Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: A [11C]SB207145 PET study

ArticleinMolecular Psychiatry 19(4) · November 2013with 411 Reads
DOI: 10.1038/mp.2013.147 · Source: PubMed
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Abstract
Identification of a biomarker that can inform on extracellular serotonin (5-HT) levels in the brains of living humans would enable greater understanding of the way brain circuits are modulated by serotonergic neurotransmission. Substantial evidence from studies in animals and humans indicates an inverse relationship between central 5-HT tonus and 5-HT type 4 receptor (5-HT4R) density, suggesting that 5-HT4R receptor density may be a biomarker marker for 5-HT tonus. Here, we investigated whether a 3-week administration of a selective serotonin reuptake inhibitor, expected to increase brain 5-HT levels, is associated with a decline in brain 5-HT4R binding. A total of 35 healthy men were studied in a placebo-controlled, randomized, double-blind study. Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine, 40 mg per day. Brain 5-HT4R binding was quantified at baseline and at follow-up with [(11)C]SB207145 positron emission tomography (PET). Three weeks of intervention with fluoxetine was associated with a 5.2% reduction in brain 5-HT4R binding (P=0.017), whereas placebo intervention did not change 5-HT4R binding (P=0.52). Our findings are consistent with a model, wherein the 5-HT4R density adjusts to changes in the extracellular 5-HT tonus. Our data demonstrate for the first time in humans that the imaging of central 5-HT4R binding may be used as an in vivo biomarker of the central 5-HT tonus.Molecular Psychiatry advance online publication, 5 November 2013; doi:10.1038/mp.2013.147.

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    • Rachel Bangle
    • Marc G. Caron
    5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR. However, our previous study entailed translational limitations, in terms of route, dose, and duration. Here we modeled oral 5-HTP SR in mice by administering 5-HTP via the food. We modeled oral SSRI treatment via fluoxetine in the water, in a regimen recapitulating clinical pharmacokinetics and pharmacodynamics. 5-HTP SR produced plasma 5-HTP levels well within the range enhancing brain 5-HT function in humans. 5-HTP SR robustly increased brain 5-HT synthesis and levels. When administered with an SSRI, 5-HTP SR enhanced 5-HT-sensitive behaviors and neurotrophic mRNA expression. 5-HTP SR’s pro-serotonergic effects were stronger in mice with endogenous brain 5-HT deficiency. In a comprehensive screen, 5-HTP SR was devoid of overt toxicological effects. The present preclinical data, appreciated in the context of published 5-HTP clinical data, suggest that 5-HTP SR could represent a new therapeutic approach to the plethora of CNS disorders potentially treatable with a pro-serotonergic drug. 5-HTP SR might in particular be therapeutically relevant when brain 5-HT deficiency is pathogenic and as an adjunctive augmentation therapy to SSRI therapy.
  • Article
    Full-text available
    • Véronique Sgambato
      Véronique Sgambato
    • Léon Tremblay
      Léon Tremblay
    Thanks to the non-human primate (NHP), we have shown that the pharmacological disturbance of the anterior striatum or of external globus pallidus triggers a set of motivation and movement disorders, depending on the functional subterritory involved. One can, therefore, assume that the aberrant activity of the different subterritories of basal ganglia (BG) could lead to different behavioral disorders in neuropsychiatric disorders as Tourette’s syndrome and Parkinson’s disease. We are now addressing in the NHP the impact of modulating dopamine or serotonin within the BG on behavioral disorders. Indeed, we have shown a prominent role of serotonergic degeneration within the ventral striatum and caudate nucleus in neuropsychiatric symptoms in de novo PD patients. Of note, the serotonergic modulation of these BG regions in the NHP plays also a critical role in the induction or treatment of behavioral disorders. Given that both dopamine and serotonin are targeted to treat neuropsychiatric disorders, we are studying the effects of modulating dopamine and serotonin transporters in the different territories of the striatum, and more particularly within the ventral striatum on decision-making processing at both behavioral and neuronal levels. Finally, we evidence the need to extend the pharmacological approach to the receptors of these two neuromodulator systems as the use of substances targeting receptor subtypes preferentially localized in the associative and limbic territories of BG could be very effective to specifically improve the behavioral disorders in Parkinson’s disease, Gilles de la Tourette syndrome but also in several psychiatric disorders such as depression, anxiety, anorexia, or impulse control disorders.
  • Article
    Full-text available
    • Claudia Gasparini
      Claudia Gasparini
    • Robert Anthony Smith
    • Lyn Griffiths
    Migraine is a brain disorder characterized by a piercing headache which affects one side of the head, located mainly at the temples and in the area around the eye. Migraine imparts substantial suffering to the family in addition to the sufferer, particularly as it affects three times more women than men and is most prevalent between the ages of 25 and 45, the years of child rearing. Migraine typically occurs in individuals with a genetic predisposition and is aggravated by specific environmental triggers. Attempts to study the biochemistry of migraine began as early as the 1960s and were primarily directed at serotonin metabolism after an increase of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin was observed in urine of migraineurs. Genetic and biochemical studies have primarily focused on the neurotransmitter serotonin, considering receptor binding, transport and synthesis of serotonin and have investigated serotonergic mediators including enzymes, receptors as well as intermediary metabolites. These studies have been mainly assayed in blood, CSF and urine as the most accessible fluids. More recently PET imaging technology integrated with a metabolomics and a systems biology platform are being applied to study serotonergic biology. The general trend observed is that migraine patients have alterations of neurotransmitter metabolism detected in biological fluids with different biochemistry from controls, however the interpretation of the biological significance of these peripheral changes is unresolved. In this review we present the biology of the serotonergic system and metabolic routes for serotonin and discuss results of biochemical studies with regard to alterations in serotonin in brain, cerebrospinal fluid, saliva, platelets, plasma and urine of migraine patients.
  • Article
    Full-text available
    • Jacqueline Scholl
      Jacqueline Scholl
    • Nils Kolling
    • Natalie Nelissen
    • Catherine Harmer
      Catherine Harmer
    To make good decisions, humans need to learn about and integrate different sources of appetitive and aversive information. While serotonin has been linked to value-based decision-making, its role in learning is less clear, with acute manipulations often producing inconsistent results. Here, we show that when the effects of a selective serotonin reuptake inhibitor (SSRI, citalopram) are studied over longer timescales, learning is robustly improved. We measured brain activity with functional magnetic resonance imaging (fMRI) in volunteers as they performed a concurrent appetitive (money) and aversive (effort) learning task. We found that 2 weeks of citalopram enhanced reward and effort learning signals in a widespread network of brain regions, including ventromedial prefrontal and anterior cingulate cortex. At a behavioral level, this was accompanied by more robust reward learning. This suggests that serotonin can modulate the ability to learn via a mechanism that is independent of stimulus valence. Such effects may partly underlie SSRIs’ impact in treating psychological illnesses. Our results highlight both a specific function in learning for serotonin and the importance of studying its role across longer timescales.
  • Article
    • Klaus Holst
      Klaus Holst
    • Erik Perfalk
    • Sofi Da Cunha-Bang
      Sofi Da Cunha-Bang
    • Vibe G. Frokjaer
    The serotonergic system integrates sex steroid information and plays a central role in mood and stress regulation, cognition, appetite and sleep. This interplay may be critical for likelihood of developing depressive episodes, at least in a subgroup of sensitive individuals. The serotonin 4 receptor (5-HT4R) indexes central serotonergic tonus, which may be related to endogenous sex-steroid levels in the mentally healthy state even though this remains elusive. Here we evaluate if peripheral levels of estradiol and testosterone are associated with 5-HT4R binding as imaged by [¹¹C]SB207145 positron emission tomography in a group of 41 healthy men. We estimated global 5-HT4R binding using a latent variable model framework, which models shared correlation between 5-HT4R across multiple brain regions (hippocampus, amygdala, posterior and anterior cingulate, thalamus, pallidostriatum and neocortex). We tested whether testosterone and estradiol predict global 5-HT4R, adjusting for age. We found that that testosterone, but not estradiol, correlated negatively with global 5-HT4R levels (p = 0.02) suggesting that men with high levels of testosterone have higher cerebral serotonergic tonus. Our findings corroborate the link between sex hormone levels and serotonin signalling. Future longitudinal studies in clinical relevant populations are needed to elucidate the potential importance of testosterone in the pathophysiology of e.g. major depression and its treatment.
  • Article
    • Christin Y Sander
      Christin Y Sander
    • Swen Hesse
    Molecular neuroimaging with PET is an integrated tool in psychiatry research and drug-development for as long as this modality has been available, in particular for studying neurotransmission and endogenous neurotransmitter release. Pharmacologic probes but also behavioral challenges are currently applied to induce changes in neurochemical levels that can be inferred through their effects on changes in receptor binding and related outcome measures. Based on the availability of tracers that are sensitive for measuring neurotransmitter release these experiments have focused on the brain's dopamine system, while recent developments have extended those studies to other targets such as the serotonin or choline system. With the introduction of hybrid, truly simultaneous PET/MRI systems, in vivo imaging of the dynamics of neuroreceptor signal transmission in the brain using PET and functional MRI (fMRI) has become possible. fMRI has the ability to provide information about the effects of receptor function that are complementary to the PET measurement. Dynamic acquisition of both PET and fMRI signals enables not only an in vivo real time assessment of neurotransmitter or drug binding to receptors but also dynamic receptor adaptations and receptor-specific neurotransmission. While fMRI temporal resolution is comparatively fast in relation to PET, the timescale of observable biological processes are highly dependent on the kinetics of radiotracers and study design. Overall, the combination of the specificity of PET radiotracers to neuroreceptors, fMRI signal as a functional readout and integrated study design promises to expand our understanding of the location, propagation and connections of brain activity in health and disease.
  • Article
    • Puja Panwar Hazari
      Puja Panwar Hazari
    • Ankita Misra
      Ankita Misra
    • Shubhra Chaturvedi
      Shubhra Chaturvedi
    • Anil Kumar Mishra
      Anil Kumar Mishra
    The critical role of serotonin (5-hydroxytryptamine; 5-HT) and its receptors (5-HTRs) in the pathophysiology of various neuropsychiatric and neurodegenerative disorders render them attractive diagnostic/therapeutic targets for brain disorders. Therefore, in vivo assessment of binding of 5-HT receptor ligands under a multitude of physiologic and pathologic scenario may support the more accurate identification of disease and its progression, patient’s response to therapy, and the screening of novel therapeutic strategies. The present review aims to focus on the current status of radioligands used for positron emission tomography and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors. We further elaborate and emphasize upon the attributes that qualify a radioligand for diagnostics from its frequency of use in clinics, its potential in assessing the functional status of the serotonergic receptors, and its continuous evolution, along with the major limitations.
  • Article
    • Justin B. Smith
    • Jordan Rosen
    • Adam Colbert
    Introduction: The symptoms of low testosterone frequently overlap with psychiatric complaints including depression and fatigue. Testosterone repletion has been shown to improve mood symptoms in men with low testosterone, although this finding has not been consistent across all studies. Despite the potential importance of low testosterone for psychiatry, the prevalence of low testosterone in men who present to psychiatric clinics with mental health complaints is unknown. Aim: To provide an overview of the current state of knowledge of the psychiatric complications of male hypogonadism, the challenges of screening for hypogonadism in a psychiatric population, and the potential mental health treatment implications of hypogonadism. Methods: A literature review was conducted using PubMed. Main outcome measures: Publications pertaining to the epidemiology, psychiatric symptomatology, and impact of treatment of male hypogonadism on psychiatric outcomes. Results: A review of the literature suggests a lack of information on the prevalence of low testosterone in patients presenting with psychiatric complaints despite an overlap in clinical symptoms. The identification of low testosterone could have a significant impact on treatment through urologic referral for testosterone repletion or the use of treatments that spare the gonadal axis. Conclusion: We hope our results will help those who care for patients in psychiatric settings to better assess for the presence of hypogonadism and its potential contribution to depressive illness. Smith JB, Rosen J, Colbert A. Low Serum Testosterone in Outpatient Psychiatry Clinics: Addressing Challenges to the Screening and Treatment of Hypogonadism. Sex Med Rev 2017;X:XXX-XXX.
  • Article
    • Marie Deen
    • Anders Hougaard
      Anders Hougaard
    • Hanne Demant Hansen
      Hanne Demant Hansen
    • Messoud Ashina
    Introduction: Serotonin (5-HT) plays a role in migraine pathophysiology, but whether brain 5-HT is involved in the conversion from episodic to chronic migraine is unknown. Here, we investigated brain 5-HT levels, as indexed by 5-HT4 receptor binding, in chronic migraine patients and evaluated whether these were associated with migraine frequency. Methods: Sixteen chronic migraine patients underwent a dynamic PET scan after injection of [11C]SB207145, a specific 5-HT4 receptor radioligand. Data from 15 episodic migraine patients and 16 controls were included for comparison. Quantification of 5-HT4 receptor binding was used as a proxy for brain 5-HT levels, since 5-HT4 receptor binding is inversely related to brain 5-HT levels. Results: Chronic migraine patients had 9.1% (95% CI: [-17%; -1.0%]) lower 5-HT4 receptor binding compared to controls ( p = 0.039). There was no difference in 5-HT4 receptor binding between chronic and episodic migraine patients ( p = 0.48) and no association between number of monthly migraine days and 5-HT4 receptor binding (slope estimate 0.003, 95% CI: [-0.004; 0.715], p = 0.39). Conclusion: The finding of low 5-HT4 receptor binding suggests that cerebral levels of 5-HT are elevated in chronic migraine patients. This is in line with observations made in patients with episodic migraine. Elevated brain 5-HT levels may thus be an inherent trait of the migraine brain rather than a risk factor for conversion from episodic to chronic migraine.
  • Article
    • Jon Lansner
    • Christian Gaden Jensen
      Christian Gaden Jensen
    • Anders Petersen
    • Gitte M Knudsen
    Rationale The serotonergic system has been repeatedly linked to visual attention in general, but the effects of selective serotonin reuptake inhibitor (SSRI) on specific components of visual attention remain unknown. Changes in distinct perceptual and cognitive processes are not readily evident in most attention paradigms. Objective In this study, we isolate basic components of visual attention to investigate potential effects of longer-term SSRI administration on non-emotional aspects of visual attention in healthy males. Methods In a randomized double-blind placebo-controlled design, 32 young healthy males were tested on multiple attentional parameters, before and after a 3-week SSRI intervention with fluoxetine (40 mg daily) or placebo. Data were modeled with a computational theory of visual attention to derive independent estimates of five distinct components of visual attention. Results The SSRI intervention selectively and significantly lowered the threshold for conscious visual perception. Specifically, we demonstrate that this improvement does not stem from a general increase in the speed of visual processing, as previously suggested, but specifically from a change in the perceptual threshold. Conclusions The study provides a novel description of the attentional dynamics affected by SSRI, while supporting previous findings on attentional effects of SSRI. Furthermore, it accentuates the utility of employing accuracy-based measures of attentional performance when conducting psychopharmacological research.
  • Article
    Full-text available
    • Ulla Knorr
      Ulla Knorr
    • Jasmine Melissa Madsen
      Jasmine Melissa Madsen
    • Lars Kessing
      Lars Kessing
    Selective serotonin reuptake inhibitors (SSRIs) are the first-line drugs in the treatment of depression. Investigations of the effects of SSRIs in healthy individuals is a useful model to understand the mechanisms of SSRI action and potentially the underlying pathophysiology of depression. We conducted an updated systematic review of all randomized multiple-dose, placebo-controlled trials on the effect of intervention with SSRI for ≥ 7 days in healthy nonpsychiatric subjects. Tables were drawn for characteristics of the trial, quality assessment, outcome measures, and the effect of intervention with SSRI. The search strategy identified a total of 51 placebo-controlled randomized trials investigating seven different SSRIs and 249 different outcome measures. Among trials, using the same outcome measure, most associations were either contradictory or statistically nonsignificant. Replication of statistically significant findings in two or more trials showed that SSRIs compared with placebo decreased divided attention, sustained attention network, negative affects, hostility, sleep quality, and platelet 5-HT content and further increased activity in the amygdala in relation to happy faces. Factors such as age, gender, family history of psychiatric disorder, and drug level influenced the findings but were rarely systematically investigated. The newly published retrieved trials fulfilled more criteria according to the CONSORT statement. This systematic review points to effects of SSRIs increasing positive emotional processing and decreasing divided and sustained attention besides physiological effects decreasing sleep quality and platelet 5-HT content in healthy subjects. Larger studies with a translational medicines approach with improved methodology are needed on the effects of SSRIs in healthy subjects. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
  • Article
    • Patrick MacDonald Fisher
      Patrick MacDonald Fisher
    • Mette Haahr
      Mette Haahr
    • Julian Macoveanu
      Julian Macoveanu
    • Hartwig Roman Siebner
      Hartwig Roman Siebner
    Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are commonly prescribed antidepressant drugs targeting the dysfunctional serotonin (5-HT) system. Yet little is known about the functional effects of prolonged serotonin reuptake inhibition in healthy individuals. Here we used functional MRI (fMRI) to investigate how a three-week fluoxetine intervention influences neural activity related to risk taking and reward processing. Employing a double-blinded parallel-group design, 29 healthy young males were randomly assigned to receive 3weeks of a daily dose of 40 milligrams fluoxetine or placebo. Participants underwent task-related fMRI prior to and after the three-week intervention while performing a card gambling task. The task required participants to choose between two decks of cards. Choices were associated with different risk levels and potential reward magnitudes. Relative to placebo, the SSRI intervention did not alter individual risk-choice preferences, but modified neural activity during decision making and reward processing: During the choice phase, SSRI reduced the neural response to increasing risk in lateral orbitofrontal cortex, a key structure for value-based decision-making. During the outcome phase, a midbrain region showed an independent decrease in the responsiveness to rewarding outcomes. This midbrain cluster included the raphe nuclei from which serotonergic modulatory projections originate to both cortical and subcortical regions. The findings corroborate the involvement of the normally functioning 5HT-system in decision-making under risk and processing of monetary rewards. The data suggest that prolonged SSRI treatment might reduce emotional engagement by reducing the impact of risk during decision-making or the impact of reward during outcome evaluation.
  • Article
    Full-text available
    • Lisbeth Marner
    • Nic Gillings
      Nic Gillings
    • Gitte M Knudsen
    • Robert A. Comley
    The serotonin 4 receptor (5-HT(4) receptor) is known to be involved in learning and memory. We evaluated for the first time the quantification of a novel 5-HT(4) receptor radioligand, (11)C-SB207145, for in vivo brain imaging with PET in humans. For evaluation of reproducibility, 6 subjects were scanned twice with (11)C-SB207145 on the same day. A further 2 subjects were scanned before and after blocking with the selective 5-HT(4) receptor inverse agonist piboserod (SB207266). Arterial blood samples were drawn for the calculation of metabolite-corrected arterial input functions. Regions of interest were delineated automatically on the individual's MR images coregistered to the PET images, and regional time-activity curves were extracted. Quantitative tracer kinetic modeling was investigated with 1- and 2-tissue-compartment models using plasma input functions and the simplified reference tissue model (SRTM). (11)C-SB207145 readily entered the brain and showed a distribution consistent with the known localization of the 5-HT(4) receptor. Using plasma input models, the time-activity data were well described by the 2-tissue-compartment model in all regions and allowed for the estimate of binding potentials relative to the reference region (BP(ND): striatum, 3.38 +/- 0.72; hippocampus, 0.82 +/- 0.19; parietal cortex, 0.30 +/- 0.08). Quantification with the 1-tissue-compartment model, 2-tissue-compartment model, and SRTM were associated with good test-retest reproducibility and time stability. However, the SRTM-generated BP(ND) values in the striatum were underestimated by 20%-43% in comparison to the 2-tissue-compartment model. The blocking study with piboserod confirmed that the radioligand was selective for the 5-HT(4) receptor, that the cerebellum was a suitable reference region devoid of specific binding, and that nonspecific binding was constant across brain regions. In vivo imaging of cerebral 5-HT(4) receptors can be determined reliably using (11)C-207145 PET with arterial input in humans. SRTM showed high reproducibility and reliability but bias in the striatum, and therefore, the use of SRTM should be considered carefully for individual applications.
  • Measuring endogenous 5-HT release by emission tomography: promises and pitfalls
    • Lm Paterson
    • Rj Tyacke
    • Dj Nutt
    • Gm Knudsen
    Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab 2010; 30: 1682–1706.
  • Article
    • Mette Haahr
      Mette Haahr
    • Patrick MacDonald Fisher
      Patrick MacDonald Fisher
    • Klaus Holst
      Klaus Holst
    • Steen G Hasselbalch
      Steen G Hasselbalch
    The cerebral serotonin (5-HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5-HT type 4 receptor (5-HT(4) R) facilitates memory and learning and further that the 5-HT(4) R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5-HT(4) R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [(11) C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5-HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BP(ND) , (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BP(ND) and delayed recall (p = 0.014). These findings provide evidence that the 5-HT(4) R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
  • Article
    • Lars H Pinborg
      Lars H Pinborg
    • Ling Feng
      Ling Feng
    • Mette Haahr
      Mette Haahr
    • Gitte M Knudsen
    The main objective of this study was to determine the sensitivity of [¹¹C]CUMI-101 to citalopram challenge aiming at increasing extracellular 5-HT. CUMI-101 has agonistic properties in human embryonic kidney 293 cells transfected with human recombinant 5-HT(1A) receptors (Hendry et al. [2011] Nucl Med Biol 38:273-277; Kumar et al. [2006] J Med Chem 49:125-134) and has previously been demonstrated to be sensitive to bolus citalopram in monkeys (Milak et al. [2011] J Cereb Blood Flow Metab 31:243-249). We studied six healthy individuals. Two PET-scans were performed on the same day in each individual before and after constant infusion of citalopram (0.15 mg/kg). The imaging data were analyzed using two tissue compartment kinetic modeling with metabolite corrected arterial input and Simplified Reference Tissue Modeling using cerebellum as a reference region. There was no significant difference in regional distribution volume or non-displaceable binding potential values before and after citalopram infusion. The mean receptor occupancy was 0.03 (range -0.14 to 0.17). Our data imply that [¹¹C]CUMI-101 binding is not sensitive to citalopram infusion in humans.
  • Article
    • Mette Haahr
      Mette Haahr
    • Peter Mondrup Rasmussen
    • Karine Madsen
      Karine Madsen
    • Gitte M Knudsen
    The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT(4) receptor (5-HT(4)R) is involved in food intake, and that pharmacological or genetic manipulation of the receptor in reward-related brain areas alters food intake. Here, we used positron emission tomography in humans to examine the association between cerebral 5-HT(4)Rs and common obesity. We found in humans a strong positive association between body mass index and the 5-HT(4)R density bilaterally in the two reward ‘hot spots’ nucleus accumbens and ventral pallidum, and additionally in the left hippocampal region and orbitofrontal cortex. These findings suggest that the 5-HT(4)R is critically involved in reward circuits that regulate people's food intake. They also suggest that pharmacological stimulation of the cerebral 5-HT(4)R may reduce reward-related overeating in humans.
  • Article
    Full-text available
    • Sudhakar Selvaraj
      Sudhakar Selvaraj
    • Federico Turkheimer
      Federico Turkheimer
    • L. Rosso
    • Oliver D Howes
      Oliver D Howes
    Serotonin (5-HT) neurotransmission is implicated in cognitive and emotional processes and a number of neuropsychiatric disorders. The use of positron emission tomography (PET) to measure ligand displacement has allowed estimation of endogenous dopamine release in the human brain; however, applying this methodology to assess central 5-HT release has proved more challenging. The aim of this study was to assess the sensitivity of a highly selective 5-HT 1A partial agonist radioligand [11C] CUMI-101 to changes in endogenous 5-HT levels induced by an intravenous challenge with the selective 5-HT re-uptake inhibitor (SSRI), citalopram, in healthy human participants. We studied 15 healthy participants who underwent PET scanning in conjunction with [11C] CUMI-101 after receiving an intravenous infusion of citalopram 10 mg or placebo in a double-blind, crossover, randomized design. Regional estimates of binding potential (BPND) were obtained by calculating total volumes of distribution (V T) for presynaptic dorsal raphe nucleus (DRN) and postsynaptic cortical regions. Relative to placebo, citalopram infusion significantly increased [11C] CUMI-101 BP ND at postsynaptic 5-HT1A receptors in several cortical regions, but there was no change in binding at 5-HT1A autoreceptors in the DRN. Across the postsynaptic brain regions, citalopram treatment induced a mean 7% in [ 11C] CUMI-101 BPND (placebo 1.3 (0.2); citalopram 1.4 (0.2); paired t-test P0.003). The observed increase in postsynaptic [ 11C] CUMI-101 availability identified following acute citalopram administration could be attributable to a decrease in endogenous 5-HT availability in cortical terminal regions, consistent with preclinical animal studies, in which acute administration of SSRIs decreases DRN cell firing through activation of 5-HT1A autoreceptors to reduce 5-HT levels in postsynaptic regions. We conclude that [11C] CUMI-101 may be sensitive to changes in endogenous 5-HT release in humans.
  • Article
    • Patrick MacDonald Fisher
      Patrick MacDonald Fisher
    • Klaus Holst
      Klaus Holst
    • Brenda Mc Mahon
      Brenda Mc Mahon
    • Gitte M Knudsen
    Serotonin (5-HT) is a neuromodulator affecting myriad aspects of personality and behavior and has been implicated in the pathophysiology of affective disorders including depression and anxiety. The 5-HTTLPR is a common genetic polymorphism within the promoter region of the gene coding for the serotonin transporter such that the S allele is associated with reduced transcriptional efficacy compared to the L allele, potentially contributing to increased serotonin levels. In humans, this genetic variant has been linked to inter-individual variability in risk for affective disorders, related aspects of personality and brain function including response to threat. However, its effects on aspects of serotonin signaling in humans are not fully understood. Studies in animals suggest that the 5-HT 4 receptor (5-HT(4)) shows a monotonic inverse association with long-term changes in serotonin levels indicating that it may be a useful measure for identifying differences in serotonergic neurotransmission. In 47 healthy adults we evaluated the association between 5-HTTLPR status and in vivo 5-HT(4) receptor binding assessed with [(11)C]SB207145 positron emission tomography (PET). We observed a significant association within the neocortex where [(11)C]SB207145 binding was 9% lower in S carriers compared to LL homozygotes. We did not find evidence for an effect of season or a season-by-5-HTTLPR interaction effect on regional [(11)C]SB207145 binding. Our findings are consistent with a model wherein the 5-HTTLPR S allele is associated with relatively increased serotonin levels. These findings provide novel evidence supporting an effect of 5-HTTLPR status on serotonergic neurotransmission in adult humans. There were no indications of seasonal effects on serotonergic neurotransmission.
  • Conference Paper
    Full-text available
    • Oline Vinter Olesen
      Oline Vinter Olesen
    • Merence Sibomana
      Merence Sibomana
    • Sune Høgild Keller
      Sune Høgild Keller
    • L. Hjgaard
    In this paper, the resolution of the Siemens high resolution research tomograph (HRRT) was centrally (r < 60 mm) homogenous with a FWHM of 1.4 mm for <sup>18</sup>F-FDG in air. This was where the main part of the brain is located if the patient has been positioned correctly. The 1.4 mm resolution was obtained using the newly develop 3D-OSEM PSF reconstruction algorithm, which was a significant improvement over 3D-OSEM reconstruction without PSF. The algorithm uses a simple PSF model that was the same for all the pixels in the FOV and does not regulate for the circular/octagonal scanner geometry. This supports that the FWHM of the radial axis is increasing with the distance from the center for r > 60mm.
  • Article
    • Steven Taylor
      Steven Taylor
    • Jonathan Abramowitz
      Jonathan Abramowitz
    • Dean Mckay
      Dean Mckay
  • Article
    Full-text available
    • Katie Jennings
      Katie Jennings
    • Cecilie Löe Licht
    • Aynsley Bruce
    • Trevor Sharp
      Trevor Sharp
    Genetic variation in 5-HT transporter (5-HTT) expression is a key risk factor for psychiatric disorder and has been linked to changes in the expression of certain 5-HT receptor subtypes. This study investigated the effect of variation in 5-HTT expression on 5-HT₄ receptor levels in both 5-HTT knockout (KO) and overexpressing (OE) mice using autoradiography with the selective 5-HT₄ receptor radioligand, [³H]SB207145. Compared to wild-type (5-HTT⁺/⁺) controls, homozygous 5-HTT KO mice (5-HTT⁻/⁻) had reduced 5-HT₄ receptor binding site density in all brain regions examined (35-65% of 5-HTT⁺/⁺). In contrast, the density of 5-HT₄ receptor binding sites was not significantly different between heterozygous 5-HTT KO mice (5-HTT⁻/⁺) and 5-HTT⁺/⁺ mice. The 5-HT synthesis inhibitor p-chlorophenylalanine (250 mg/kg twice daily for 3 d) abolished the difference in 5-HT₄ binding between 5-HTT⁻/⁻ and 5-HTT⁺/⁺ mice in all brain regions. Compared to wild-type (WT) littermate controls, 5-HTT OE mice had increased 5-HT₄ binding density across all brain regions, except amygdala (118-164% of WT) and this difference between genotypes was reduced by the 5-HTT inhibitor, fluoxetine (20 mg/kg twice daily, 3 d). Together, these findings suggest that variation in 5-HTT expression causes adaptive changes in 5-HT₄ receptor levels which are directly linked to alterations in 5-HT availability.
  • Article
    • Karine Madsen
      Karine Madsen
    • Lisbeth Marner
    • Mette Haahr
      Mette Haahr
    • Gitte M Knudsen
    Attention to tracer dose principles is crucial in positron emission tomography (PET), and deviations can induce serious errors. In this study, we devise a method for determining receptor occupancy of the mass dose of the radioligand itself and the in vivo affinity. The approach was used for [(11)C]SB207145, a new PET radioligand for imaging the cerebral 5-HT(4) receptors in humans. Test-retest PET studies with varying specific activities of [(11)C]SB207145 were conducted in seven healthy subjects, and the output parameter regional BP(ND) was modeled. Individual occupancy plots were first computed to estimate the mass dose that saturates 50% of receptors (ID(50)), and subsequently, the maximal mass dose that can be injected (arbitrarily set at an occupancy <5%) was calculated. Scatchard plots were computed to estimate the in vivo K(D). Increasing the mass dose resulted in a decrease in BP(ND), whilst the relative cerebellar uptake was unchanged. The ID(50) was 85.4±30.2 μg, and the upper mass dose limit was 4.5±1.6 μg, which does not require ultrahigh specific activity. The estimated in vivo K(D) was 2.8 nM (range 1.0-4.8), without any regional differences. The presented method for estimating the upper mass dose limit is suggested as part of validation of PET radioligands.
  • Article
    • Rebeca Vidal
      Rebeca Vidal
    • Elsa M Valdizán
      Elsa M Valdizán
    • M. Teresa Vilaró
      M. Teresa Vilaró
    • Elena Castro
      Elena Castro
    The 5-HT(4) receptor may be a target for antidepressant drugs. Here we have examined the effects of the dual antidepressant, venlafaxine, on 5-HT(4) receptor-mediated signalling events. The effects of 21 days treatment (p.o.) with high (40 mg·kg(-1)) and low (10 mg·kg(-1)) doses of venlafaxine, were evaluated at different levels of 5-HT(4) receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg·kg(-1), 21 days) was also evaluated on 5-HT(4) receptor density. Treatment with a high dose (40 mg·kg(-1)) of venlafaxine did not alter 5-HT(4) mRNA expression, but decreased the density of 5-HT(4) receptors in caudate-putamen (% reduction = 26 ± 6), hippocampus (% reduction = 39 ± 7 and 39 ± 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 ± 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg·kg(-1)) while it was attenuated in rats treated with 40 mg·kg(-1) of venlafaxine (% reduction = 51 ± 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT(4) receptor density. Our data indicate a functional desensitization of 5-HT(4) receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake.
  • Article
    Full-text available
    • Gitte M Knudsen
    • Louise M Paterson
      Louise M Paterson
    • Robin J Tyacke
      Robin J Tyacke
    • David J Nutt
      David J Nutt
    Molecular in vivo neuroimaging techniques can be used to measure regional changes in endogenous neurotransmitters, evoked by challenges that alter synaptic neurotransmitter concentration. This technique has most successfully been applied to the study of endogenous dopamine release using positron emission tomography, but has not yet been adequately extended to other neurotransmitter systems. This review focuses on how the technique has been applied to the study of the 5-hydroxytryptamine (5-HT) system. The principles behind visualising fluctuations in neurotransmitters are introduced, with reference to the dopaminergic system. Studies that aim to image acute, endogenous 5-HT release or depletion at 5-HT receptor targets are summarised, with particular attention to studies in humans. Radiotracers targeting the 5-HT(1A), 5-HT(2A), and 5-HT(4) receptors and the serotonin reuptake transporter have been explored for their sensitivity to 5-HT fluctuations, but with mixed outcomes; tracers for these targets cannot reliably image endogenous 5-HT in humans. Shortcomings in our basic knowledge of the mechanisms underlying changes in binding potential are addressed, and suggestions are made as to how the selection of targets, radiotracers, challenge paradigms, and experimental design might be optimised to improve our chances of successfully imaging endogenous neurotransmitters in the future.
  • Article
    • Klaus Holst
      Klaus Holst
    • Gitte M Knudsen
    • Jan Kalbitzer
    • David Erritzoe
      David Erritzoe
    A polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been associated with seasonality both in patients with seasonal affective disorder and in the general population. We used in vivo molecular imaging to measure cerebral serotonin transporter (5-HTT) binding in 57 healthy Scandinavians and related the outcome to season of the year and to the 5-HTTLPR carrier status. We found that the number of daylight minutes at the time of scanning correlated negatively with 5-HTT binding in the putamen and the caudate, with a similar tendency in the thalamus, whereas this association was not observed for the midbrain. Furthermore, in the putamen, an anatomic region with relatively dense serotonin innervation, we found a significant gene x daylight effect, such that there was a negative correlation between 5-HTT binding and daylight minutes in carriers of the short 5-HTTLPR allele but not in homozygote carriers of the long allele. Our findings are in line with S-carriers having an increased response in neural circuits involved in emotional processing to stressful environmental stimuli but here demonstrated as a endophenotype with dynamic changes in serotonin reuptake.
  • Article
    • Lisbeth Marner
    • Nic Gillings
      Nic Gillings
    • Karine Madsen
      Karine Madsen
    • Gitte M Knudsen
    Pharmacological stimulation of the serotonin 4 (5-HT(4)) receptor has shown promise for treatment of Alzheimer's disease and major depression. A new selective radioligand, [(11)C]SB207145, for positron emission tomography (PET) was used to quantify brain 5-HT(4) receptors in sixteen healthy subjects (20-45 years, 8 males) using the simplified reference tissue model. We tested within our population the effect of age and other demographic factors on the endpoint. In seven subjects, we tested the vulnerability of radioligand binding to a pharmacolological challenge with citalopram, which is expected to increase competition from endogenous serotonin. Given radiotracer administration at a range of specific activities, we were able to use the individual BP(ND) measurements for population-based estimation of the saturation binding parameters; B(max) ranged from 0.3 to 1.6 nM. B(max) was in accordance with post-mortem brain studies (Spearman's r=0.83, p=0.04), and the regional binding potentials, BP(ND), were on average 2.6 in striatum, 0.42 in prefrontal cortex, and 0.91 in hippocampus. We found no effect of sex but a decreased binding with age (p=0.046). A power analysis showed that, given the low inter-and intrasubject variation, use of the present method will enable detection of a 15% difference in striatum with only 7-13 subjects in a 2-sample test and with only 4-5 subjects in a paired test. The citalopram challenge did not discernibly alter [(11)C]SB207145 binding. In conclusion, the 5-HT(4) receptor binding in human brain can be reliably assessed with [(11)C]SB207145, which is encouraging for future PET studies of drug occupancy or patients with neuropsychiatric disorders.
  • Article
    • Daniela Popa
      Daniela Popa
    • Julie Cerdan
    • Christelle Repérant
    • Alain M Gardier
      Alain M Gardier
    The onset of a therapeutic response to antidepressant treatment exhibits a delay of several weeks. The present study was designed to know whether extracellular serotonin (5-HT) levels need to be increased in territories of 5-HT innervation in order to obtain beneficial effects from a chronic treatment with a serotonin-selective reuptake inhibitor (SSRI). Thus, we performed a longitudinal study of a chronic fluoxetine treatment in a model of highly emotional mice (BALB/cJ). The function of the 5-HT system in the raphe nuclei and hippocampus, was assessed by using repeated in vivo microdialysis sessions in awake freely moving mice, then studying its relation with behavior, analyzed mainly with open field paradigm. One of the neural mechanisms underlying such delay has been proposed to be the functional status of 5-HT1A autoreceptors in raphe nuclei. Thus, we also assessed the degree of 5-HT1A autoreceptor desensitization by using a local infusion in the raphe of the antagonist, WAY 100635 via reverse microdialysis. We report that the anxiolytic-like effects of fluoxetine correlate in time and amplitude with 5-HT1A autoreceptor desensitization, but neither with the extracellular levels of 5-HT in the raphe nuclei, nor in the hippocampus. Our study suggests that the beneficial anxiolytic/antidepressant-like effects of chronic SSRI treatment indeed depend on 5-HT1A autoreceptor internalization, but do not require a sustained increase in extracellular 5-HT levels in a territory of 5-HT projection such as hippocampus.
  • Article
    • Rebeca Vidal
      Rebeca Vidal
    • Elsa M Valdizán
      Elsa M Valdizán
    • Elena Castro
      Elena Castro
    • Ricardo Mostany
      Ricardo Mostany
    The mode of action of antidepressant drugs may be related to mechanisms of monoamines receptor adaptation, including serotonin 5-HT(4) receptor subtypes. Here we investigated the effects of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine for 21 days (5 and 10 mg/kg, p.o., once daily) on the sensitivity of 5-HT(4) receptors by using receptor autoradiography, adenylate cyclase assays and extracellular recording techniques in rat brain. Fluoxetine treatment decreased the density of 5-HT(4) receptor binding in the CA1 field of hippocampus as well as in several areas of the striatum over the doses of 5-10 mg/kg. In a similar way, we found a significant lower response to zacopride-stimulated adenylate cyclase activity in the fluoxetine 10 mg/kg/day treated group. Furthermore, post-synaptic 5-HT(4) receptor activity in hippocampus-measured as the excitatory action of zacopride in the pyramidal cells of CA1 evoked by Schaffer collateral stimulation was attenuated in rats treated with both doses of fluoxetine. Taken together, these results support the concept that a net decrease in the signalization pathway of 5-HT(4) receptors occurs after chronic selective serotonin reuptake inhibitor treatment: this effect may underlie the therapeutic efficacy of these drugs.
  • Article
    • Cecilie Löe Licht
    • Gitte M Knudsen
    • Anders Bue Klein
      Anders Bue Klein
    • Gregers Wegener
      Gregers Wegener
    The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography, and related this to 5-HT transporter (S)-[N-methyl-(3)H]citalopram binding. We also determined the regulation of 5-HT(4) receptor binding by 1, 14, and 21 days of paroxetine administration and subchronic 5-HT depletion, and compared this with changes in 5-HT(2A) receptor [(3)H]MDL100907 binding. In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4) receptor binding in all regions evaluated including the basal ganglia and hippocampus, while 5-HT depletion increased the 5-HT(4) receptor binding in the dorsal hippocampus, hypothalamus, and lateral globus pallidus. In comparison, the 5-HT(2A) receptor binding was decreased in the frontal and cingulate cortices after chronic paroxetine administration, and markedly reduced in several regions after 5-HT depletion. Thus, the 5-HT(4) receptor binding was decreased in the Flinders Sensitive Line depression model and in response to chronic paroxetine administration.
  • Serotonin 4 receptor and a 3-week SSRI intervention ME Haahr et al 6 Molecular
    Serotonin 4 receptor and a 3-week SSRI intervention ME Haahr et al 6 Molecular Psychiatry (2013), 1 – 6
  • Article
    • N Bel
    • Francesc Artigas
    The effects of systemic administration of fluvoxamine on extracellular serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the frontal cortex and raphe nuclei of freely moving rats were examined. Fluvoxamine significantly increased extracellular 5-HT concentrations in both regions at the two doses used (1 and 10 mg/kg i.p.). However, the increase in the raphe nuclei was several-fold that in the frontal cortex. Dialysate 5-HIAA concentrations decreased after treatment with fluvoxamine. These results confirm that 5-HT uptake inhibitors preferentially increase extracellular concentrations of 5-HT in the vicinity of cell bodies and dendrites of serotonergic neurones.
  • Article
    • Roberto William Invernizzi
      Roberto William Invernizzi
    • Stefano Belli
    • R Samanin
    Administered intraperitoneally to rats at 1 mg/kg, citalopram, a potent and selective inhibitor of serotonin uptake, significantly increased dialysate serotonin in the dorsal raphe, but not in the frontal cortex. At 10 mg/kg citalopram had a greater effect on raphe serotonin and a moderate and short-lasting increase in the dialysate serotonin in the frontal cortex. Citalopram 1 mg/kg i.p. significantly increased the extracellular concentration of serotonin in the frontal cortex of rats which had received a continuous infusion of 1 microM methiothepine in the dorsal raphe, a condition which by itself did not change cortical serotonin concentrations. The results suggest that the ability of serotonin uptake inhibitors to enhance the extracellular concentrations of serotonin in the dorsal raphe attenuates the drug's effect in the frontal cortex.
  • Article
    • Roger P. Woods
    • Simon R Cherry
      Simon R Cherry
    • John C. Mazziotta
    A computer algorithm for the three-dimensional (3D) alignment of PET images is described. To align two images, the algorithm calculates the ratio of one image to the other on a voxel-by-voxel basis and then iteratively moves the images relative to one another to minimize the variance of this ratio across voxels. Since the method relies on anatomic information in the images rather than on external fiducial markers, it can be applied retrospectively. Validation studies using a 3D brain phantom show that the algorithm aligns images acquired at a wide variety of positions with maximum positional errors that are usually less than the width of a voxel (1.745 mm). Simulated cortical activation sites do not interfere with alignment. Global errors in quantitation from realignment are less than 2%. Regional errors due to partial volume effects are largest when the gantry is rotated by large angles or when the bed is translated axially by one-half the interplane distance. To minimize such partial volume effects, the algorithm can be used prospectively, during acquisition, to reposition the scanner gantry and bed to match an earlier study. Computation requires 3-6 min on a Sun SPARCstation 2.
  • Article
    • D A Lewis
    • Michael Campbell
      Michael Campbell
    • Stephen L. Foote
    • John H Morrison
      John H Morrison
    In brain, the monoamines, dopamine, norepinephrine, and serotonin, are confined to anatomically distinct neuronal systems, each of which furnishes widespread projections to neocortex. In primate, but not in rat, the terminal patterns of each of these systems have a high degree of regional and laminar specificity. These findings suggest that there are different sites of action and possibly different functional roles for each of the monoamines. This type of precise anatomic information is essential to our understanding of the possible involvement of monoamines in human disease states.
  • Article
    • Stark PS
    • Ray W. Fuller
    • D T Wong
    Fluoxetine is a selective inhibitor of serotonin uptake in vitro. Unlike many antidepressant drugs, fluoxetine has little affinity for muscarinic, histaminic H1, serotonergic 5-HT1 or 5-HT2, or noradrenergic alpha 1 or alpha 2 receptors on rat brain membranes in vitro. Fluoxetine inhibits serotonin uptake in vivo without affecting norepinephrine uptake. Neuroendocrine and behavioral consequences of enhanced serotonergic function resulting from fluoxetine's inhibition of serotonin uptake in vivo are described. Fluoxetine is relatively nontoxic in several animal species. The specificity of action of fluoxetine makes it a good candidate as an antidepressant drug.
  • Article
    • Sheldon Cohen
      Sheldon Cohen
    • Tom Kamarck
    • Robin Mermelstein
      Robin Mermelstein
    This paper presents evidence from three samples, two of college students and one of participants in a community smoking-cessation program, for the reliability and validity of a 14-item instrument, the Perceived Stress Scale (PSS), designed to measure the degree to which situations in one's life are appraised as stressful. The PSS showed adequate reliability and, as predicted, was correlated with life-event scores, depressive and physical symptomatology, utilization of health services, social anxiety, and smoking-reduction maintenance. In all comparisons, the PSS was a better predictor of the outcome in question than were life-event scores. When compared to a depressive symptomatology scale, the PSS was found to measure a different and independently predictive construct. Additional data indicate adequate reliability and validity of a four-item version of the PSS for telephone interviews. The PSS is suggested for examining the role of nonspecific appraised stress in the etiology of disease and behavioral disorders and as an outcome measure of experienced levels of stress.
  • Article
    • John P. Rice
    • Theodore Reich
    • Kathleen K Bucholz
      Kathleen K Bucholz
    • Henri Begleiter
    Using data from The Collaborative Study on the Genetics of Alcoholism, we compare direct interview diagnoses of alcohol dependence to those obtained by history from family members. Using a requirement of three or more positive implications by history, the specificity, sensitivity, and positive predictive values are 98%, 39%, and 45%, respectively. A logistic analysis found the gender of the relative and alcoholism in the informant to be significant, but not the gender of the informant. The partial odds ratio of a diagnosis at interview associated with a positive family history diagnosis was 13.6. The relationship between the informant and relative was significant, with negative reports from an offspring or mate more influential than a negative report from a parent or second-degree relative. We derived a recursive equation to combine a variable number of family history reports, wherein the probabilities associated with a single report are computed from the logistic analysis. This permits the use of family history information both as a proxy for an uninterviewed relative, as well as a second source of information to be used in the analysis of genetic family data.
  • Article
    • A Lucchelli
    • Maria Grazia Santagostino-Barbone
    • Annalisa Barbieri
      Annalisa Barbieri
    • M Tonini
    1. A combined study of receptor binding in central neuronal cell membranes and functional responses in isolated segments of guinea-pig small intestine allowed characterization of the interaction of four antidepressant drugs with central and peripheral 5-HT3 and 5-HT4 receptors. 2. Clomipramine, paroxetine and fluoxetine inhibited [3H]-DAU 6215 binding to 5-HT3 recognition sites in NG 108-15 cells with IC50 values in the range 1.3-4 microM. Litoxetine had an IC50 of 0.3 microM. The specific binding of [3H]-GR 113808 to 5-HT4 recognition sites in pig striatal membranes was inhibited by all four antidepressants with negligible potency (IC50 values > or = 20 microM). 3. In whole ileal segments, concentration-response curves to 5-HT were biphasic, with the high- and low-potency phases involving 5-HT4 and 5-HT3 receptors, respectively. Curves to 2-methyl-5-hydroxytryptamine (2-methyl-5-HT: a 5-HT3 receptor agonist) and 5-methoxytryptamine (5-MeOT: a 5-HT4 receptor agonist) were monophasic. All antidepressants were used at concentrations lacking anticholinoceptor properties, as demonstrated in both electrically stimulated longitudinal muscle-myenteric plexus preparations (LMMPs) and in unstimulated LMMPs following addition of acetylcholine (100 nM). 4. Fluoxetine (0.1-1 microM) and litoxetine (0.3-3 microM) antagonized both the high- and low-potency phases of the 5-HT curve. Schild analysis for the low-potency phase yielded pA2 estimates of 6.6 +/- 0.3 (Schild slope of 1.1) and of 6.6 +/- 0.1 (Schild slope of 1.1), respectively. At higher concentrations (3 microM), fluoxetine markedly inhibited the 5-HT response maximum. Clomipramine (10-300 nM) inhibited, by a mechanism independent of concentration, both phases of the 5-HT curve with a reduction of the maximum response. Paroxetine (1 microM) was ineffective on the high-potency phase, but caused a rightward shift of the low-potency phase (pKB: 6.1 +/- 0.01). 5. Responses to 2-methyl-5-HT were inhibited by 1 microM fluoxetine (pKB: 5.4 +/- 0.02). Like clomipramine(30 and 100 nM), litoxetine (1 and 3 microM) produced rightward displacements of 2-methyl-5-HT-induced contractions, which were virtually independent of antidepressant concentration (pKB values: 6.0 +/- 0.02 and 5.5 +/- 0.01, respectively). At higher concentrations, fluoxetine (3 microM) and clomipramine (300 nM)markedly reduced the 2-methyl-5-HT response maximum. Paroxetine (1 micro M) was ineffective.6. Responses to 5-MeOT were shifted to the right by fluoxetine (0.1-1 micro M) and litoxetine (1 and 3 microM)in a concentration-dependent manner. At higher concentrations, fluoxetine (3 microM) markedly reduced the 5-MeOT response maximum, an effect also observed with 100 and 300 nM clomipramine. Paroxetine(1 microM) was ineffective.7. In unstimulated LMMPs, the excitatory effects evoked by 5-HT, 2-methyl-5-HT and 5-MeOT and the antagonism produced by 300 nM clomipramine were comparable to those obtained in whole ileal segments. This suggests that 5-HT contained in the mucosa of whole preparations does not interfere with agonist-induced contractile responses and with the inhibitory effect of antidepressant drugs.8. In conclusion, our results show that clomipramine, fluoxetine, paroxetine and litoxetine possess low to moderate potency/affinity at both central and peripheral (enteric) 5-HT3 receptors. In contrast, all four antidepressants are virtually ineffective at central 5-HT4 receptors. Inhibition of 5-HT4 receptor mediated ileal contractions by fluoxetine, litoxetine and clomipramine may result from allostericant agonism or, more likely, from post-receptor blockade of second messenger generation. The interaction of antidepressants with central and peripheral 5-HT3 and 5-HT4 receptors may be relevant for both potential therapeutic action and adverse effects at gastrointestinal level.
  • Article
    • Anne Bruinvels
      Anne Bruinvels
    • Bernhard Landwehrmeyer
      Bernhard Landwehrmeyer
    • Eric L. Gustafson
    • Jose M. Palacios
      Jose M. Palacios
    In situ hybridization histochemistry (ISHH) was used to study the distribution of various 5-HT1 receptor messenger RNAs (mRNA) in the mammalian nervous system. Since the cDNAs encoding the different 5-HT1 receptors, have not been cloned in one single species, brains of the species appropriate for the 5-HT1 receptor messenger RNA (mRNA) have been used. Thus, 5-HT1B and 5-HT1Dα, mRNA were determined in rat and mouse brain, while 5-HT1E and 5-HT1F mRNA were studied in human (and monkey) and guinea-pig brain, respectively.
  • Article
    • David T. Wong
    • Frank P. Bymaster
    • Leroy R. Reid
    • David W. Robertson
    Like fluoxetine, the N-demethylated metabolite norfluoxetine exists in R- and S-enantiomeric forms. S-Norfluoxetine inhibited serotonin (5-HT) uptake and [3H]paroxetine binding to 5-HT uptake sites with a pKi of 7.86 and 8.88 or 14 and 1.3 nM, respectively, whereas R-norfluoxetine was 22 and 20 times, respectively, less potent. R- and S-Norfluoxetine were less potent than the corresponding enantiomers of fluoxetine as inhibitors of norepinephrine uptake and [3H]tomoxetine binding to norepinephrine uptake sites. Ex vivo studies showed that S-norfluoxetine inhibited 5-HT uptake with an ED50 of 3 mg/kg intraperitoneally, 4.7 mg/kg subcutaneously, and 9 mg/kg orally (7.3, 11.4 and 21.9 mumol/kg, respectively), while the ED50 for R-norfluoxetine exceeded 20 mg/kg intraperitoneally (48.6 mumol/kg). Inhibition of 5-HT uptake in cerebral cortex ex vivo and decrease in 5-HIAA levels in hypothalamus persisted for 24 hours after administration of S-norfluoxetine as demonstrated with the administration of fluoxetine. Thus, S-norfluoxetine is the active N-demethylated metabolite responsible for the persistently potent and selective inhibition of 5-HT uptake in vivo.
  • Article
    Full-text available
    • K P Lesch
    • Dietmar Bengel
      Dietmar Bengel
    • Armin Heils
    • Dennis L. Murphy
    Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.
  • Article
    • John Zajecka
      John Zajecka
    • Jay D. Amsterdam
    • Frederic M. Quitkin
    • Charles Merritt Beasley, Jr.
      Charles Merritt Beasley, Jr.
    Although a period of 6 to 12 months of antidepressant therapy is recommended for most patients with depression, systematic examinations of the course of adverse events over time, the resolution of early-onset events, and the possible emergence of later-onset events are limited. We examined the safety of fluoxetine, 20 mg/day, in a large, prospective, long-term treatment trial, and we report a comparison of early- and late-onset adverse events and the course of adverse events over 26 weeks of treatment. Adverse events were recorded at each visit in a uniform format by open-ended questioning, regardless of perceived causality. New or worsened events reported in either the first 4 weeks of treatment (early-reporting interval) or weeks 22 through 26 of treatment (late-reporting interval) were compared. Patients (N = 299) whose depression (DSM-III-R) remitted with 12 weeks of fluoxetine treatment entered continuation therapy, and 174 completed 26 weeks of therapy. All events that occurred in > or =5% of patients early in treatment decreased in frequency over time (p<.05), and no events occurred significantly more frequently during continuation therapy. No previously uncommon adverse events became common during long-term treatment. Common adverse events associated with initiating fluoxetine treatment in depressed patients, including nausea, insomnia, nervousness, and somnolence, resolve in the majority of patients and become significantly less frequent with continued treatment over a 6-month period. No adverse events present initially become more frequent late in treatment. Therapy with fluoxetine, 20 mg/day, is well tolerated over 6 months, and most adverse events observed early in treatment resolve.
  • Article
    • Thressa D. Smith
    • Ron Kuczenski
      Ron Kuczenski
    • Karen P George-Friedman
    • Stephen L. Foote
    Fluoxetine (FLU) rapidly enhances extracellular (EC) serotonin (5-HT) in rodent brain, whereas the antidepressant effects of this drug in humans are typically not observed for 2-3 weeks. Thus, the effects of chronic oral FLU administration on neocortical and hippocampal EC 5-HT, and on caudate EC 5-HT and dopamine (DA), were examined in awake monkeys (Macaca fascicularis) using in vivo microdialysis (10.0 mg/kg; 3, 7, 14, and 21 days). On day 3, 5-HT was significantly increased above baseline levels in hippocampus (HC) and caudate. There was a trend for an increase in neocortex EC 5-HT levels. However, by day 7 5-HT remained significantly elevated only in HC, although 5-HT levels elsewhere had not completely returned to baseline. In contrast, levels of the 5-HT metabolite, 5-HIAA, were significantly reduced in all brain regions at all time points. Caudate DA levels tended to be decreased throughout FLU treatment. Local FLU and K(+) infusion were also used at various times during chronic systemic FLU administration to evaluate changes in functional synaptic regulation. In general, these results, along with the significant decrease in 5-HIAA levels and the tendency for basal EC 5-HT levels to remain modestly elevated only in HC during sustained FLU administration, suggest a reduction in releasable pools of 5-HT. Taken together with the trend for a decrease in caudate EC DA levels, these results do not appear to support the current hypothesis regarding the mechanism of action of SSRI antidepressants-that monoaminergic neurotransmission is progressively augmented during chronic treatment.
    • C Charlier
    • Emmanuel Pinto
      Emmanuel Pinto
    • M Ansseau
    • G Plomteux
    The relationship between clinical effects and plasma concentrations of citalopram, fluoxetine, clomipramine, paroxetine and venlafaxine was studied in 119 cases of major depression. Clinical effects were evaluated using the Clinical Global Impression (CGI) improvement scale. Antidepressants were quantified by a separative chromatographic methodology. Plasma concentrations in responder patients were compared with the plasma concentrations proposed in literature as effective values. We found that the usual therapeutic window is convenient for citalopram and clomipramine, but could be reduced for fluoxetine and increased for venlafaxine and paroxetine. Concurrent drug interactions were also evaluated and clomipramine or citalopram plasma levels were found to be influenced by the presence of associated drugs. A larger study is needed, taking into account not only plasma concentrations and clinical effects, but also some pharmacokinetic data, especially the metabolic activity characterising the patient, and the presence or not of associated drugs. Copyright 2000 John Wiley & Sons, Ltd.
  • Article
    • Claus Svarer
    • Karine Madsen
      Karine Madsen
    • Steen G Hasselbalch
      Steen G Hasselbalch
    • Gitte M Knudsen
    The purpose of this study was to develop and validate an observer-independent approach for automatic generation of volume-of-interest (VOI) brain templates to be used in emission tomography studies of the brain. The method utilizes a VOI probability map created on the basis of a database of several subjects' MR-images, where VOI sets have been defined manually. High-resolution structural MR-images and 5-HT(2A) receptor binding PET-images (in terms of (18)F-altanserin binding) from 10 healthy volunteers and 10 patients with mild cognitive impairment were included for the analysis. A template including 35 VOIs was manually delineated on the subjects' MR images. Through a warping algorithm template VOI sets defined from each individual were transferred to the other subjects MR-images and the voxel overlap was compared to the VOI set specifically drawn for that particular individual. Comparisons were also made for the VOI templates 5-HT(2A) receptor binding values. It was shown that when the generated VOI set is based on more than one template VOI set, delineation of VOIs is better reproduced and shows less variation as compared both to transfer of a single set of template VOIs as well as manual delineation of the VOI set. The approach was also shown to work equally well in individuals with pronounced cerebral atrophy. Probability-map-based automatic delineation of VOIs is a fast, objective, reproducible, and safe way to assess regional brain values from PET or SPECT scans. In addition, the method applies well in elderly subjects, even in the presence of pronounced cerebral atrophy.
  • Article
    • Yvonne Forsell
    This study examined the association between the Major Depression Inventory (MDI) and the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). A questionnaire including the MDI was sent out to an adult population and was completed by a total of 10,448 persons. Psychiatrists used SCAN and interviewed a subsample (n=1093). The specificity of the MDI was 0.22, the sensitivity 0.67 and Kappa 0.25 when Major Depression according to SCAN was considered as the index of validity, and with all depressive disorders the specificity was 0.44, the sensitivity 0.51 and Kappa 0.33. Higher educated persons and those with reported disability were less likely to be false negatives. The sensitivity and specificity for different cut-off scores when using the MDI total score were calculated. The result from this study suggests that, when MDI is used in population-based samples, cut-off scores rather than the algorithm for depression should be used. The optimal cut-off score must be chosen according to the aims of the study.
  • Article
    Full-text available
    • Henricus G Ruhé
      Henricus G Ruhé
    • Jochanan Huyser
    • Jan A Swinkels
      Jan A Swinkels
    • Aart H Schene
      Aart H Schene
    Although selective serotonin reuptake inhibitors (SSRIs) are frequently used for major depressive disorder, only 50-60% of patients respond to a standard dose. For non-responders, dose escalation is often applied. To systematically review the evidence for dose escalation of SSRIs. A systematic literature search in MEDLINE, EMBASE, CINAHL and PsycInfo was performed. Randomised controlled trials and meta-analyses investigating dose escalation of SSRIs were identified. Relevant articles were retrieved and critically appraised. Results were summarised in an evidence table. Pooling was not justified because of heterogeneity of the identified studies. Eight true dose-escalation studies and three meta-analyses were identified. The available data provided no unequivocal base for dose escalation. Dose escalation before 4 weeks of treatment at a standard dose appeared to be ineffective. Dose escalation of SSRIs is equivocally supported by evidence of randomised controlled trials; methodological difficulties in the studies may account for this lack of evidence.
  • Article
    • Suresh Bada Math
      Suresh Bada Math
    • Y.C. Janardhan Reddy
    Obsessive-compulsive disorder (OCD) preferentially responds to a class of antidepressants called serotonin reuptake inhibitors (SRI). This review discusses certain issues unique to pharmacological treatment of OCD: choice of SRI, dose and duration of treatment, options after first failed SRI trial and treatment of SRI non-responders. We performed a MEDLINE search for pharmacotherapy studies published until December 2006. In addition, the reference sections of major articles, and reviews were also screened. We also considered clinical guidelines and narrative reviews in writing this review. The SRIs are equally effective in treating OCD. Meta-analyses suggest that clomipramine may be superior to other SRIs. OCD tends to respond to higher doses of SRIs than that used to treat depression. Response to treatment is usually delayed and may take up to 8-12 weeks. Atypical antipsychotics are the only proven augmenting agents in SRI non-responders. Cognitive behaviour therapy (CBT) is an effective treatment strategy in treating OCD and possibly has a role in treating SRI non-responders. Side effect profile and drug-drug interactions largely determine the choice of SRI. Those who fail to respond to one SRI trial may well respond to another SRI trial. Clomipramine is recommended if 2-3 trials of SRIs fail to produce response. Atypical antipsychotics are the first-line augmenting agents in SRI non-responders. CBT should be considered in all patients with OCD and is a potential option in SRI non-responders. OCD is a chronic and debilitating disorder. In responders, SRIs have to be continued in the same doses (if possible) for a minimum of 1-2 years and may be lifelong in those with persistent symptoms and in those with multiple relapses. CBT has to be offered in combination with SRIs wherever facilities for CBT exist.
  • Article
    Full-text available
    • F.C. Sureau
    • Andrew Reader
      Andrew Reader
    • Claude Comtat
      Claude Comtat
    • Régine Trébossen
      Régine Trébossen
    Brain PET in small structures is challenged by low resolution inducing bias in the activity measurements. Improved spatial resolution may be obtained by using dedicated tomographs and more comprehensive modeling of the acquisition system during reconstruction. In this study, we assess the impact of resolution modeling (RM) during reconstruction on image quality and on the estimates of biologic parameters in a clinical study performed on a high-resolution research tomograph. An accelerated list-mode ordinary Poisson ordered-subset expectation maximization (OP-OSEM) algorithm, including sinogram-based corrections and an experimental stationary model of resolution, has been designed. Experimental phantom studies are used to assess contrast and noise characteristics of the reconstructed images. The binding potential of a selective tracer of the dopamine transporter is also assessed in anatomic volumes of interest in a 5-patient study. In the phantom experiment, a slower convergence and a higher contrast recovery are observed for RM-OP-OSEM than for OP-OSEM for the same level of statistical noise. RM-OP-OSEM yields contrast recovery levels that could not be reached without RM as well as better visual recovery of the smallest spheres and better delineation of the structures in the reconstructed images. Statistical noise has lower variance at the voxel level with RM than without at matched resolution. In a uniform activity region, RM induces higher positive and lower negative correlations with neighboring voxels, leading to lower spatial variance. Clinical images reconstructed with RM demonstrate better delineation of cortical and subcortical structures in both time-averaged and parametric images. The binding potential in the striatum is also increased, a result similar to the one observed in the phantom study. In high-resolution PET, RM during reconstruction improves quantitative accuracy by reducing the partial-volume effects.