CiteULike: Group: Glimcher_Lab - with tag serotonin

Differences in Cortical Serotonergic Innervation among Humans, Chimpanzees, and Macaque Monkeys: A Comparative Study

Mary Raghanti — 2007-11-16T13:58:07-00:00

Cereb. Cortex (22 June 2007), bhm089.

In this study, we assess the possibility that the evolution of human intellectual capacities was supported by changes in the supply of serotonin to the frontal cortex. To this end, quantitative comparative analyses were performed among humans, chimpanzees, and macaques. Immunohistochemical methods were used to visualize serotonin transporter-immunoreactive (SERT-ir) axons within the cerebral cortex. Areas 9 and 32 were chosen for evaluation due to their roles in working memory and theory of mind, respectively. Primary motor cortex was also evaluated because it is not associated with higher cognitive functions. The findings revealed that humans do not display a quantitative increase in serotonin innervation. However, the results indicated region- and layer-specific differences among species in serotonergic innervation pattern. Compared with macaques, humans and chimpanzees together displayed a greater density of SERT-ir axons relative to neuron density in layers V/VI. This change was detected in cortical areas 9 and 32, but not in primary motor cortex. Further, morphological specializations, coils of axons, were observed in humans and chimpanzees that were absent in macaques. These features may represent a greater capacity for cortical plasticity exclusive to hominoids. Taken together, these results indicate a significant reorganization of cortical serotonergic transmission in humans and chimpanzees. 10.1093/cercor/bhm089

Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia

Tomas Furmark — 2007-06-15T15:53:40-00:00

Neuroscience Letters, Vol. 362, No. 3. (27 May 2004), pp. 189-192.

A functional polymorphism in the promoter region of the human serotonin transporter (5-HTT) gene has been related to negative affect and amygdala activity. We studied amygdala activation during social anxiety provocation in relation to affective ratings and 5-HTT genetic variation. [H2 15O]positron emission tomography was used to estimate amygdala blood flow during private and public speaking (baseline and anxiety conditions) in 17 patients with social phobia. Genotyping identified patients with long and short alleles in the promoter region of the 5-HTT. Individuals with one or two copies of the short allele exhibited significantly increased levels of anxiety-related traits, state anxiety, and enhanced right amygdala responding to anxiety provocation, compared with subjects homozygous for the long allele. Thus, 5-HTT genetic variation was associated with symptom severity and amygdala excitability in social phobia.

Serotonin transporter genetic variation and the response of the human amygdala.

AR Hariri — 2006-08-09T09:39:05-00:00

Science, Vol. 297, No. 5580. (19 July 2002), pp. 400-403.

A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.

The molecular genetic architecture of human personality: beyond self-report questionnaires

RP Ebstein — 2006-03-14T11:12:19-00:00

Molecular Psychiatry, Vol. aop, No. current.

Effects of 5-HT on Memory and the Hippocampus: Model and Data

Martijn Meeter — 2005-08-31T16:22:42-00:00

Neuropsychopharmacology, Vol. aop, No. current. (31 August 2005)

Stop signal response inhibition is not modulated by tryptophan depletion or the serotonin transporter polymorphism in healthy volunteers: implications for the 5-HT theory of impulsivity.

L Clark — 2007-05-18T17:06:21-00:00

Psychopharmacology (Berl), Vol. 182, No. 4. (November 2005), pp. 570-578.

RATIONALE: Reduced serotonin neurotransmission is implicated in disorders of impulse control, but the involvement of serotonin in inhibitory processes in healthy human subjects remains unclear. OBJECTIVES: To investigate the effects of an acute manipulation of serotonin and genotype at a functional polymorphism in a gene coding for the serotonin transporter (5-HTT) on an established measure of response inhibition. METHODS: Serotonin function was reduced by the acute tryptophan depletion (ATD) procedure in a double-blind, crossover design in 42 healthy subjects. The Stop Signal Task (SST) was administered 5-7 h after drink administration. The influences of 5-HTT polymorphism, gender and trait impulsivity were investigated. RESULTS: ATD was associated with significant depletion of plasma tryptophan levels but did not increase the stop signal reaction time in comparison to the balanced (placebo) amino acid mixture. Subjects possessing the short allele of the 5-HTT polymorphism were not more impulsive on the SST than subjects homozygous for the long allele under placebo conditions and were not disproportionately sensitive to the effects of ATD. There was no effect of gender or trait impulsivity on ATD-induced change. CONCLUSIONS: We find no support for the involvement of brain serotonin neurotransmission in this form of inhibitory control in healthy human subjects.

Acute tryptophan depletion reduces activation in the right hippocampus during encoding in an episodic memory task.

FM van der Veen — 2007-05-18T17:04:06-00:00

Neuroimage, Vol. 31, No. 3. (1 July 2006), pp. 1188-1196.

Acute tryptophan depletion (ATD), a well-recognized method to lower central serotonin levels, was used to examine the effects of lower central serotonin levels on memory function in healthy males. Functional Magnetic Resonance Imaging (fMRI) was used to examine changes in brain activation during the encoding and the retrieval phase of a visual verbal episodic memory task. ATD led to more positively rated words in the encoding phase and to poorer recognition of these positively rated words in the retrieval phase. Furthermore, encoding was accompanied by enhanced brain activation in occipital, middle and superior frontal, anterior and posterior cingulate and striatal areas. Retrieval attempt was accompanied by enhanced activation in the cuneus, inferior occipital gyrus and inferior and middle frontal areas. Retrieval success was accompanied by activation in an extensive network including frontal, parietal, temporal, cingulate, striatal and cerebellar areas. In the encoding phase ATD attenuated activation in the right hippocampus and ATD did not affect brain activity in the retrieval phase. These results show that serotonin is important in long term memory processes, and that serotonin acts on the encoding phase and not on the retrieval phase.

Serotonin Transporter Polymorphism Mediates Vulnerability to Loss of Incentive Motivation Following Acute Tryptophan Depletion

Jonathan Roiser — 2006-07-21T19:07:22-00:00

Neuropsychopharmacology, Vol. aop, No. current.

The computational neurobiology of learning and reward

Nathaniel Daw — 2007-04-19T16:11:56-00:00

Current Opinion in Neurobiology, Vol. 16, No. 2. (April 2006), pp. 199-204.

Following the suggestion that midbrain dopaminergic neurons encode a signal, known as a `reward prediction error', used by artificial intelligence algorithms for learning to choose advantageous actions, the study of the neural substrates for reward-based learning has been strongly influenced by computational theories. In recent work, such theories have been increasingly integrated into experimental design and analysis. Such hybrid approaches have offered detailed new insights into the function of a number of brain areas, especially the cortex and basal ganglia. In part this is because these approaches enable the study of neural correlates of subjective factors (such as a participant's beliefs about the reward to be received for performing some action) that the computational theories purport to quantify.

Opponent interactions between serotonin and dopamine

Nathaniel Daw — 2006-11-09T17:17:53-00:00

Neural Networks, Vol. 15, No. 4-6. ( 2002), pp. 603-616.

Anatomical and pharmacological evidence suggests that the dorsal raphe serotonin system and the ventral tegmental and substantia nigra dopamine system may act as mutual opponents. In the light of the temporal difference model of the involvement of the dopamine system in reward learning, we consider three aspects of motivational opponency involving dopamine and serotonin. We suggest that a tonic serotonergic signal reports the long-run average reward rate as part of an average-case reinforcement learning model; that a tonic dopaminergic signal reports the long-run average punishment rate in a similar context; and finally speculate that a phasic serotonin signal might report an ongoing prediction error for future punishment.

Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation.

Lise Gutknecht — 2007-04-09T20:34:43-00:00

Int J Neuropsychopharmacol (19 December 2006), pp. 1-12.

Variation in the tryptophan hydroxylase-2 gene (TPH2) coding for the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain modulates responses of limbic circuits to emotional stimuli and has been linked to a spectrum of clinical populations characterized by emotional dysregulation. Here, we tested a set of common single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of TPH2 for association with personality traits and with risk for personality disorders in two cohorts comprising of 336 healthy individuals and 420 patients with personality disorders. Personality dimensions were assessed by the Tridimensional Personality Questionnaire (TPQ) and the revised NEO Personality Inventory (NEO-PI-R). Personality disorders were diagnosed with the Structured Clinical Interview of DSM-IV and were allocated to clusters A, B, and C. Individual SNP and haplotype analyses revealed significant differences in genotype frequencies between controls and cluster B as well as cluster C patients, respectively. In both patient groups, we observed overrepresentation of T allele carriers of a functional polymorphism in the upstream regulatory region of TPH2 (SNP G-703T, rs4570625) which was previously shown to bias responsiveness of the amygdala, a structure critically involved in emotionality. Furthermore, significant effects of TPH2 variants on anxiety-related traits defined primarily by the TPQ Harm Avoidance were found in healthy individuals. The results link potentially functional TPH2 variants to personality traits related to emotional instability as well as to cluster B and cluster C personality disorders. These findings implicate alterations of 5-HT synthesis in emotion regulation and confirm TPH2 as a susceptibility and/or modifier gene of affective spectrum disorders.

Gene–gene effects on central processing of aversive stimuli

MN Smolka — 2007-01-09T19:32:40-00:00

Molecular Psychiatry, Vol. aop, No. current.

Association of a serotonin receptor 2A gene polymorphism with cognitive functions in patients with schizophrenia.

Alp Uçok — 2007-04-09T20:24:48-00:00

Am J Med Genet B Neuropsychiatr Genet (12 January 2007)

The aim of this study was to investigate the association between the T102C polymorphism on the 5HT2A gene and cognitive function as well as clinical manifestations in patients with schizophrenia. Eighty-two outpatients with schizophrenia participated in this study. The Brief Psychiatric Rating Scale (BPRS) was used to assess the severity of each patient's symptoms. In order to evaluate their short-term attention capacity, a Digit Span Test was used. The Continuous Performance Test (CPT) was used to test the sustained attention span of each of the subjects. Cognitive flexibility was measured with the Wisconsin Card Sorting Test (WCST). The polymorphism of the 5-HT2A gene at codon 102 (T/C) was genotyped by sequence specific polymerase chain reaction. The T allele at codon 102 correlated with a lower hit rate and more commission errors in the CPT and patients with the heterogeneous genotype (TC) had more commission errors than those who were of homogeneous type (CC or TT). Patients with the TC genotype also had significantly fewer correct responses in the WCST compared to those who were type CC or TT. No relationship was found to exist between the C allele and cognitive variables. There was also no relationship established between the codon 102 polymorphism and clinical parameters. These findings suggest that the TC genotype might be related to certain cognitive impairments in patients with schizophrenia. (c) 2007 Wiley-Liss, Inc.

Midbrain serotonin transporter binding potential measured with [(11)C]DASB is affected by serotonin transporter genotype.

M Reimold — 2007-04-09T20:20:57-00:00

J Neural Transm (18 January 2007)

Background. Homozygote carriers of two long (L) alleles of the serotonin transporter (5-HTT) regulatory region displayed in vitro a twofold increase in 5-HTT expression compared with carriers of one or two short (S) alleles. However, in vivo imaging studies yielded contradictory results. Recently, an A > G exchange leading to differential transcriptional activation of 5-HTT mRNA in lymphobalstoid cell lines was discovered in the 5-HTT regulatory region. In vitro and in vivo evidence suggests that [(11)C]DASB, a new 5-HTT ligand offers some advantages over the ligands used in previous studies in measuring 5-HTT density independent of synaptic levels of serotonin. Method. We assessed 5-HTT binding potential (BP (2)) in the midbrain of 19 healthy subjects with positron emission tomography and [(11)C]DASB. Accounting for the hypothesized functional similarity of L (G) and S in driving 5-HTT transcription, we assessed whether L (A) L (A) homozygotes display increased midbrain BP (2) compared with carriers of at least one S allele. Results. BP (2) in the midbrain was significantly increased in L (A) L (A) homozygotes compared with carriers of at least one S allele. Interestingly, the genotype effect on the midbrain was significantly different from that on the thalamus and the amygdala where no group differences were detected. Conclusions. This in vivo study provides further evidence that subjects homozygous for the L (A) allele display increased expression of 5-HTT in the midbrain, the origin of central serotonergic projections.

Impaired executive control is associated with a variation in the promoter region of the tryptophan hydroxylase 2 gene.

M Reuter — 2007-04-09T20:04:58-00:00

J Cogn Neurosci, Vol. 19, No. 3. (March 2007), pp. 401-408.

Current models of attention describe attention not as a homogenous entity but as a set of neural networks whose measurement yields a set of three endophenotypes-alerting, orienting, and executive control. Previous findings revealed different neuroanatomical regions for these subsystems, and data from twin studies indicate differences in their heritability. The present study investigated the molecular genetic basis of attention in a sample of 100 healthy subjects. Attention performance was assessed with the attention network test that distinguishes alerting, orienting, and executive control (conflict) using a simple reaction time paradigm with different cues and congruent and incongruent flankers. Two gene loci on candidate genes for cognitive functioning, the functional catechol-O-methyltransferase (COMT) VAL158MET and the tryptophan hydroxylase 2 (TPH2) -703 G/T promoter polymorphism, were tested for possible associations with attention. COMT is involved in the catabolism of dopamine, and TPH is the rate-limiting enzyme for serotonin synthesis. Results showed no effect of the COMT polymorphism on attention performance. However, the TT genotype of TPH2 -03 G/T was significantly associated with more errors (a possible indicator of impaired impulse control; p = .001) and with decreased performance in executive control (p = .001). This single-nucleotide polymorphism on the TPH2 gene explained more than 10% of the variance in both indicators of attention stressing the role of the serotonergic system for cognitive functions.

Nature and Nurture Predispose to Violent Behavior: Serotonergic Genes and Adverse Childhood Environment

Andreas Reif — 2007-03-08T11:23:21-00:00

Neuropsychopharmacology, Vol. aop, No. current.

Serotonin transporter polymorphisms and the occurrence of adverse events during treatment with selective serotonin reuptake inhibitors.

K Smits — 2007-04-09T20:00:47-00:00

Int Clin Psychopharmacol, Vol. 22, No. 3. (May 2007), pp. 137-143.

During treatment with selective serotonin reuptake inhibitors, some patients experience adverse events whereas others do not. Assessment of predictors for selective serotonin reuptake inhibitors-induced adverse events would be useful for the identification of patients likely to develop these events. This study evaluates the association between adverse events during selective serotonin reuptake inhibitor treatment and two polymorphisms in the serotonin transporter (5-HTTLPR and STin2) gene. We included 214 patients meeting Diagnostic and statistical manual of mental disorder-IV criteria for major depression and using an selective serotonin reuptake inhibitor for at least 6 weeks. Blood samples or buccal swabs were taken to determine 5-HTTLPR and STin2 genotype. Information on adverse events was gathered through interviews and general practitioners' files. The association between serotonin transporter genotype and adverse events was assessed by use of logistic regression. Patients with the 5-HTTLPR s/s or s/l genotype appeared to have an increased risk of adverse events, especially general adverse events (dermatologic reactions, weight change and fatigue); odds ratio 1.77 (95% confidence interval 0.80-3.92) for the s/s genotype, odds ratio 2.37 (95% confidence interval 1.13-4.96) for the s/l genotype. For STin2, results were inconsistent and observed associations were weak and statistically nonsignificant. Our findings indicate that patients with the 5-HTTLPR s/s or s/l genotype have an increased risk of developing adverse events during selective serotonin reuptake inhibitor treatment.

The influence of four serotonin-related genes on decision-making in suicide attempters.

Fabrice Jollant — 2007-02-21T01:38:53-00:00

Am J Med Genet B Neuropsychiatr Genet (12 January 2007)

Genetic factors have been associated with the vulnerability to suicidal behavior. We previously reported decision-making impairment in suicide attempters and hypothesized that these cognitive alterations may represent an endophenotype of suicidal behavior. In this study, we aimed to investigate the influence of four serotonin-related genes relevant to suicidal behavior on decision-making, in a large population of suicide attempters. The Iowa Gambling Task was used to assess decision-making in 168 patients with a personal history of attempted suicide. Patients were genotyped for four serotonergic polymorphisms: 5HTTLPR, TPH1 A218C, MAOA u-VNTR, and TPH2 rs1118997. Patients carrying the 5HTTLPR-ll and -sl, TPH1-CC and -AC, MAOA-HH (in women) and TPH2-AA genotypes significantly improved their performance during the task, suggesting a genetic modulation of the learning process required for advantageous decision-making. In contrast, genotypes previously associated with a higher risk of suicidal behavior, a greater sensitivity to the environment and a higher propensity to negative feelings are those conferring poorer learning abilities. We hypothesize that the influence of genetic factors on the vulnerability to suicidal behavior may partly be achieved through their modulation of decision-making and particularly its learning component. (c) 2007 Wiley-Liss, Inc.

Serotonin regulation of the human stress response.

SD Hood — 2007-02-20T22:41:45-00:00

Psychoneuroendocrinology, Vol. 31, No. 9. (October 2006), pp. 1087-1097.

Acute tryptophan depletion (ATD) is a technique that has been used to evaluate the effects on humans of acutely reducing serotonin neurotransmission. We have developed a model using a single breath of 35% CO(2) that activates the hormonal axis and produces autonomic and behavioural arousal, thus modelling a stress response. This study combines ATD and single breath 35% CO(2) inhalation to study stress responses in volunteers. A randomised, double-blinded, placebo-controlled, cross-over trial involving 14 healthy adult volunteers aged between 18 and 65 years was undertaken. Subjects underwent double-blind tryptophan depletion over 2 days and were then crossed over 1 week later. During each study day, at the time of peak depletion, participants were single blinded to receive a single breath of 35% CO(2) or air. This was followed 40 min later by the other gas. Psychological outcomes were assessed with the Spielberger State Anxiety Inventory (SSAI), Visual Analogue Scales (VAS), Panic Inventory (PI), Panic and Agoraphobia Scale (PSI) and Beck Depression Inventory (BDI). Physiological outcome was measured by serial plasma cortisol, prolactin and tryptophan levels, pulse and blood pressure. Tryptophan depletion did not exacerbate 35% CO(2) inhalation effects on anxiety symptoms. Single breath CO(2) robustly increased plasma cortisol levels in comparison to an air inhalation; this was less certain for prolactin levels. ATD influenced the HPA axis (associated with higher cortisol levels), apparently independent of CO(2) or air inhalation stressors. ATD and 35% CO(2) inhalation both induced a pressor response and bradycardia in these normal volunteers. Thirty-five percent CO(2) inhalation and ATD independently activate the human stress response, but do not appear to produce synergistic effects when combined, at least for the conditions produced in this study.

Learning is bitter and sweet in ventral striatum.

ML Platt — 2005-02-22T21:25:24-00:00

Neuron, Vol. 38, No. 4. (22 May 2003), pp. 518-519.