Reduced availability of serotonin transporters in obsessive-compulsive disorder correlates with symptom severity – a [11C]DASB PET study

Summary Reduced availability of brainstem serotonin transporters (5-HTT) has been observed in vivo in obsessive-compulsive disorder (OCD). However, results vary and may be influenced by competition with endogenous serotonin. Using positron emission tomography (PET) and [¹¹C]DASB, a specific 5-HTT ligand that showed no competition with serotonin for 5-HTT binding in vitro, we tested the hypothesis that 5-HTT availability is reduced in OCD patients and correlated with OCD severity. Methods. 5-HTT availability in the thalamus and the midbrain was measured in nine drug-free OCD patients and compared with 19 healthy controls, matched for the individual combination of 5-HTT genotype, gender and smoking status. OCD severity was assessed with the Yale-Brown obsessive compulsive scale (Y-BOCS). Results. 5-HTT availability was significantly reduced in the thalamus and midbrain of OCD patients. Age and 5-HTT in the thalamus explained 83% of OCD severity in patients that were drug-free for at least 1 year. Conclusion. This PET study confirms a central role of the serotonergic system, particularly the thalamus in the pathogenesis of obsessive compulsive disorder. The first two authors contributed equally     

Reduced serotonin transporter–availability in obsessive–compulsive disorder (OCD)

Abstract. We investigated the availability of brain serotonin transporters in 10 drug–free patients with obsessive–compulsive disorder (OCD) and age–matched healthy controls in vivo using single–photon emission computed tomography (SPECT) and the radioligand [¹²³I]–2–carbomethoxy–3–(4–idiophenyl)-tropane ([¹²³I]–CIT). For quantification of regional serotonin transporter a ratio of specific to non–specific [¹²³I]–CIT–binding was used. The availability of serotonin transporter was calculated using regions of interests (ROI) for thalamus/hypothalamus, midbrain, brainstem (highest density of serotonin transporter) and cerebellum as a reference. The mean specific to non–specific [¹²³I]–CIT binding ratios in the thalamic/hypothalamic ROI were 4.95 ± 0.57 (OCD patients), and 5.48 ± 0.87 (control group). The mean ratios in the midbrain ROI were 3.51 ± 0.45 (OCD patients) and 4.89 ± 1.23 (controls) and in the brainstem ROI the ratios were 2.38 ± 0.76 (OCD patients) and 3.53 ± 1.01 (controls). This in vivo finding of significant reduced serotonin transporter availability in midbrain/brainstem using [¹²³I] –CIT SPECT further supports the serotonin deficit hypothesis of OCD.     

Serotonergic neurotransmission in the living human brain: a positron emission tomography study using [¹¹C]dasb and [¹¹C]WAY100635 in young healthy men

The central serotonergic (5-HT) system is closely involved in regulating various mental functions such as mood and emotion. In this system, the serotonin transporter (5-HTT) and the 5-HT(1A) receptor play important roles in the pathophysiology and treatment of mood and anxiety disorders. However, only a few integrated databases have considered the intraindividual relationship between pre- and postsynaptic serotonergic transmission. In the present study, we constructed a database of 5-HTT and 5-HT(1A) receptors using positron emission tomography (PET) with [11C]DASB and [11C]WAY100635, respectively. Seventeen healthy young men participated in this study. After anatomic standardization of original images, BP(ND) was calculated on a voxel-by-voxel basis using reference tissue methods. The highest binding to 5-HTT was observed in the dorsal raphe nucleus, striatum, and thalamus; moderate binding, in the insula and cingulate cortex; and very low binding, in the cerebral neocortex. In contrast, the highest binding to 5-HT(1A) receptors was seen in the hippocampal regions, insula, neocortical regions, and dorsal raphe nucleus, and very low binding was found in the thalamus and basal ganglia. These distribution patterns were in agreement with those reported in human postmortem studies and previous PET investigations. In addition, exploratory analysis indicated significant negative correlations between the BP(ND) values with both radiotracers in certain regions of the brain, such as the cingulate, insula, and frontal, temporal and parietal cortices (Pearson's correlation, P < 0.05). These databases facilitate the understanding of the regional distribution of serotonergic neurotransmission function in the living human brain and the pathophysiology of various neuropsychiatric disorders.     

How well can young people with Asperger's disorder recognize threat and learn about affect in faces?: A pilot study

The abilities to identify threat and learn about affect in facial photographs were compared between a non-autistic university student group (NUS), a matched Asperger's group (MAS) on the Standard Progressive Matrices (SPM), and an unmatched Asperger's group (UAS) who scored lower on the SPM. Participants were given pairs of faces and asked which person looked more dangerous. In addition, they engaged in explicit learning of the facial affect features. This study indicated (a) that the ability to identify threat in faces was intact in the MAS group, but poor in the UAS group; (b) a graded degree of performance in facial affect recognition (NUS > MAS > UAS); (c) that all groups improved their facial affect recognition after the brief explicit teaching intervention. This pilot study obtained first indications for the feasible assessment of the ability to distinguish threat in faces and potential remediation effects of the brief explicit teaching of facial emotions for young people with Asperger's disorder.     

Is the serotonin transporter polymorphism (5-HTTLPR) associated with harm avoidance and internalising problems in childhood and adolescence?

Summary. The S allele of the 5-HTTLPR has been associated with anxiety-related behavioural traits and harm avoidance. The 5-HTTLPR polymorphism is suggested to modulate the serotonergic response to stress, meaning that individuals carrying the SS genotype who have significant stress histories may tend to develop depressive symptoms. In the Mannheim Study of Risk Children, which followed a cohort of n = 384 from birth to adolescence, the association of 5-HTTLPR with harm avoidance and internalising problems was examined, including gender and early life stress as possible moderators. Child and adolescent characteristics were assessed using the Junior Temperament and Character Inventory, the Child Behaviour Checklist and the Youth Self Report. Early life stress was determined by a risk index measuring the presence of 11 adversity factors. Results did not reveal an association with 5-HTTLPR genotype. There were no moderating effects of early life stress or gender. An explanation for the negative findings is that the S allele may be a necessary but not sufficient component cause in a composite risk factor.     

Dopamine and serotonin transporter availability in chronic heroin users: a [¹²³I]β-CIT SPECT imaging study

Dopamine (DA) and serotonin (5-HT) transporter availability in heroin users and healthy controls was measured using [123I]β-CIT and SPECT imaging. Heroin users had statistically similar striatal DA and brainstem and diencephalon 5-HT transporter availability compared with controls. No associations between transporter availability and heroin use characteristics were found.     

Assessing the sensitivity of [¹¹C]p943, a novel 5-HT1B radioligand, to endogenous serotonin release

The main objective of the current study was to determine the sensitivity of the positron emission tomography (PET) radioligand [11C]P943 to fenfluramine-induced changes in endogenous 5-HT in nonhuman primate brain. Fenfluramine-induced changes in 5-HT(1B) occupancy were compared to those obtained by self-block with unlabeled P943. Two baboons and 1 rhesus monkey were given preblocking or displacing doses of fenfluramine (1-5 mg/kg) or preblocking doses of unlabeled P943 (0.2 mg/kg) and imaged with [11C]P943 PET. Receptor occupancy by the low dose of fenfluramine (1 mg/kg) in the baboons was 25 and 29% and by the high dose of fenfluramine (5 mg/kg) in the rhesus macaque was 42%. Receptor occupancy by P943 (0.2 mg/kg) was 68 and 86% in the baboons. PET imaging of 5-HT(1B) receptors with [11C]P943 may be a useful approach for measuring changes in endogenous 5-HT in the living human brain.     

Involvement of 5-HT(2A) receptor and α(2)-adrenoceptor blockade in the asenapine-induced elevation of prefrontal cortical monoamine outflow

The psychotropic drug asenapine is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. Asenapine exhibits higher affinity for several 5-HT receptors and α(2)-adrenoceptors than for D(2) receptors. Noteworthy, blockage of both the 5-HT(2A) and α(2)-adrenergic receptors has been shown to enhance prefrontal dopamine release induced by D(2) receptor antagonists. Previous results show that asenapine, both systemically and locally, increases dopamine, noradrenaline, and serotonin release in the medial prefrontal cortex (mPFC), and that the increased dopamine release largely depends on an intracortical action. Using reverse microdialysis in freely moving rats, we here assessed the potency of low concentrations of asenapine to cause a pharmacologically significant blockage in vivo of 5-HT(2A) receptors and α(2)-adrenoceptors within the mPFC, and thus its ability to affect cortical monoamine release by these receptors. Intracortical administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT(2A/2C) receptor agonist, increased cortical monoamine release, effects that were antagonized both by asenapine and the selective 5-HT(2A) antagonist M100907. Application of clonidine, an α(2)-adrenoceptor agonist, significantly reduced monoamine release in the mPFC. The selective α(2)-adrenoceptor antagonist idazoxan blocked, whereas asenapine partially blocked clonidine-induced cortical dopamine and noradrenaline decrease. The effects of asenapine and idazoxan on clonidine-induced serotonin decrease were less pronounced. Our results propose that low concentrations of asenapine in the mPFC exhibit a pharmacologically significant 5-HT(2A) and α(2) receptor antagonistic activity, which may contribute to enhance prefrontal monoamine release in vivo and, secondarily, its clinical effects in schizophrenia and bipolar disorder.     

Distribution of serotonin 5-HT2A and 5-HT7 receptors in the Onuf’s nucleus of the rat spinal cord*★

BACKGROUND：Motoneurons from the Onuf’s nucleus of the spinal cord, which innervate the striated muscle of the pelvic floor, play an important role in erection, ejaculation, and urine control. Serotonin （5-hydroxytryptamine, 5-HT） regulates motoneuron activity from the Onuf’s nucleus of the spinal cord. However, few studies exist that describe 5-HT receptor distribution in the Onuf’s nucleus. In addition, the nature of the effects of 5-HT receptor on the innervating striated muscle of the pelvic floor is controversial. OBJECTIVE： To investigate the distribution of serotonin 5-HT2A and 5-HT7 receptors in motoneurons of Onuf’s nucleus in the spinal cord of male rats, and to analyze the relationship of 5-HT2A and 5-HT7 receptor to central modulation of urogenital function. DESIGN, TIME AND SETTING： The neural morphology experiment was performed at the Ultramicro-structure Laboratory of Reproductive Medicine, Basic Medical College, Chongqing Medical University, China from April to December 2007. MATERIALS： Ten adult, Sprague Dawley rats （eight males and two females） were randomly divided into gender control group （n = 4, 50% male and 50% female） and a retrograde tracing group （n = 6, 100% male） Recombinant pseudorabies virus （PRV-152） was provided by Professor LW Enquist from Princeton University, USA. Rabbit anti-5-HT2A and 5-HT7 receptor antibodies were purchased from Diasorin, France. METHODS： In the gender control group, the spinal L5-6 segments were harvested, sliced, and then incubate antibodies specific against 5-HT2A or 5-HT7 receptors for immunohistochemical staining. In the retrograde tracing group, PRV-152 was separately injected into the right ischiocavernosus （ischiocavernosus subgroup, n = 3） and the right external urethral sphincter （external urethral sphincter subgroup, n = 3）. Four days after injection, L5-6 segments were harvested, sliced, and incubated with antibodies specific against 5-HT2A or 5-HT7 receptors for double-labeling immunofluorescence stain     

Is the 5-HT(1Dbeta) receptor gene implicated in the pathogenesis of obsessive-compulsive disorder?

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a psychiatric condition for which strong evidence of a genetic component and serotonergic system involvement exists. Recent studies have shown that sumatriptan, a selective ligand of the serotonin (5-HT)(1Dbeta) autoreceptor, modifies OCD symptoms. The aim of this study was to investigate the presence of linkage disequilibrium between the 5-HT(1Dbeta) receptor gene, which has a variant caused by a silent G to C substitution at nucleotide 861 of the coding region, and OCD. METHOD: DNA was collected from 67 probands who met DSM-IV criteria for OCD and from their living parents or siblings. Transmission Disequilibrium Test/sib-Transmission Disequilibrium Test analyses were then conducted with the DNA data. RESULTS: Thirty-two families were informative for the analysis, which showed a preferential transmission of the G allele to the affected subjects. CONCLUSIONS: If the results are confirmed, there may be important implications for the 5-HT(1Dbeta) receptor gene in the pathogenesis and treatment of OCD.     

Long-term test–retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [11C]raclopride and high-resolution PET

We measured the long-term test–retest reliability of [¹¹C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [¹¹C]raclopride assessments, with a 5-week retest interval. D_2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test–retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test–retest studies of [¹¹C]raclopride binding in the striatum. A novel finding is the relatively low variability of [¹¹C]raclopride binding, providing suggestive evidence that extrastriatal D_2/3 binding can be studied in vivo with [¹¹C]raclopride PET to be verified in future studies.     

Differences of cortical 5-HT2A receptor binding index with SPECT in subtypes of anorexia nervosa: relationship with personality traits?

OBJECTIVE: Using single photon emission computed tomography and the 5-HT2A receptor antagonist, 123I-5-I-R91150, we explored differences in 5-HT2A binding index in anorexia nervosa patients with and without bulimic features. We also searched for associations between temperament dimensions and cortical 5-HT2) binding. METHOD: About 9 restrictive and 7 bulimic anorexia nervosa patients were examined and cortical 123I-5-I-R91150 binding index values were compared between the two subgroups. Open explorative correlation analysis was used to examine any relationships between binding index values and temperament scores, as assessed with the Temperament and Character Inventory. RESULTS: 5-HT2A binding index was significantly reduced in the parietal cortex in bulimic anorexia nervosa patients in comparison with restrictive anorectics. Further, a positive correlation was documented between reward dependence and parietal 5-HT2A binding index across patients in the two subgroups. DISCUSSION: Restrictive anorexia nervosa patients differ from binging/purging anorexia nervosa patients on the basis of a reduced parietal 5-HT2A binding index in the latter. We speculate that the finding of a positive correlation between parietal 5-HT2A binding and reward dependence might reflect an association between these two variables, at least in anorexia nervosa patients.     

Neuroinflammation in bipolar disorder – A [11C]-(R)-PK11195 positron emission tomography study

Background: The “monocyte-T-cell theory of mood disorders” regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [¹¹C]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential focus of neuroinflammation in bipolar disorder. We aim to determine if there is increased [¹¹C]-(R)-PK11195 binding to activated microglia in the hippocampus of patients with bipolar I disorder when compared to healthy controls.Material and methods: Fourteen patients with bipolar I disorder and eleven healthy controls were included in the analyses. Dynamic 60-min PET scans were acquired after the injection of [¹¹C]-(R)-PK11195. All subjects underwent psychiatric interviews as well as an MRI scan, which was used for anatomic co-registration in the data analysis. The data from the PET scans was analyzed with a two-tissue-compartment model to calculate the binding potential, using the metabolite-corrected plasma and blood curve as input.Results: A significantly increased [¹¹C]-(R)-PK11195 binding potential, which is indicative of neuroinflammation, was found in the right hippocampus of the patients when compared to the healthy controls (1.66 (CI 1.45–1.91) versus 1.33 (CI 1.16–1.53); p = 0.033, respectively). Although the same trend was observed in the left hippocampus, this difference was not statistically significant.Conclusion: This study is the first to demonstrate the presence of focal neuroinflammation in the right hippocampus in bipolar I disorder.     

Prebiotic administration normalizes lipopolysaccharide (LPS)-induced anxiety and cortical 5-HT2A receptor and IL1-β levels in male mice

The manipulation of the enteric microbiota with specific prebiotics and probiotics, has been shown to reduce the host’s inflammatory response, alter brain chemistry, and modulate anxiety behaviour in both rodents and humans. However, the neuro-immune and behavioural effects of prebiotics on sickness behaviour have not been explored. Here, adult male CD1 mice were fed with a specific mix of non-digestible galacto-oligosaccharides (Bimuno®, BGOS) for 3 weeks, before receiving a single injection of lipopolysaccharide (LPS), which induces sickness behaviour and anxiety. Locomotor and marble burying activities were assessed 4 h after LPS injection, and after 24 h, anxiety in the light–dark box was assessed. Cytokine expression, and key components of the serotonergic (5-Hydroxytryptamine, 5-HT) and glutamatergic system were evaluated in the frontal cortex to determine the impact of BGOS administration at a molecular level. BGOS-fed mice were less anxious in the light–dark box compared to controls 24 h after the LPS injection. Elevated cortical IL-1β concentrations in control mice 28 h after LPS were not observed in BGOS-fed animals. This significant BGOS × LPS interaction was also observed for 5HT2A receptors, but not for 5HT1A receptors, 5HT, 5HIAA, NMDA receptor subunits, or other cytokines. The intake of BGOS did not influence LPS-mediated reductions in marble burying behaviour, and its effect on locomotor activity was equivocal. Together, our data show that the prebiotic BGOS has an anxiolytic effect, which may be related to the modulation of cortical IL-1β and 5-HT2A receptor expression. Our data suggest a potential role for prebiotics in the treatment of neuropsychiatric disorders where anxiety and neuroinflammation are prominent clinical features.     

Is psychological stress in man associated with increased striatal dopamine levels?: A [11C]raclopride PET study

In rodents, stress causes rapid increases in extracellular dopamine (DA) concentration in cortical and subcortical brain regions, and positron emission tomography (PET) studies in healthy humans have suggested psychological and pharmacological stressors are associated with increased DA concentration in the striatum. In this experiment, we measured the effect of stress, induced by difficult mental arithmetic, on [11C]raclopride binding in order to index striatal DA release. To refine measurements and facilitate interpretation of results a combination of head movement correction, a carefully designed control condition and bolus infusion administration of [11C]raclopride were employed. Fourteen healthy volunteers were scanned using [11C]raclopride PET. Physiological and psychological responses to the task were consistent with a stress response with changes in cardiovascular, hormonal, and subjective state indices. No change of ventral or dorsal striatal [11C]raclopride binding was found in the stress condition compared to nonstress. This negative result suggests that significant DA release does not occur in the striatum in healthy humans after mild, psychological stress.     

Course and predictors of DSM-5 somatic symptom disorder in patients with vertigo and dizziness symptoms – A longitudinal study

BackgroundSomatic symptom disorder (SSD) is a diagnosis that was newly included in DSM-5. Currently, data on the course of SSD are largely lacking. The present study aimed to evaluate the natural course of SSD in a one-year follow-up study in patients with vertigo and dizziness (VD) symptoms.MethodsWe investigated n = 239 outpatients presenting in a tertiary care neurological setting over a one-year period. Patients had a medical examination at baseline and completed self-report questionnaires, which were re-assessed after 12 months. DSM-5 SSD was assigned retrospectively. We evaluated the prevalence of SSD at baseline and 12-month follow-up and investigated predictors of the persistence of SSD during the study period.ResultsThe prevalence rate of SSD was 36% at baseline and 62% at 12-months follow-up. The persistence rate of SSD was 82% and the incidence rate was high, leading to a markedly increased prevalence rate at follow-up. Risk factors for persistent SSD were a self-concept of bodily weakness (OR: 1.52, 95% CI: 1.30–1.78) and an increase of depression during the study period (OR: 1.11, 95% CI: 1.02–1.22). Further, the diagnosis of an anxiety disorder (OR: 7.52, 95% CI: 1.17–48.23) or both anxiety and depressive disorder (OR: 23.14, 95% CI: 2.14–249.91) at baseline were significant predictors.ConclusionsOur findings point out that SSD is highly prevalent in patients with VD symptoms, the incidence of the disorder widely outweighs its remission. Potential predictors of a persistence of SSD are discussed and can be chosen as a focus in therapy.     

The selective 5-HT2a receptor antagonist MDL 100,907 counteracts the psychomotor stimulation ensuing manipulations with monoaminergic,glutamatergic or muscarinic neurotransmission in the mouse — implications for psychosis

Summary The present study has shown that a subthreshold dose of the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801, combined with a subthreshold dose of LSD, produces marked locomotor stimulation in monoamine-depleted mice. Likewise, MK-801, as well as the muscarine receptor antagonist atropine and the -adrenoceptor agonist clonidine, were found to interact synergistically with the putative 5-HT₂ receptor agonist UH-232 to produce locomotor activation in monoamine-depleted mice. All these responses were effectively blocked by the highly selective 5-HT_2a receptor antagonist MDL 100,907. On the other hand, MDL 100,907 did not antagonize the hyperactivity response produced by clonidine given in combination with MK-801 or atropine in monoamine-depleted mice, nor the response produced by the mixed DA receptor agonist apomorphine, underlining the selectivity in the antagonistic action of MDL 100,907. Furthermore, MDL 100,907 attenuated the hyperactivity produced in intact mice by such disparate agents as MK-801, atropine or the DA uptake inhibitor GBR 12 909. A putative permissive role of the 5-HT₂ receptor in the context of psychomotor activation is discussed, as well as its possible importance as target for antipsychotic therapy.     

Fluorophore assisted light inactivation (FALI) of recombinant 5-HT₃A receptor constitutive internalization and function

Fluorescent proteins and molecules are now widely used to tag and visualize proteins resulting in an improved understanding of protein trafficking, localization, and function. In addition, fluorescent tags have also been used to inactivate protein function in a spatially and temporally-defined manner, using a technique known as fluorophore-assisted light inactivation (FALI) or chromophore-assisted light inactivation (CALI). In this study we tagged the serotonin? A subunit with the α-bungarotoxin binding sequence (BBS) and subsequently labeled 5-HT?A/BBS receptors with fluorescently conjugated α-bungarotoxin in live cells. We show that 5-HT?A/BBS receptors are constitutively internalized in the absence of an agonist and internalization as well as receptor function are inhibited by fluorescence. The fluorescence-induced disruption of function and internalization was reduced with oxygen radical scavengers suggesting the involvement of reactive oxygen species, implicating the FALI process. Furthermore, these data suggest that intense illumination during live-cell microscopy may result in inadvertent FALI and inhibition of protein trafficking.     

The α-endomannosidase gene (MANEA) is associated with panic disorder and social anxiety disorder

Unbiased genome-wide approaches can provide novel insights into the biological pathways that are important for human behavior and psychiatric disorder risk. The association of α-endomannosidase gene (MANEA) variants and cocaine-induced paranoia (CIP) was initially described in a study that used a whole-genome approach. Behavioral effects have been reported for other mannosidase genes, but MANEA function in humans and the clinical potential of the previous findings remain unclear. We hypothesized that MANEA would be associated with psychiatric phenotypes unrelated to cocaine use. We used a multi-stage association study approach starting with four psychiatric disorders to show an association between a MANEA single-nucleotide polymorphism (SNP; rs1133503) and anxiety disorders. In the first study of 2073 European American (EA) and 2459 African American subjects mostly with comorbid drug or alcohol dependence, we observed an association in EAs of rs1133503 with panic disorder (PD) (191 PD cases, odds ratio (OR)=1.7 (95% confidence interval (CI): 1.22–2.41), P=0.002). We replicated this finding in an independent sample of 142 PD cases (OR =1.53 (95% CI: 1.00–2.31), P=0.043) and extended it in an independent sample of 131 generalized social anxiety disorder cases (OR=2.15 (95% CI: 1.27–3.64), P=0.004). MANEA alleles and genotypes were also associated with gene expression differences in whole blood cells. Using publically available data, we observed a consistent effect on expression in brain tissue. We conclude that pathways involving α-endomannosidase warrant further investigation in relation to anxiety disorders.