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Markus Mitterhauser - One of the best experts on this subject based on the ideXlab platform.
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PW01-155 - Seasonal alterations of Serotonin-1A Receptor binding in the healthy human brain
European Psychiatry, 2020Co-Authors: Christoph Spindelegger, P. Stein, Wolfgang Wadsak, M. Fink, Markus Mitterhauser, U. Moser, Markus Savli, L.k. Mien, E. Akimova, Andreas HahnAbstract:Objectives Serotonergic neurotransmission plays a key role in seasonal changes of mood and behaviour. Higher Serotonin transporter availability in healthy human subjects in times of lesser light has been reported in recent studies. Furthermore, seasonal alterations of postsynaptic Serotonin-1A Receptors have been suggested by a recent animal study. Following that, this study aimed at identifying seasonal alterations of Serotonin-1A Receptor binding in the living human brain. Methods Thirty-six healthy, drug-naive subjects were investigated using PET and the specific tracer [carbonyl-11C]WAY-100635. Regional Serotonin-1A Receptor binding (5-HT1A BPND) was related to the individual exposure to global radiation. Furthermore, the subjects were divided into two groups depending on individual exposure to global radiation, and the group differences in regional 5-HT1A BPND were determined. Results Correlation analysis controlled for age and gender revealed highly significant positive correlations between regional postsynaptic 5-HT1A BPND and global radiation accumulated for 5 days (r=.32 to .48, p=.030 to .002). Highly significant differences in 5-HT1A BPND binding between subjects with low compared to high exposure to global radiation were revealed (T=-2.63 to -3.77, p .013 to .001). 20% to 30% lower 5-HT1A BPND was found in the subject group exposed to lower amount of global radiation. Conclusion Seasonal factors such as exposure to global radiation influence postsynaptic Serotonin-1A Receptor binding in various brain regions in healthy human subjects. In combination with seasonal alterations in Serotonin turnover and 5-HTT availability revealed in recent studies, our results provide an essential contribution of molecular mechanisms in seasonal changes of human serotonergic neurotransmission.
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P02-337 - Cortisol plasma levels are associated with Serotonin - 1A Receptor binding in postmenopausal women
European Psychiatry, 2020Co-Authors: Georg S. Kranz, P. Stein, Markus Mitterhauser, Andreas Hahn, Anna Hoflich, Pia Baldinger, J Ungersbock, Ulrike Kaufmann, S. Zgud, Wolfgang WadsakAbstract:Introduction Alterations of the Serotonin-1A Receptor (5-HT1A) and the hypothalamic-pituitary-adrenal (HPA) axis have been reported in depression and anxiety disorders. We previously showed a strong negative correlation between cortisol plasma levels and 5-HT1A Receptor binding potential (BP) in patients with social anxiety disorder but not in healthy controls using PET [1]. Objectives To investigate the relationship of cortisol and the 5-HT1A BP in postmenopausal women, a population that is at increased risk of suffering from depressive symptoms. Methods Subjects: 19 postmenopausal women, aged 55.26 ± 4.98, medication free, no current substance abuse or hormone replacement therapy. PET Dynamic measurements (50 frames, 90 min) were performed using the radioligand [carbonyl-11C]WAY100635 and a GE-Advance scanner. PET data were normalized to a ligand-specific template [2]. Regions-of-interest (ROI) were defined as given in [3]. TACs within ROIs were averaged and the 5-HT1A Receptor BP was quantified using Logan-plot and PMOD 3.1. Measurement of total cortisol plasma levels was done using electrochemoluminescence. Results We found negative correlations between cortisol and 5-HT1A BP in the midbrain (Spearman's rs = −0.54, p = 0.02), the median raphe nucleus (rs = −0.47, p = 0.04) and the nucleus accumbens (rs = −0.505, p = 0.03). Conclusions In line with our previous findings [1], the observed negative association between cortisol plasma levels and 5-HT1A BP might reflect an increased vulnerability for mood disorders in postmenopausal women.
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The influence of the rs6295 gene polymorphism on Serotonin-1A Receptor distribution investigated with PET in patients with major depression applying machine learning
Translational Psychiatry, 2017Co-Authors: Alexander Kautzky, Wolfgang Wadsak, G.m. James, Cécile Philippe, Pia Baldinger-melich, Christoph Kraus, Georg S. Kranz, Thomas Vanicek, Gregor Gryglewski, Markus MitterhauserAbstract:The influence of the rs6295 gene polymorphism on Serotonin-1A Receptor distribution investigated with PET in patients with major depression applying machine learning
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the influence of the rs6295 gene polymorphism on Serotonin 1A Receptor distribution investigated with pet in patients with major depression applying machine learning
Translational Psychiatry, 2017Co-Authors: Alexander Kautzky, Wolfgang Wadsak, G.m. James, Cécile Philippe, Christoph Kraus, Georg S. Kranz, Thomas Vanicek, Gregor Gryglewski, Pia Baldingermelich, Markus MitterhauserAbstract:Major depressive disorder (MDD) is the most common neuropsychiatric disease and despite extensive research, its genetic substrate is still not sufficiently understood. The common polymorphism rs6295 of the Serotonin-1A Receptor gene (HTR1A) is affecting the transcriptional regulation of the 5-HT1A Receptor and has been closely linked to MDD. Here, we used positron emission tomography (PET) exploiting advances in data mining and statistics by using machine learning in 62 healthy subjects and 19 patients with MDD, which were scanned with PET using the radioligand [carbonyl-11C]WAY-100635. All the subjects were genotyped for rs6295 and genotype was grouped in GG vs C allele carriers. Mixed model was applied in a ROI-based (region of interest) approach. ROI binding potential (BPND) was divided by dorsal raphe BPND as a specific measure to highlight rs6295 effects (BPDiv). Mixed model produced an interaction effect of ROI and genotype in the patients’ group but no effects in healthy controls. Differences of BPDiv was demonstrated in seven ROIs; parahippocampus, hippocampus, fusiform gyrus, gyrus rectus, supplementary motor area, inferior frontal occipital gyrus and lingual gyrus. For classification of genotype, ‘RandomForest’ and Support Vector Machines were used, however, no model with sufficient predictive capability could be computed. Our results are in line with preclinical data, mouse model knockout studies as well as previous clinical analyses, demonstrating the two-pronged effect of the G allele on 5-HT1A BPND for, we believe, the first time. Future endeavors should address epigenetic effects and allosteric heteroReceptor complexes. Replication in larger samples of MDD patients is necessary to substantiate our findings.
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effects of silexan on the Serotonin 1A Receptor and microstructure of the human brain a randomized placebo controlled double blind cross over study with molecular and structural neuroimaging
The International Journal of Neuropsychopharmacology, 2015Co-Authors: P Baldinger, Wolfgang Wadsak, Markus Mitterhauser, Andreas Hahn, Anna Hoflich, Christina Ramimark, Marie Spies, Rupert Lanzenberger, S KasperAbstract:Background: Recently, Silexan, a patented active substance comprised of an essential oil produced from Lavandula angustifolia flowers, has been authorized in Germany as a medicinal product for the treatment of states of restlessness related to anxious mood. Its efficacy has been shown in several forms of anxiety disorders. Findings from preclinical and clinical studies attribute a major role to the Serotonin-1A Receptor in the pathogenesis and treatment of anxiety. Methods: To elucidate the effect of Silexan on Serotonin-1A Receptor binding, 17 healthy men underwent 2 positron emission tomography measurements using the radioligand [ carbonyl -11C]WAY-100635 following the daily intake of 160mg Silexan or placebo for a minimum of 8 weeks (randomized, double-blind, cross-over design). Additionally, structural magnetic resonance imaging and voxel-based morphometry analysis was performed to determine potential effects on gray matter microstructure. Results: Serotonin-1A Receptor binding potential was shown to be significantly reduced following the intake of Silexan compared with placebo in 2 large clusters encompassing the temporal gyrus, the fusiform gyrus and the hippocampus on one hand as well as the insula and anterior cingulate cortex on the other hand. No effects of Silexan on gray matter volume could be detected in this investigation. Conclusion: This positron emission tomography study proposes an involvement of the Serotonin-1A Receptor in the anxiolytic effects of Silexan. The study was registered in the International Standard Randomized Controlled Trial Number Register as [ISRCTN30885829][1] ( ). [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN30885829
Stephanie C Dulawa - One of the best experts on this subject based on the ideXlab platform.
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behavioral effects of chronic fluoxetine in balb cj mice do not require adult hippocampal neurogenesis or the Serotonin 1A Receptor
Neuropsychopharmacology, 2008Co-Authors: Kerri A Holick, Stephanie C DulawaAbstract:Behavioral Effects of Chronic Fluoxetine in BALB/cJ Mice Do Not Require Adult Hippocampal Neurogenesis or the Serotonin 1A Receptor
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Behavioral Effects of Chronic Fluoxetine in BALB/cJ Mice Do Not Require Adult Hippocampal Neurogenesis or the Serotonin 1A Receptor
Neuropsychopharmacology, 2007Co-Authors: Kerri A Holick, Stephanie C DulawaAbstract:Behavioral Effects of Chronic Fluoxetine in BALB/cJ Mice Do Not Require Adult Hippocampal Neurogenesis or the Serotonin 1A Receptor
Wolfgang Wadsak - One of the best experts on this subject based on the ideXlab platform.
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PW01-155 - Seasonal alterations of Serotonin-1A Receptor binding in the healthy human brain
European Psychiatry, 2020Co-Authors: Christoph Spindelegger, P. Stein, Wolfgang Wadsak, M. Fink, Markus Mitterhauser, U. Moser, Markus Savli, L.k. Mien, E. Akimova, Andreas HahnAbstract:Objectives Serotonergic neurotransmission plays a key role in seasonal changes of mood and behaviour. Higher Serotonin transporter availability in healthy human subjects in times of lesser light has been reported in recent studies. Furthermore, seasonal alterations of postsynaptic Serotonin-1A Receptors have been suggested by a recent animal study. Following that, this study aimed at identifying seasonal alterations of Serotonin-1A Receptor binding in the living human brain. Methods Thirty-six healthy, drug-naive subjects were investigated using PET and the specific tracer [carbonyl-11C]WAY-100635. Regional Serotonin-1A Receptor binding (5-HT1A BPND) was related to the individual exposure to global radiation. Furthermore, the subjects were divided into two groups depending on individual exposure to global radiation, and the group differences in regional 5-HT1A BPND were determined. Results Correlation analysis controlled for age and gender revealed highly significant positive correlations between regional postsynaptic 5-HT1A BPND and global radiation accumulated for 5 days (r=.32 to .48, p=.030 to .002). Highly significant differences in 5-HT1A BPND binding between subjects with low compared to high exposure to global radiation were revealed (T=-2.63 to -3.77, p .013 to .001). 20% to 30% lower 5-HT1A BPND was found in the subject group exposed to lower amount of global radiation. Conclusion Seasonal factors such as exposure to global radiation influence postsynaptic Serotonin-1A Receptor binding in various brain regions in healthy human subjects. In combination with seasonal alterations in Serotonin turnover and 5-HTT availability revealed in recent studies, our results provide an essential contribution of molecular mechanisms in seasonal changes of human serotonergic neurotransmission.
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P02-337 - Cortisol plasma levels are associated with Serotonin - 1A Receptor binding in postmenopausal women
European Psychiatry, 2020Co-Authors: Georg S. Kranz, P. Stein, Markus Mitterhauser, Andreas Hahn, Anna Hoflich, Pia Baldinger, J Ungersbock, Ulrike Kaufmann, S. Zgud, Wolfgang WadsakAbstract:Introduction Alterations of the Serotonin-1A Receptor (5-HT1A) and the hypothalamic-pituitary-adrenal (HPA) axis have been reported in depression and anxiety disorders. We previously showed a strong negative correlation between cortisol plasma levels and 5-HT1A Receptor binding potential (BP) in patients with social anxiety disorder but not in healthy controls using PET [1]. Objectives To investigate the relationship of cortisol and the 5-HT1A BP in postmenopausal women, a population that is at increased risk of suffering from depressive symptoms. Methods Subjects: 19 postmenopausal women, aged 55.26 ± 4.98, medication free, no current substance abuse or hormone replacement therapy. PET Dynamic measurements (50 frames, 90 min) were performed using the radioligand [carbonyl-11C]WAY100635 and a GE-Advance scanner. PET data were normalized to a ligand-specific template [2]. Regions-of-interest (ROI) were defined as given in [3]. TACs within ROIs were averaged and the 5-HT1A Receptor BP was quantified using Logan-plot and PMOD 3.1. Measurement of total cortisol plasma levels was done using electrochemoluminescence. Results We found negative correlations between cortisol and 5-HT1A BP in the midbrain (Spearman's rs = −0.54, p = 0.02), the median raphe nucleus (rs = −0.47, p = 0.04) and the nucleus accumbens (rs = −0.505, p = 0.03). Conclusions In line with our previous findings [1], the observed negative association between cortisol plasma levels and 5-HT1A BP might reflect an increased vulnerability for mood disorders in postmenopausal women.
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The influence of the rs6295 gene polymorphism on Serotonin-1A Receptor distribution investigated with PET in patients with major depression applying machine learning
Translational Psychiatry, 2017Co-Authors: Alexander Kautzky, Wolfgang Wadsak, G.m. James, Cécile Philippe, Pia Baldinger-melich, Christoph Kraus, Georg S. Kranz, Thomas Vanicek, Gregor Gryglewski, Markus MitterhauserAbstract:The influence of the rs6295 gene polymorphism on Serotonin-1A Receptor distribution investigated with PET in patients with major depression applying machine learning
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the influence of the rs6295 gene polymorphism on Serotonin 1A Receptor distribution investigated with pet in patients with major depression applying machine learning
Translational Psychiatry, 2017Co-Authors: Alexander Kautzky, Wolfgang Wadsak, G.m. James, Cécile Philippe, Christoph Kraus, Georg S. Kranz, Thomas Vanicek, Gregor Gryglewski, Pia Baldingermelich, Markus MitterhauserAbstract:Major depressive disorder (MDD) is the most common neuropsychiatric disease and despite extensive research, its genetic substrate is still not sufficiently understood. The common polymorphism rs6295 of the Serotonin-1A Receptor gene (HTR1A) is affecting the transcriptional regulation of the 5-HT1A Receptor and has been closely linked to MDD. Here, we used positron emission tomography (PET) exploiting advances in data mining and statistics by using machine learning in 62 healthy subjects and 19 patients with MDD, which were scanned with PET using the radioligand [carbonyl-11C]WAY-100635. All the subjects were genotyped for rs6295 and genotype was grouped in GG vs C allele carriers. Mixed model was applied in a ROI-based (region of interest) approach. ROI binding potential (BPND) was divided by dorsal raphe BPND as a specific measure to highlight rs6295 effects (BPDiv). Mixed model produced an interaction effect of ROI and genotype in the patients’ group but no effects in healthy controls. Differences of BPDiv was demonstrated in seven ROIs; parahippocampus, hippocampus, fusiform gyrus, gyrus rectus, supplementary motor area, inferior frontal occipital gyrus and lingual gyrus. For classification of genotype, ‘RandomForest’ and Support Vector Machines were used, however, no model with sufficient predictive capability could be computed. Our results are in line with preclinical data, mouse model knockout studies as well as previous clinical analyses, demonstrating the two-pronged effect of the G allele on 5-HT1A BPND for, we believe, the first time. Future endeavors should address epigenetic effects and allosteric heteroReceptor complexes. Replication in larger samples of MDD patients is necessary to substantiate our findings.
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effects of silexan on the Serotonin 1A Receptor and microstructure of the human brain a randomized placebo controlled double blind cross over study with molecular and structural neuroimaging
The International Journal of Neuropsychopharmacology, 2015Co-Authors: P Baldinger, Wolfgang Wadsak, Markus Mitterhauser, Andreas Hahn, Anna Hoflich, Christina Ramimark, Marie Spies, Rupert Lanzenberger, S KasperAbstract:Background: Recently, Silexan, a patented active substance comprised of an essential oil produced from Lavandula angustifolia flowers, has been authorized in Germany as a medicinal product for the treatment of states of restlessness related to anxious mood. Its efficacy has been shown in several forms of anxiety disorders. Findings from preclinical and clinical studies attribute a major role to the Serotonin-1A Receptor in the pathogenesis and treatment of anxiety. Methods: To elucidate the effect of Silexan on Serotonin-1A Receptor binding, 17 healthy men underwent 2 positron emission tomography measurements using the radioligand [ carbonyl -11C]WAY-100635 following the daily intake of 160mg Silexan or placebo for a minimum of 8 weeks (randomized, double-blind, cross-over design). Additionally, structural magnetic resonance imaging and voxel-based morphometry analysis was performed to determine potential effects on gray matter microstructure. Results: Serotonin-1A Receptor binding potential was shown to be significantly reduced following the intake of Silexan compared with placebo in 2 large clusters encompassing the temporal gyrus, the fusiform gyrus and the hippocampus on one hand as well as the insula and anterior cingulate cortex on the other hand. No effects of Silexan on gray matter volume could be detected in this investigation. Conclusion: This positron emission tomography study proposes an involvement of the Serotonin-1A Receptor in the anxiolytic effects of Silexan. The study was registered in the International Standard Randomized Controlled Trial Number Register as [ISRCTN30885829][1] ( ). [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN30885829
Ramin V Parsey - One of the best experts on this subject based on the ideXlab platform.
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relations between cortical thickness Serotonin 1A Receptor binding and structural connectivity a multimodal imaging study
Human Brain Mapping, 2018Co-Authors: Rajapillai L I Pillai, Maria A Oquendo, John J Mann, Ashwin Malhotra, Deborah D Rupert, Bennett Wechsler, John C Williams, Mengru Zhang, Jie Yang, Ramin V ParseyAbstract:Serotonin 1A (5-HT1A ) Receptors play a direct role in neuronal development, cell proliferation, and dendritic branching. We hypothesized that variability in 5-HT1A binding can affect cortical thickness, and may account for a subtype of major depressive disorder (MDD) in which both are altered. To evaluate this, we measured cortical thickness from structural magnetic resonance imaging (MRI) and 5-HT1A binding by positron emission tomography (PET) in an exploratory study. To examine a range of 5-HT1A binding and cortical thickness values, we recruited 25 healthy controls and 19 patients with MDD. We hypothesized increased 5-HT1A binding in the raphe nucleus (RN) would be negatively associated with cortical thickness due to reduced serotonergic transmission. Contrary to our hypothesis, raphe 5-HT1A binding was positively correlated with cortical thickness in right posterior cingulate cortex (PCC), a region implicated in the default mode network. Cortical thickness was also positively correlated with 5-HT1A in each cortical region. We further hypothesized that the strength of 5-HT1A -cortical thickness correlation depends on the number of axons between the raphe nucleus and each region. To explore this we related 5-HT1A -cortical thickness correlation coefficients to the number of tracts connecting that region and the raphe, as measured by diffusion tensor imaging (DTI) in an independent sample. The 5-HT1A -cortical thickness association correlated significantly with the number of tracts to each region, supporting our hypothesis. We posit a defect in the raphe may affect the PCC within the default mode network in MDD through serotonergic fibers, resulting in increased ruminative processing.
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brain Serotonin 1A Receptor binding as a predictor of treatment outcome in major depressive disorder
Biological Psychiatry, 2013Co-Authors: Jeffrey M Miller, Maria A Oquendo, Natalie Hesselgrave, Todd R Ogden, Francesca Zanderigo, John J Mann, Ramin V ParseyAbstract:Background We previously reported higher Serotonin 1A Receptor (5-HT1A) binding in subjects with major depressive disorder (MDD) during a major depressive episode using positron emission tomography imaging with [ 11 C]WAY-100635. 5-HT1A Receptor binding is also associated with treatment outcome after nonstandardized antidepressant treatment. We examined whether pretreatment 5-HT1A binding is associated with treatment outcome following standardized escitalopram treatment in MDD. We also compared 5-HT1A binding between all MDD subjects in this cohort and a sample of healthy control subjects. Methods Twenty-four MDD subjects in a current major depressive episode and 51 previously studied healthy control subjects underwent positron emission tomography scanning with [ 11 C]WAY-100635, acquiring a metabolite-corrected arterial input function and free-fraction measurement to estimate 5-HT1A binding potential (BP F = B max /K D , where B max = available Receptors and K D = dissociation constant). Major depressive disorder subjects then received 8 weeks of treatment with escitalopram; remission was defined as a posttreatment 24-item Hamilton Depression Rating Scale Results Remitters to escitalopram had 33% higher baseline 5-HT1A binding in the raphe nuclei than nonremitters ( p = .047). Across 12 cortical and subcortical regions, 5-HT1A binding did not differ between remitters and nonremitters ( p = .86). Serotonin 1A Receptor binding was higher in MDD than control subjects across all regions ( p = .0003). Remitters did not differ from nonremitters in several relevant clinical measures. Conclusions Elevated 5-HT1A binding in raphe nuclei is associated with subsequent remission with the selective Serotonin reuptake inhibitor escitalopram; this is consistent with data from a separate cohort receiving naturalistic antidepressant treatment. We confirmed our previous findings of higher 5-HT1A binding in current MDD compared with control subjects.
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imaging the Serotonin 1A Receptor using 11c way100635 in healthy controls and major depression
Philosophical Transactions of the Royal Society B, 2013Co-Authors: Natalie Hesselgrave, Ramin V ParseyAbstract:As a neurotransmitter, Serotonin (5-HT) is widely used throughout the brain and known to play a role in many processes including emotion and brain development. Of the 15 subtypes of 5-HT Receptors, the 1A Receptor (5-HT1A) has been implicated in depression and suicide. Using the [carbonyl-11C]WAY100635 ([11C]WAY) ligand and positron emission tomography, we have studied the 5-HT1A Receptor, first in a group of healthy controls, then in two separate groups of subjects with major depressive disorder (MDD) (antidepressant exposed and not recently medicated), and, lastly, in a group of subjects remitted from MDD. All MDD subjects were medication-free at the time of scan. We found higher 5-HT1A binding potential (BPF) in MDD subjects not recently exposed to an antidepressant compared with controls and recently medicated MDD subjects; and higher BPF in subjects with the C(-1019)G promoter polymorphism. We replicated these findings in a novel cohort and reconciled our discrepant findings with other groups using alternate quantification techniques. We also reported higher BPF in subjects remitted from a major depressive episode than in controls. From this work, we proposed a temporal model in which 5-HT1A BPF may be a trait abnormality of MDD. To further explore the genetic components of MDD and utility of 5-HT1A imaging as a potential tool for biomarker or treatment response prediction, these findings should be replicated in a larger cohort using the [11C]CUMI-101 agonist tracer.
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positron emission tomography quantification of Serotonin 1A Receptor binding in medication free bipolar depression
Biological Psychiatry, 2009Co-Authors: Gregory M Sullivan, Maria A Oquendo, Todd R Ogden, John J Mann, J Dileep S Kumar, Norman R Simpson, Yungyu Huang, Ramin V ParseyAbstract:Background Little is known about the Serotonin-1A Receptor (5-HT1A) in bipolar depression despite altered 5-HT1A binding in major depressive disorder. Utilizing positron emission tomography (PET) and the radioligand N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide ([Carbonyl-C-11]WAY-100635), 5-HT1A binding was compared between depressed bipolar disorder (BD) and controls. Methods Brain 5-HT1A binding potential ( BP F = B max / K D , where B max = total available Receptors, and 1/ K D = ligand affinity) was measured in 32 currently depressed, medication-free BD subjects and 47 controls. Participants were genotyped for the 5-HT1A promoter polymorphism C(-1019)G. Results The bipolar depressed group demonstrated higher 5-HT1A BP F across all regions of interest (ROIs; p = .022). Post hoc analyses indicated that male BD patients had higher 5-HT1A BP F than male controls ( p = .025), with higher 5-HT1A BP F found in every region (by 102% in raphe nuclei and 29% to 50% in the forebrain ROIs); whereas, female subgroups did not differ in 5-HT1A BP F ( p = .32). Serotonin-1A BP F did not correlate with depression severity. The GG genotype was overrepresented at trend level in the BD group ( p = .057). Number of G-allele copies was associated with higher 5-HT1A BP F in raphe ( p = .0050), amygdala ( p = .022), and hippocampus ( p = .041). Conclusions Higher 5-HT1A BP F in bipolar depressed males suggests higher raphe autoReceptor binding, potentially causing less Serotonin release and compensatory upregulation of forebrain postsynaptic 5-HT1A Receptors. The raphe effect may be partly genetic. No difference in 5-HT1A BP F between BD and control females may reflect greater effect of prior antidepressant exposure in BD females.
Amitabha Chattopadhyay - One of the best experts on this subject based on the ideXlab platform.
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Sphingolipid-Binding Domain in the Serotonin 1A Receptor
Advances in Experimental Medicine and Biology, 2020Co-Authors: Amitabha Chattopadhyay, Yamuna Devi Paila, Pushpendra Singh, Sandeep Shrivastava, Shrish Tiwari, Jacques FantiniAbstract:Sphingolipids are essential components of eukaryotic cell membranes and are responsible for important cellular functions. A characteristic feature of sphingolipid organization in cellular membranes is their segregation in membrane domains. Serotonin1A Receptors are representative members of the superfamily of G-protein coupled Receptors (GPCRs) and are implicated in the generation and modulation of various cognitive, developmental, and behavioral functions. We previously reported that sphingolipids are necessary for ligand binding and cellular signaling of the human Serotonin1A Receptor. Proteins that interact with (glyco)sphingolipids are reported to have a characteristic amino acid sequence, termed the “sphingolipid-binding domain” (SBD). We report here that the human Serotonin1A Receptor contains a putative SBD, corresponding to amino acids 99 to 109. Interestingly, our analysis shows that the SBD motif appears to be an inherent feature of the Serotonin1A Receptor and is conserved over natural evolution across various phyla. However, experiments with the 11-mer SBD peptide in model membranes utilizing intrinsic tryptophan fluorescence did not show significant binding, probably highlighting the importance of the overall “context” of the Receptor architecture in lipid–GPCR interactions. These results constitute the first report of the presence of SBD in Serotonin Receptors and could provide novel insight into the molecular nature of GPCR–sphingolipid interaction.
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Organization and Dynamics of the Serotonin-1A Receptor in Live Cells
Biophysical Journal, 2012Co-Authors: Amitabha ChattopadhyayAbstract:It is important to understand the dynamic organization of membrane-bound molecules in order to arrive at a comprehensive view of cellular signaling mediated by membrane-bound Receptors.1 We addressed the organization and dynamics of the human Serotonin1A Receptor fused to enhanced yellow fluorescent protein expressed in CHO cells. Serotonin1A Receptors are prototypical members of the G-protein coupled Receptor superfamily and represent a prime target for therapeutic actions of several anxiolytic and antidepressant drugs.2 Our recent work using z-scan fluorescence correlation spectroscopy (zFCS) provides novel insight on the effects of cholesterol depletion and actin cytoskeleton destabilization on Receptor confinement.3 Interestingly, results from FRAP measurements performed under conditions of mild cytoskeletal destabilization suggest that Receptor signaling is correlated with Receptor mobility.4 We recently proposed, utilizing homo-FRET in live cells, that the Serotonin1A Receptor is present as constitutive oligomers and implicated the presence of higher-order oligomers.5,6 Taken together, these results on the cellular organization and dynamics of the Serotonin1A Receptor provide useful insight in understanding the function of the Receptor in healthy and diseased states.1. Saxena, R., and Chattopadhyay, A. (2011) J. Neurochem. 116: 726-733.2. Pucadyil, T.J., Kalipatnapu, S., and Chattopadhyay, A. (2005) Cell. Mol. Neurobiol. 25: 553-580.3. Ganguly, S., and Chattopadhyay, A. (2010) Biophys. J. 99: 1397-1407.4. Ganguly, S., Pucadyil, T.J., and Chattopadhyay, A. (2008) Biophys. J. 95: 451-463.5. Ganguly, S., Clayton, A.H., and Chattopadhyay, A. (2011) Biophys. J. 100: 361-368.6. Paila, Y.D., Kombrabail, M., Krishnamoorthy, G., and Chattopadhyay, A. (2011) J. Phys. Chem. B (in press).
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Organization and dynamics of the Serotonin 1A Receptor in live cells using fluorescence microscopy
2011 Functional Optical Imaging, 2011Co-Authors: Amitabha ChattopadhyayAbstract:It is important to understand the dynamic organization of membrane-bound molecules in order to arrive at a comprehensive view of cellular signaling mediated by membrane-bound Receptors.1 We addressed the organization and dynamics of the human Serotonin 1A Receptor fused to enhanced yellow fluorescent protein expressed in CHO cells. Serotonin 1A Receptors are prototypical members of the G-protein coupled Receptor superfamily and represent a prime target for therapeutic actions of several anxiolytic and antidepressant drugs.2 Interestingly, we observed significant retention in fluorescence of Serotonin 1A Receptors upon Triton X-100 treatment of intact cells at low temperature demonstrating their detergent insolubility.3 We analyzed the role of cholesterol in the plasma membrane organization of the Serotonin 1A Receptor by fluorescence recovery after photobleaching (FRAP) measurements with varying bleach spot sizes. Our results show that lateral diffusion parameters of Serotonin 1A Receptors are altered in cholesterol-depleted cells in a manner that is consistent with dynamic confinement of Serotonin 1A Receptors in the plasma membrane.4 Our recent work using z-scan fluorescence correlation spectroscopy (zFCS) provides novel insight on the effects of cholesterol depletion and actin cytoskeleton destabilization on Receptor confinement.5 Interestingly, results from FRAP measurements performed under conditions of mild cytoskeletal destabilization suggest that Receptor signaling is correlated with Receptor mobility, in agreement with the ‘mobile Receptor hypothesis’.6 In addition, we developed a novel microscopy-based image reconstruction approach to quantitatively monitor dynamic changes in actin cytoskeletal network upon signaling.7 We recently proposed utilizing Homo-FRET in live cells, that the Serotonin 1A Receptor is present as constitutive oligomers and implicated the presence of higher-order oligomers.8 Taken together, these results on the cellular organization and dynamics of the Serotonin 1A Receptor would be valuable in understanding the function of the Receptor in healthy and diseased states.
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Metabolic depletion of sphingolipids enhances the mobility of the human Serotonin1A Receptor.
Biochemical and Biophysical Research Communications, 2011Co-Authors: Sourav Ganguly, Yamuna Devi Paila, Amitabha ChattopadhyayAbstract:Abstract Sphingolipids are essential components of eukaryotic cell membranes. We recently showed that the function of the Serotonin 1A Receptor is impaired upon metabolic depletion of sphingolipids using fumonisin B 1 (FB 1 ), a specific inhibitor of ceramide synthase. Serotonin 1A Receptors belong to the family of G-protein coupled Receptors and are implicated in the generation and modulation of various cognitive, behavioral and developmental functions. Since function and dynamics of membrane Receptors are often coupled, we monitored the lateral dynamics of the Serotonin 1A Receptor utilizing fluorescence recovery after photobleaching (FRAP) under these conditions. Our results show an increase in mobile fraction of the Receptor upon sphingolipid depletion, while the diffusion coefficient of the Receptor did not exhibit any significant change. These novel results constitute the first report on the effect of sphingolipid depletion on the mobility of the Serotonin 1A Receptor. Our results assume greater relevance in the broader context of the emerging role of Receptor mobility in understanding cellular signaling.
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Reorganization of the actin cytoskeleton upon G-protein coupled Receptor signaling
Biochimica et Biophysica Acta, 2011Co-Authors: Sourav Ganguly, Roopali Saxena, Amitabha ChattopadhyayAbstract:Abstract The actin cytoskeleton is involved in a multitude of cellular responses besides providing structural support. While the role of the actin cytoskeleton in cellular processes such as trafficking and motility has been extensively studied, reorganization of the actin cytoskeleton upon signaling by G-protein coupled Receptors (GPCRs) represents a relatively unexplored area. The G-protein coupled Receptor superfamily is an important protein family in mammals, involved in signal transduction across membranes. G-protein coupled Receptors act as major signaling hubs and drug targets. The Serotonin 1A Receptor is a representative member of the G-protein coupled Receptor superfamily and plays a crucial role in the generation and modulation of various cognitive, developmental and behavioral functions. In order to monitor the changes in the actin cytoskeleton upon Serotonin 1A Receptor signaling in a quantitative manner, we developed an approach based on high magnification imaging of F-actin in cells, followed by image reconstruction. Our results suggest that the actin cytoskeleton is reorganized in response to Serotonin 1A Receptor signaling. In addition, we show that reorganization of the actin cytoskeleton is strongly dependent on adenosine 3′,5′-cyclic monophosphate level, and is mediated by the activation of protein kinase A. Our results are consistent with the possibility of a feedback mechanism involving the actin cytoskeleton, adenosine 3′,5′-cyclic monophosphate level and the Serotonin 1A Receptor.
