Emotion appraisal and the tryptophan hydroxylase 2 (TPH2) gene

The purpose of this study was to investigate the association between the G-703T polymorphism of the tryptophan hydroxylase 2 (TPH2) gene (rs4570625) and emotion appraisal in healthy volunteers. Participants were asked to recall a situation characterized by a strong emotion and to rate appraisal processes: novelty/expectation, pleasantness, goal-conduciveness, fairness, responsibility/causation, coping ability, morality, and relationship to self-concept. Results revealed that in the case of fear- and sadness-related autobiographical memories, participants with the GG genotype achieved higher appraisal scores for goal-conduciveness and lower scores for coping ability compared with participants with the TT genotype. In the case of joy, no differences were observed across genotypes. These results suggest that the TPH2 polymorphism affects appraisal processes in the case of negative emotions.     

Emotional behavior and expression patterns of tyrosine hydroxylase and tryptophan hydroxylase in senescence-accelerated mouse (SAM) P6 mice

Senescence-accelerated prone mouse 6 (SAMP6) is a model for senile osteoporosis. It was recently reported that SAMP6 has a memory deficit in the water maze test. Because emotion and cognition are thought to interact, in the present study to examine emotional behavior in SAMP6, we employed a battery of tasks (open field, elevated plus maze, light-dark exploration, marble-burying behavior, tail suspension), using three age groups (1, 4, and 8 months of age) of SAMP6 mice and age-matched control SAMR1 (senescence-accelerated resistant mouse 1) mice. All three age groups of SAMP6 showed higher activity than SAMR1 in the open field test and reduced anxiety as measured in terms of time spent on the open arms in the elevated plus maze, time spent in the light box in the light-dark exploration, and time spent in marble-burying behavior in the marble-burying test. All three age groups of SAMP6 showed reduced immobility time compared with SAMR1 in the tail suspension test. Western blot analyses showed increased expression levels of tyrosine hydroxylase phosphorylated at serine-40 in striatum and nucleus accumbens and of tryptophan hydroxylase phosphorylated at serine-58 in brain stem of 1-month-old SAMP6. These results suggest that one possible reason for the alterations of motor activity and emotional behavior of SAMP6, at least after 1 month of age, is increased dopamine and serotonin levels.     

Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity

The aim of the present study was to test a possible effect of the A218C tryptophan hydroxylase (TPH) gene variant on the antidepressant activity of fluvoxamine in a sample of major and bipolar depressives, with or without psychotic features. Two hundred and seventeen inpatients were treated with fluvoxamine 300 mg and either placebo or pindolol in a double blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. TPH allelic variants were determined in each subject by using a PCR-based technique. No significant finding was observed in the overall sample as well as in the pindolol group, while TPH*A/A was associated with a slower response to fluvoxamine treatment in subjects not taking pindolol (P = 0.001). This effect was independent from the previously reported influence of 5-HTTLPR polymorphism. If confirmed, these results may shed further light on the genetically determined component of the response to pharmacological treatments, thus helping the clinician to individualize each patient's therapy according to their genetic pattern.     

Investigation of tryptophan hydroxylase 2 (TPH2) in schizophrenia and in the response to antipsychotics

Serotonergic transmission is considered relevant in the pathophysiology and the treatment of schizophrenia. Tryptophan hydroxylase (TPH) is the rate limiting enzyme in the biosynthesis of serotonin. While the TPH1 gene has been found to be associated with schizophrenia, studies focusing on TPH2 variants did not yield conclusive results for schizophrenia or the response to antipsychotic medication. We analyzed eleven TPH2 SNPs in two case–control samples consisting of 4453 individuals in total. Six SNPs were selected because of their potential functional relevance (rs4570625, rs11178997, rs11178998, rs7954758, rs7305115, and, rs4290270) and were supported by another 5 tagging SNPs selected based on HapMap LD information. In the discovery sample (1476 individuals), we observed a significant association with schizophrenia for rs10784941 (p = 0.009, OR minor G-allele 0.82 [0.71–0.95]) and rs4565946 (p = 0.011, OR minor T-allele 0.83 [0.71–0.96]). Association was also observed with a common rs4570625–rs4565946 haplotype (OR G-C haplotype 1.20 [1.02–1.40]; p = 0.0046). Single-marker associations could not be replicated in the replication sample consisting of 2977 individuals, but there was a strong trend regarding the rs4570625–rs4565946 G-C haplotype (OR 1.10 [0.98–1.24]; p(one-sided test) = 0.054). In smaller sub-samples, the rare rs4570625–rs4565946 T-T haplotype was associated with reduced processing speed (n = 193, p = 0.004) and sensorimotor gating (n = 68, p = 0.006) of schizophrenia patients. TPH2 variants and the rs4570625–rs4565946 G-C haplotype did not influence the beneficial response to antipsychotic drugs (n = 210) after four weeks of treatment administering the Positive and Negative Syndrome Scale of Schizophrenia (PANSS). We also investigated the association of the SNPs to treatment response, but did not get significant results. In sum, our results argue for only a minor role of TPH2 in schizophrenia.     

Promoter polymorphism of second tryptophan hydroxylase isoform (TPH2) in schizophrenia and suicidality

Allele and haplotype frequencies of a promoter polymorphism in the gene encoding tryptophan hydroxylase (TPH2) did not differ in 83 suicidal schizophrenic patients compared with 170 non-suicidal schizophrenic patients. These findings suggest that these 5' marker haplotypes in the TPH2 gene do not influence suicidal behavior in schizophrenia.     

Genetic variants in the tryptophan hydroxylase 2 gene (TPH2) and depression during and after pregnancy

BackgroundA number of studies indicate that altered serotonergic transmission may be a risk factor for depression in the peripartum period. The aim of this study was to investigate whether genetic polymorphisms in the TPH2 gene, the gene product of which is the rate-limiting enzyme in the biosynthesis of serotonin in the central nervous system, are associated with depressive symptoms in pregnancy and the postpartum period.MethodsIn a cohort of 361 Caucasians, the severity of depression was assessed prospectively during pregnancy (third trimester) and the postpartum period (2–3 days and 6–8 months) using the Edinburgh Postnatal Depression Scale (EPDS). Tagging single nucleotide polymorphisms (SNPs) in TPH2 and SNPs that are known to be of functional relevance were genotyped. For each haplotype block or SNP, a multifactorial linear mixed model was performed to analyse the EPDS values over time.ResultsThe haplotype block in the promoter region of TPH2 showed significant associations with depression values during pregnancy and 6–8 months afterwards. Additionally, a haplotype block in intron 8 had an influence on depression values during pregnancy, but not after birth. There was a significant interaction between time and haplotypes and the severity of depression. The effect of TPH2 haplotypes on EPDS values was strongest during pregnancy and 6 months after birth, with a low depression rating in the first few days after delivery for all women.ConclusionsIn this cohort, TPH2 haplotypes known to be of functional relevance were found to be associated with different EPDS values during and after pregnancy. These haplotypes were associated with depressive symptoms both before and after delivery and were thus not specific for postpartum-onset depression. This underlines the relevance of these functional polymorphisms for depression in general and the importance of longitudinal assessments in research on postpartum depression.     

Allelic variants of the tryptophan hydroxylase (A218C) and serotonin 1B receptor (A-161T) and personality traits

Human personality traits have a considerable hereditary component, and central serotonergic activity is implicated in the personality factors of the Tridimensional Personality Questionnaire (TPQ). Our population-based association study tested the hypothesis that the tryptophan hydroxylase (TPH) A218C and serotonin 1B receptor (HTR1B) A-161T polymorphisms were associated with TPQ personality trait scores in a sample population of 209 young healthy Chinese. No significant differences were demonstrated comparing scores of subjects bearing different TPH or HTR1B genotypes; however, a trend for difference in the novelty seeking score comparing TPH genotype groups was determined for the male population. Our negative findings suggest that the TPH A218C and HTR1B polymorphisms do not play major roles in the determination of TPQ personality traits.     

Circadian tryptophan hydroxylase levels and serotonin release in the suprachiasmatic nucleus of the rat

Serotonin (5-HT) plays an important role in the regulation of the time-keeping system in rodents. In the present study, we have investigated the interplay between the rhythms of 5-HT synthesis and release in the suprachiasmatic nuclei (SCN) of the rat. The quantitative distribution of tryptophan hydroxylase (TpH) protein was used as an index of 5-HT synthesis, in perikarya and terminals areas. In the raphe medianus, the maximal levels of TpH was reached in the early daytime period, followed by a decrease before the onset of darkness. Conversely, in the axon terminals of the SCN the highest levels of TpH were found before the onset of the dark-period. Furthermore, TpH amount in SCN displays variations depending on the anatomical area of the SCN. Extracellular 5-HT peaked at the beginning of the night, as evidenced by in vivo microdialysis in the SCN. The 5-HT metabolite, 5-HIAA, presented a similar pattern, but the acrophase occurred in the middle of the dark period. These results suggest that TpH is transported from the soma to the nerve terminals in which 5-HT is synthesized during daytime. This would fill the intracellular stores of 5-HT to provide for its nocturnal release.     

Ipsilateral alterations in tryptophan hydroxylase activity in rat brain after hypothalamic 5,7-di-hydroxytryptamine lesion

The in vivo relationship between the amounts of tryptophan hydroxylase (TPH) protein and its intrinsic synthetic activity, measured by quantifying the amounts of α-[³H]methyl-5-hydroxytryptamine (α-[³H]M5-HT), is reported in cell body and terminal areas of intact and disturbed serotonergic neurons following a unilateral 5,7-dihydroxytryptamine (5,7-DHT) lesion of the dorsolateral hypothalamus. Five days after the lesion, the relationships between TPH and its synthetic product 5-HT were evaluated on adjacent brain sections in serotonergic cells bodies of the dorsal raphe nucleus (DRN) and nerve fibres of the medial forebrain bundle (MFB). On the side contralateral to the lesion, TPH and α-[³H]M5-HT levels in the intact hemi-DRN exhibited a caudo-rostral distribution and were positively and significantly correlated (P 0.001); the calculated TPH-specific activity was 0.76 nCi of α-[³H]M5-HT formed per U TPH. In the MFB, quantitative measurements of TPH and α-[³H]M5-HT showed no correlation between enzyme and product and no specific activity for TPH could be determined. On the side ipsilateral to the lesion, the density of TPH-immunoreactive fibers was drastically decreased in the dorsolateral hypothalamus where a significant reduction in TPH content (45.5% of control side,P < 0.001) was found. In the overall ipsilateral hemi-DRN, TPH and α-[³H]M5-HT levels, their correlation as well as TPH-specific activity were unaltered by the lesion but a significant increase in α-[³H]M5-HT and TPH contents was observed in the lateral wings of the DRN. The lesion also induced a significant increase in α-[³H]M5-HT and TPH levels (136% and 93.8%,P < 0.001, respectively) in the ipsilateral MFB, which resulted in a positive and significant correlation between these two markers and yielded a TPH-specific activity of 1.0 nCi of α-[³H]M5-HT formed per U TPH. TPH topological area was also significantly increased in the lateral aspect of the ipsilateral MFB 5 days post lesion. These results show that 5-HT synthesis in the intact DRN is proportional to and dependent on TPH activity while in the MFB, 5-HT accumulation appears unrelated to TPH content which is most likely in an inactive enzymatic form. Moreover, the data show that a local disruption of serotonergic terminals in the dorsolateral hypothalamus does not affect 5-HT synthesis in the overall ipsilateral DRN neurons but results in local activation of TPH within the serotonergic projection neurons and the ipsilateral MFB, as evidenced by active de novo synthesis of 5-HT. Altogether the results point to circumscribed activation of compensatory mechanisms in 5-HT synthesis after selective destruction of serotonergic terminals.     

Lipopolysaccharide administration produces time-dependent and region-specific alterations in tryptophan and tyrosine hydroxylase activities in rat brain

Summary. The present study examined the effect of systemic administration of lipopolysaccharide (LPS; 100 and 250 μg/kg, i.p.) on tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities in frontal cortex, striatum and midbrain of the rat. Enzyme activities were determined by measuring accumulation of the transient intermediates 5-hydroxytrptophan (5-HTP) and L-dihydroxyphenylalanine (L-DOPA) following in vivo administration of the decarboxylase inhibitor, NSD 1015. TPH activity was increased 2 hours after administration of LPS (100 and 250 μg/kg) in both frontal cortex and midbrain, and a secondary increase was seen in the midbrain 12 hours after challenge. LPS provoked an increase in TH activity in the midbrain only, and this was evident for up to 24 hours after LPS administration. Thus in addition to previous studies demonstrating that LPS increases in vivo NA, DA and 5-HT release, this study shows that LPS increases the activity of the rate-limiting enzymes responsible for their synthesis. Received May 4, 2000; accepted June 16, 2000     

A case-control association study of serotonin 1A receptor gene and tryptophan hydroxylase 2 gene in attention deficit hyperactivity disorder

Serotonergic system-related genes are likely to be involved in mechanisms underlying attention deficit hyperactivity disorder (ADHD). We investigated the association of serotonin the 1A receptor C-1019G single nucleotide polymorphism (HTR1A C-1019G SNP) and tryptophan hydroxylase 2 gene –703G/T (TPH2 –703G/T) SNP with ADHD.     

色氨酸羟化酶1与5-羟色胺2A受体基因对抑郁症患者额叶情绪加工的影响

目的:分析色氨酸羟化酶1 (TPH1)基因A218C多态性、5-羟色胺(5-HT)2A受体基因(HTR2A) T102C多态性对抑郁症患者额叶情绪识别功能异常的影响. 方法:28例抑郁症患者(患者组)及34名性别、年龄、受教育年限相匹配的健康对照(对照组)均进行情绪识别任务态下功能磁共振扫描,并以聚合酶链式反应-限制...     

p-Hydroxyamphetamine causes prepulse inhibition disruption in mice: contribution of serotonin neurotransmission

p-Hydroxyamphetamine (p-OHA) has been shown to have a number of pharmacological actions, including causing abnormal behaviors such as increased locomotor activity and head-twitch response in rodents. We have recently reported that intracerebroventricular (i.c.v.) administration of p-OHA dose-dependently induces prepulse inhibition (PPI) disruption in mice, which is attenuated by pretreatment with haloperidol, clozapine or several dopaminergic agents. Haloperidol and clozapine have affinities for serotonergic (especially 5-HT_2A) receptors. To investigate the involvement of the central serotonergic systems in p-OHA-induced PPI disruption, herein we tested several serotonergic agents to determine their effects on p-OHA-induced PPI disruption. p-OHA-induced PPI disruption was attenuated by pretreatment with 5,7-dihydroxytryptamine (5,7-DHT, a neurotoxin which targets serotonin-containing neurons) and p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor). p-OHA-induced PPI disruption was also attenuated by pretreatment with ketanserin (a 5-HT_2A/2C receptor antagonist) and MDL100,907 (a selective 5-HT_2A receptor antagonist). These data suggest that p-OHA-induced PPI disruption may involve increased serotonin release into the synaptic cleft, which then interacts with the post-synaptic 5-HT_2A receptor.     

Tryptophan hydroxylase(2) gene polymorphisms predict brain serotonin synthesis in the orbitofrontal cortex in humans

Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[((11))C]methyl-L-tryptophan ((11)C-AMT) trapping (K*) as a proxy. Recently, we reported evidence of lower normalized (11)C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH(2)). In all, 46 healthy controls had PET (11)C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH(2) gene and its 5' upstream region. Several TPH(2) SNPs were associated with lower normalized blood-to-brain clearance of (11)C-AMT in the OBFC. Dose-effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5' upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC.     

Association between tryptophan hydroxylase gene polymorphism (A218C) and schizophrenic disorders

The human tryptophan hydroxylase (TPH) gene, the rate-limiting enzyme in serotonin biosynthesis, was localized on human chromosome 11p14-p15.3. Variation within intron 7 of the TPH gene was found to influence serotonin metabolism in the brain. To explore the possible role of TPH in the pathogenesis of schizophrenic disorders, we genotyped the TPH A218C polymorphism in 196 schizophrenic patients and 251 controls. The results demonstrated that genotype distribution was significantly different between schizophrenic patients and control subjects (P=0.002). No association was found between TPH genotypes and suicidal history in schizophrenic patients (P=0.239). The positive finding in this study suggests that the TPH 218A allele is a risk factor for schizophrenic disorders or is in linkage disequilibrium with the putative schizophrenia susceptibility locus in Han Chinese population.     

A detailed association analysis between the tryptophan hydroxylase 2 (TPH2) gene and autism spectrum disorders in a Japanese population

We conducted a detailed association analysis between the tryptophan hydroxylase 2 gene and autism spectrum disorders in a Japanese population using 19 markers, including tagging single nucleotide polymorphisms and a novel missense variation, p.R225Q, identified through exon resequencing. However, we failed to obtain supportive evidence for an association.     

Gene-environment interaction in psychiatric disorders as indicated by season of birth variations in tryptophan hydroxylase (TPH), serotonin transporter (5-HTTLPR) and dopamine receptor (DRD4) gene polymorphisms

Genetic and environmental factors, as well as their interactions, are likely to be involved in psychiatric disorders. Considerable progress has been made in association and linkage studies with various candidate genes, at times with conflicting or ambiguous results. An environmental factor that has persistently shown associations with several psychiatric and neurological disorders is the season of birth. If it is the interaction of a specific gene allele with a specific season of birth that constitutes an increased (or decreased) risk for a disorder, then the individuals with this disorder are likely to have a season of birth variation in this gene allele. We investigated the variations in TPH, 5-HTTLPR and DRD4 gene polymorphisms according to seasonality of birth in 954 patients with unipolar affective disorder, bipolar affective disorder, and schizophrenia, respectively, and in 395 controls. We first analyzed season of birth variations in the gene alleles with one cycle or two cycles per year, and then compared specified birth seasons with each other. We found season of birth variations in these gene alleles that were different for different psychiatric disorders. Significant differences between cases and controls could be obtained when restricting the analysis within certain birth seasons but not within others. Our results thus suggest an interaction between the seasons of birth and the expression of the candidate genes, and that season of birth is a confounding variable when investigating the role of the candidate genes in susceptibility to psychiatric disorders.