose.

Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain

Studies in vitro suggest that the expression of the serotonin transporter (5-HTT) is regulated by polymorphic variation in the promoter region of the 5-HTT gene (5-HTTLPR); however, results from human brain imaging studies examining the relation between 5-HTT genotype and 5-HTT radioligand binding in vivo have been inconsistent. This inconsistency could reflect small participant numbers or the use of sub-optimal radiotracer for measuring the 5-HTT. We used positron emission tomography in conjunction with the selective 5-HTT ligand [11C] DASB to examine the availability of the 5-HTT in seven brain regions in 63 healthy European caucasian volunteers who were genotyped for short (S) and long (L) variants (SLC6A4 and rs25531) of the 5-HTTLPR. [11C] DASB binding potential was not influenced by the allelic status of participants whether classified on a biallelic or triallelic basis in any of the regions studied. Our PET findings, in a relatively large sample with a near optimal radiotracer, suggest that 5-HTTLPR polymorphic variation does not affect the availability of 5-HTT to [11C] DASB binding in adult human brain. The reported impact of 5-HTTLPR polymorphic variation on emotional processing and vulnerability to depression are more likely therefore to be expressed through effects exerted during neurodevelopment.

Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice

Epidemiological evidence links exposure to stressful life events with increased risk for mental illness. However, there is significant individual variability in vulnerability to environmental risk factors, and genetic variation is thought to play a major role in determining who will become ill. Several studies have shown, for example, that individuals carrying the S (short) allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) have an increased risk for major depression following exposure to stress in adulthood. Identifying the molecular mechanisms underlying this gene-by-environment risk factor could help our understanding of the individual differences in resilience to stress. Here, we present a mouse model of the 5-HTT-by-stress risk factor. Wild-type and heterozygous 5-HTT knockout male mice were subjected to three weeks of chronic psychosocial stress. The 5-HTT genotype did not affect the physiological consequences of stress as measured by changes in body temperature, body weight gain and plasma corticosterone. However, when compared with wild-type littermates, heterozygous 5-HTT knockout mice experiencing high levels of stressful life events showed significantly depressed locomotor activity and increased social avoidance toward an unfamiliar male in a novel environment. Heterozygous 5-HTT knockout mice exposed to high stress also showed significantly lower levels of serotonin turnover than wild-type littermates, selectively in the frontal cortex, which is a structure that is known to control fear and avoidance responses, and that is implicated in susceptibility to depression. These data may serve as a useful animal model for better understanding the increased vulnerability to stress reported in individuals carrying the 5-HTTLPR S allele, and suggest that social avoidance represents a behavioral endophenotype of the interaction between 5-HTT and stress.

The influence of 5-HTT and COMT genotypes on verbal fluency in ecstasy users

Deficits in verbal fluency associated with ecstasy use have been well established; however, the mechanisms underlying this impairment have yet to be elucidated. In this study we investigated for the first time whether there was a disproportionate impairment in two cognitive subcomponents of verbal fluency: clustering (ability to generate words within the same subcategory) and switching (ability to change the subcategory). We also investigated a possible association between ecstasy use and verbal fluency in subjects genotyped for 5-HTT (5-HTTLPR and 5-HTTVNTR) and COMT (val(108/158)met, rs165599 and rs2097603) polymorphisms, in order to find a potential implication of genetic factors. Ecstasy polydrug users (n = 30) and non-ecstasy users (n = 41) were evaluated in both semantic and phonemic fluency. Results showed that ecstasy users had poorer semantic (but not phonemic) fluency performance than controls. Detailed analysis of clustering and switching performance revealed that this impairment was associated with poorer clustering mechanisms. Clustering was also modulated by the COMT rs165599 polymorphism independently of the group. A specific effect of the 5-HTTLPR polymorphism on switching performance was also found, with ss carriers performing significantly worse than ls and ll carriers, suggesting a serotonin modulation of frontal-executive flexibility. Based on the impaired clustering and switching strategies observed in ecstasy users, it might be proposed that both semantic knowledge and retrieval are impaired in this population. The verbal fluency deficit in ecstasy users may be attributable to a disruption of frontal-striatal circuits directly related with the serotonin function as well as a depletion of lexical-semantic stores mediated by temporal structures.

Drinking Histories in Alcohol-Use-Disordered Youth: Preliminary Findings on Relationships to Platelet Serotonin Transporter Expression With Genotypes of the Serotonin Transporter

The serotonin (5-HT) transporter (5-HTT) is thought to play a key role in the onset of alcohol use, with potential behavioral and biological mechanisms mediated by the level of 5-HT in the synapse and in cerebral spinal fluid. Although 5-HT dysregulation has been related to poor impulse control, the biological mechanism is unknown, although functional control of the serotonergic system has been shown to be regulated in part by differential expression of the 5-HTT. The gene responsible for encoding 5-HTT has a functional polymorphism at the 5'-regulatory promoter region, which results in two forms: long (L) and short (S). The LL genotype is hypothesized to play a key role in the early onset of alcohol use and may be related to poor impulse control. The objective of this pilot study is to determine whether adolescents with a current alcohol-use disorder (AUD) (N = 21) have platelet measures of the 5-HTT functioning that are related to 5-HTT genotype and poor impulse control. Specifically, we wanted to examine the relationships between the following: platelet 5-HTT and 5-HTT genotype; platelet 5-HTT parameters and age at onset, as well as duration of drinking; and 5-HTT genotype and impulse control. Adolescents with current AUD were recruited from the community to participate in a cross-section pilot study. Our main findings showed significantly higher paroxetine binding (density of 5-HTT) in LL genotype versus S carriers (SS or SL genotypes); also, the LL group had a significantly earlier age at onset of drinking and longer duration of drinking, and poorer impulse control. These findings provide partial support for the hypothesis that, among currently drinking adolescents with an AUD, differential expression of 5-HTT may play an important role in the onset of adolescent AUD.

Modulation of behavioural profile and stress response by 5-HTT genotype and social experience in adulthood

Behavioural profiles can be shaped by genotype and environmental factors during early phases of life. The aim of this study was to investigate whether anxiety-like behaviour, exploration and adrenocortical stress responses can be modulated by genotype and social experiences in adulthood. Male mice lacking the serotonin transporter gene which is under scrutiny for anxiety disorders were compared with heterozygous and wildtype controls. Concerning social experiences, the males of all three genotypes were provided with a winner or a loser experience in a resident-intruder paradigm on three consecutive days. Anxiety-like behaviour and exploration were recorded in the dark-light, elevated plus-maze and open-field test. To non-invasively assess adrenocortical activity, corticosterone metabolites were determined from feces. The main findings were: Repeated social experience, irrespective of winning or losing, elevated levels of anxiety-like behaviour and decreased exploration. In losers a distinct effect of genotype occurred, with homozygous knockout males showing more anxiety-like behaviour and less exploration than the other genotypes. In winners no genotype-dependent variation was found. Genotypes did not differ in basal stress hormone secretion. There was, however, a main effect of social experience with higher activation of the stress hormone system in losers than in winners. This effect was strongest in the heterozygous genotype. In conclusion, our data show that anxiety circuits retain their plasticity throughout adulthood and can be shaped by genotype and social experiences during this phase of life. Moreover, responsiveness towards negative life experiences is influenced significantly by the 5-HTT genotype.

1. Clinical: P1.1 Autonomic nervous system and its association with brain function in major depressive disorder

We recently demonstrated elevated brain serotonin turnover in untreated major depressive disorder (MDD), with over a 2-fold increase in turnover being associated with carriage of the s allele of the serotonin transporter (5-HTT) gene. Further, sympathetic nervous activity (SNA) followed a bimodal distribution, with some extraordinarily high values and some marginally lower than in healthy subjects. Therefore, we hypothesized that the bimodal distribution of SNA may be related to the 5-HTT genotype and hence, the degree of SNA in MDD may be dependent upon the level of brain serotonin turnover.

The research of the correlation about the serotonin transporter gene rs9863857 with depression and its clinical features

Objective To detect the correlation about the polymorphism of serotonin transporter（5-HTT） gene rs9863857 with depression and its clinical features in the HaM nationality in China. Methods Observed in a sample of 82 parent/offspring trios where the proband net the American Classification and diagnostic Criteria for Mental Disorders The Forth Revised Edition, criteria for depression using correlation analysis. The polymorphism of 5-HTT gene was detected with PCR methods and SNP typing in all nucleus families. According to HAMD score, the polymorphism of 5-HTT gene was explored the association between the polymorphism and clinical symptoms of depression. Results Rs9863857 allele was associated with depression （ X2 = 4.63, P 〈 0.05 ）, which was the allele A protective factors （ Z = - 2. 142）, G as a risking factor （ Z -- 2. 142 ）. The analysis of symptomatology factors showed that depressive symptoms was significantly associated with 5-HTT genotypes or alleles in that pa- tients with A/A genotype and A allele had a significantly lower depressive scores compared to other genotypes or alleles （F = 3.23, P 〈 0.05）. Conclusion 5-HTT gene rs9863857 may be associated with depression. A/A geno- type and A allele may be the protective factors for depressive symptoms of depression. Key words: Depression ; Serotonin transporter gene; Polymorphism ; Correlation analysis