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Gitte M Knudsen - One of the best experts on this subject based on the ideXlab platform.

  • acute serotonin 2a receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala
    Journal of Psychopharmacology, 2013
    Co-Authors: Bettina Hornboll, Olaf B. Paulson, Julian Macoveanu, James B Rowe, Rebecca Elliott, Hartwig R Siebner, Gitte M Knudsen
    Abstract:

    Background:The serotonin 2A (5-HT2A) receptor has been implicated in neural-processing of emotionally salient information. To elucidate its role in processing of fear and anger, healthy individuals were studied with functional magnetic resonance imaging (fMRI) after 5-HT2A receptor blockade, while judging the gender of neutral, fearful and angry faces.Methods:5-HT2A receptors were blocked with ketanserin to a variable degree across subjects by adjusting the time between ketanserin-infusion and onset of the fMRI protocol. Neocortical 5-HT2A receptor binding in terms of the binding potential (BPp) was assessed prior to fMRI with 18F-Altanserin positron emission tomography (PET) and subsequently integrated in the fMRI data analysis. Also functional connectivity analysis was employed to evaluate the effect of ketanserin blocking on connectivity.Results:Compared to a control session, 5-HT2A receptor blockade reduced the neural response to fearful faces in the medial orbitofrontal cortex (OFC), independently of...

  • direct comparison of 18f mh mz and 18f Altanserin for 5 ht2a receptor imaging with pet
    Synapse, 2013
    Co-Authors: Hanne D Hansen, Anders Ettrup, Matthias M Herth, Agnete Dyssegaard, Cecilia Ratner, Nic Gillings, Gitte M Knudsen
    Abstract:

    Imaging the cerebral serotonin 2A (5-HT2A ) receptors with positron emission tomography (PET) has been carried out in humans with [(11) C]MDL 100907 and [(18) F]Altanserin. Recently, the MDL 100907 analogue [(18) F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine-18. Here, we present a direct comparison of [(18) F]Altanserin and [(18) F]MH.MZ. 5-HT2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [(3) H]MDL 100907, [(18) F]MH.MZ, and [(18) F]Altanserin. [(18) F]MH.MZ and [(18) F]Altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue-compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [(18) F]MH.MZ and [(18) F]Altanserin. Significant 5-HT2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [(18) F]MH.MZ and [(18) F]Altanserin was blocked by ketanserin supporting that both radioligands bind to 5-HT2A receptors in the pig brain. In the HPLC analysis of pig plasma, [(18) F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [(18) F]Altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [(18) F]MH.MZ in high-binding regions in vivo, we suggest that [(18) F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [(18) F]Altanserin is a suitable tracer for high-binding regions.

  • loss of serotonin 2a receptors exceeds loss of serotonergic projections in early alzheimer s disease a combined 11c dasb and 18f Altanserin pet study
    Neurobiology of Aging, 2012
    Co-Authors: Lisbeth Marner, Vibe G. Frokjaer, Jan Kalbitzer, Szabolcs Lehel, Karine Madsen, William F C Baare, Gitte M Knudsen, Steen G. Hasselbalch
    Abstract:

    In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [(18)F]Altanserin and [(11)C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([(11)C]DASB). Overall [(18)F]Altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [(11)C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [(11)C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT(2A) receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections.

  • a nonlinear relationship between cerebral serotonin transporter and 5 ht 2a receptor binding an in vivo molecular imaging study in humans
    The Journal of Neuroscience, 2010
    Co-Authors: David Erritzoe, Vibe G. Frokjaer, Finn Årup Nielsen, Claus Svarer, Jacob Madsen, Klaus K. Holst, Jan Kalbitzer, Cecilie Loe Licht, Gitte M Knudsen
    Abstract:

    Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT(2A)) receptor and the presynaptic serotonin transporter (SERT) are sensitive to chronic changes in cerebral 5-HT levels. Additionally, experimental studies suggest that alterations in either the 5-HT(2A) receptor or SERT level can affect the protein level of the counterpart. The aim of this study was to explore the covariation between cerebral 5-HT(2A) receptor and SERT in vivo in the same healthy human subjects. Fifty-six healthy human subjects with a mean age of 36 +/- 19 years were investigated. The SERT binding was imaged with [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) and 5-HT(2A) receptor binding with [(18)F]Altanserin using positron emission tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT(2A) receptor binding. An inverted U-shaped relationship between the 5-HT(2A) receptor and the SERT binding was identified. The observed regional intercorrelation for both the 5-HT(2A) receptor and the SERT cerebral binding suggests that, within the single individual, each marker has a set point adjusted through a common regulator. A quadratic relationship between the two markers is consistent with data from experimental studies of the effect on SERT and 5-HT(2A) receptor binding of chronic changes in 5-HT levels. That is, the observed association between the 5-HT(2A) receptor and SERT binding could be driven by the projection output from the raphe nuclei, but other explanations are also at hand.

  • species differences in blood brain barrier transport of three positron emission tomography radioligands with emphasis on p glycoprotein transport
    Drug Metabolism and Disposition, 2009
    Co-Authors: Stina Syvanen, Gitte M Knudsen, Orjan Lindhe, Mikael Palner, Birgitte Rahbek Kornum, Obaidur Rahman, Bengt Langstrom, Margareta Hammarlundudenaes
    Abstract:

    Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. This study was designed to compare brain uptake of three radiolabeled P-glycoprotein (P-gp) substrates across species using positron emission tomography. Brain concentrations and brain-to-plasma ratios were compared; [11C]verapamil in rats, guinea pigs, and monkeys; [11C](S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine (GR205171) in rats, guinea pigs, monkeys, and humans; and [18F]Altanserin in rats, minipigs, and humans. The fraction of the unbound radioligand in plasma was studied along with its metabolism. The effect of P-gp inhibition was investigated by administering cyclosporin A (CsA). Pronounced species differences were found in the brain and brain-to-plasma concentrations of [11C]verapamil, [11C]GR205171, and [18F]Altanserin with higher brain distribution in humans, monkeys, and minipigs than in rats and guinea pigs. For example, the brain-to-plasma ratio of [11C]GR205171 was almost 9-fold higher in humans compared with rats. The species differences were still present after P-gp inhibition, although the increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species. Differences in plasma protein binding and metabolism did not explain the species-related differences. The findings are important for interpretation of brain drug delivery when extrapolating preclinical data to humans. Compounds found to be P-gp substrates in rodents are likely to also be substrates in higher species, but sufficient blood-brain barrier permeability may be retained in humans to allow the compound to act at intracerebral targets.

Vibe G. Frokjaer - One of the best experts on this subject based on the ideXlab platform.

  • loss of serotonin 2a receptors exceeds loss of serotonergic projections in early alzheimer s disease a combined 11c dasb and 18f Altanserin pet study
    Neurobiology of Aging, 2012
    Co-Authors: Lisbeth Marner, Vibe G. Frokjaer, Jan Kalbitzer, Szabolcs Lehel, Karine Madsen, William F C Baare, Gitte M Knudsen, Steen G. Hasselbalch
    Abstract:

    In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [(18)F]Altanserin and [(11)C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([(11)C]DASB). Overall [(18)F]Altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [(11)C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [(11)C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT(2A) receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections.

  • in vivo imaging of cerebral serotonin transporter and serotonin2a receptor binding in 3 4 methylenedioxymethamphetamine mdma or ecstasy and hallucinogen users
    Archives of General Psychiatry, 2011
    Co-Authors: David Erritzoe, Vibe G. Frokjaer, Claus Svarer, Jacob Madsen, Klaus K. Holst, Maria Christoffersen, Sys Stybe Johansen, Peter Rasmussen, Thomas Z Ramsoy, Terry L Jernigan
    Abstract:

    Context Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) have direct agonistic effects on postsynaptic serotonin 2A receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin. Objective To assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin 2A receptor binding. Design A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 ( 11 C)–labeled 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile (DASB) and fluorine 18 ( 18 F)–labeled Altanserin, respectively. Scans were performed in the user group after a minimum drug abstinence period of 11 days, and the group was subdivided into hallucinogen-preferring users (n = 10) and MDMA-preferring users (n = 14). Participants Twenty-four young adult users of MDMA and/or hallucinogenic drugs and 21 nonusing controls. Main Outcome Measures In vivo cerebral SERT and serotonin 2A receptor binding. Results Compared with nonusers, MDMA-preferring users showed significant decreases in SERT nondisplaceable binding potential (neocortex, −56%; pallidostriatum, −19%; and amygdala, −32%); no significant changes were seen in hallucinogen-preferring users. Both cortical and pallidostriatal SERT nondisplaceable binding potential was negatively correlated with the number of lifetime MDMA exposures, and the time of abstinence from MDMA was positively correlated with subcortical, but not cortical, SERT binding. A small decrease in neocortical serotonin 2A receptor binding in the serotonin 2A receptor agonist users (both user groups) was also detected. Conclusions We found evidence that MDMA but not hallucinogen use is associated with changes in the cerebral presynaptic serotonergic transmitter system. Because hallucinogenic drugs primarily have serotonin 2A receptor agonistic actions, we conclude that the negative association between MDMA use and cerebral SERT binding is mediated through a direct presynaptic MDMA effect rather than by the serotonin 2A agonistic effects of MDMA. Our cross-sectional data suggest that subcortical, but not cortical, recovery of SERT binding might take place after several months of MDMA abstinence.

  • familial risk for mood disorder and the personality risk factor neuroticism interact in their association with frontolimbic serotonin 2a receptor binding
    Neuropsychopharmacology, 2010
    Co-Authors: Vibe G. Frokjaer, Erik Lykke Mortensen, David Erritzoe, Jacob Madsen, Klaus K. Holst, Terry L Jernigan, William F C Baare, Haroon Arfan, Maj Vinberg, Lars Vedel Kessing
    Abstract:

    Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability and is positively correlated to frontolimbic serotonin 2A (5-HT2A) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT2A receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co-twin history of mood disorder were included. They answered self-report personality questionnaires and underwent [18F]Altanserin positron emission tomography. We found a significant interaction between neuroticism and familial risk in predicting the frontolimbic 5-HT2A receptor binding (p=0.026) in an analysis adjusting for age and body mass index. Within the high-risk group only, neuroticism and frontolimbic 5-HT2A receptor binding was positively associated (p=0.0037). In conclusion, our data indicate that familial risk and neuroticism interact in their relation to frontolimbic 5-HT2A receptor binding. These findings point at a plausible neurobiological link between genetic and personality risk factors and vulnerability to developing mood disorders. It contributes to our understanding of why some people at high risk develop mood disorders while others do not. We speculate that an increased stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission.

  • a nonlinear relationship between cerebral serotonin transporter and 5 ht 2a receptor binding an in vivo molecular imaging study in humans
    The Journal of Neuroscience, 2010
    Co-Authors: David Erritzoe, Vibe G. Frokjaer, Finn Årup Nielsen, Claus Svarer, Jacob Madsen, Klaus K. Holst, Jan Kalbitzer, Cecilie Loe Licht, Gitte M Knudsen
    Abstract:

    Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT(2A)) receptor and the presynaptic serotonin transporter (SERT) are sensitive to chronic changes in cerebral 5-HT levels. Additionally, experimental studies suggest that alterations in either the 5-HT(2A) receptor or SERT level can affect the protein level of the counterpart. The aim of this study was to explore the covariation between cerebral 5-HT(2A) receptor and SERT in vivo in the same healthy human subjects. Fifty-six healthy human subjects with a mean age of 36 +/- 19 years were investigated. The SERT binding was imaged with [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) and 5-HT(2A) receptor binding with [(18)F]Altanserin using positron emission tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT(2A) receptor binding. An inverted U-shaped relationship between the 5-HT(2A) receptor and the SERT binding was identified. The observed regional intercorrelation for both the 5-HT(2A) receptor and the SERT cerebral binding suggests that, within the single individual, each marker has a set point adjusted through a common regulator. A quadratic relationship between the two markers is consistent with data from experimental studies of the effect on SERT and 5-HT(2A) receptor binding of chronic changes in 5-HT levels. That is, the observed association between the 5-HT(2A) receptor and SERT binding could be driven by the projection output from the raphe nuclei, but other explanations are also at hand.

  • a pet 18f Altanserin study of 5 ht2a receptor binding in the human brain and responses to painful heat stimulation
    NeuroImage, 2009
    Co-Authors: Ron Kupers, Vibe G. Frokjaer, Arne Naert, Rune Christensen, Esben Budtzjoergensen, Henrik Kehlet, Gitte M Knudsen
    Abstract:

    Abstract There is a large body of evidence that serotonin [5-hydroxytryptamine (5-HT)] plays an important role in the transmission and regulation of pain. Here we used positron emission tomography (PET) to study the relationship between baseline 5-HT2A binding in the brain and responses to noxious heat stimulation in a group of young healthy volunteers. Twenty-one healthy subjects underwent PET scanning with the 5-HT2A antagonist, [18F]Altanserin. In addition, participants underwent a battery of pain tests using noxious heat stimulation to assess pain threshold, pain tolerance and response to short-lasting phasic and long-lasting (7-minute) tonic painful stimulation. Significant positive correlations were found between tonic pain ratings and [18F]Altanserin binding in orbitofrontal (r = 0.66; p = 0.005), medial inferior frontal (r = 0.60; p = 0.014), primary sensory–motor (r = 0.61; p = 0.012) and posterior cingulate (r = 0.63; p = 0.009) cortices. In contrast, measures of regional [18F]Altanserin binding did not correlate with pain threshold, pain tolerance, or suprathreshold phasic pain responses. These data suggest that cortical 5-HT2A receptor availability co-varies with responses to tonic pain. The correlation between [18F]Altanserin binding in prefrontal cortex and tonic pain suggests a possible role of this brain region in the modulation and/or cognitive-evaluative appreciation of pain.

Claus Svarer - One of the best experts on this subject based on the ideXlab platform.

  • serotonin 2a receptor agonist binding in the human brain with 11 c cimbi 36 test retest reproducibility and head to head comparison with the antagonist 18 f Altanserin
    NeuroImage, 2016
    Co-Authors: Anders Ettrup, Claus Svarer, Szabolcs Lehel, Brenda Mcmahon, Sofi Da Cunhabang, Kirsten Moller, Agnete Dyssegaard
    Abstract:

    Introduction [11C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test–retest variability of cerebral [11C]Cimbi-36 PET and compare [11C]Cimbi-36 and the 5-HT2A receptor antagonist [18F]Altanserin. Methods Sixteen healthy volunteers (mean age 23.9 ± 6.4 years, 6 males) were scanned twice with a high resolution research tomography PET scanner. All subjects were scanned after a bolus of [11C]Cimbi-36; eight were scanned twice to determine test–retest variability in [11C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [18F]Altanserin. Regional differences in the brain distribution of [11C]Cimbi-36 and [18F]Altanserin were assessed with a correlation of regional binding measures and with voxel-based analysis. Results Test–retest variability of [11C]Cimbi-36 non-displaceable binding potential (BPND) was consistently < 5% in high-binding regions and lower for reference tissue models as compared to a 2-tissue compartment model. We found a highly significant correlation between regional BPNDs measured with [11C]Cimbi-36 and [18F]Altanserin (mean Pearson's r: 0.95 ± 0.04) suggesting similar cortical binding of the radioligands. Relatively higher binding with [11C]Cimbi-36 as compared to [18F]Altanserin was found in the choroid plexus and hippocampus in the human brain. Conclusions Excellent test–retest reproducibility highlights the potential of [11C]Cimbi-36 for PET imaging of 5-HT2A receptor agonist binding in vivo. Our data suggest that Cimbi-36 and Altanserin both bind to 5-HT2A receptors, but in regions with high 5-HT2C receptor density, choroid plexus and hippocampus, the [11C]Cimbi-36 binding likely represents binding to both 5-HT2A and 5-HT2C receptors.

  • serotonin 2a receptor agonist binding in the human brain with 11 c cimbi 36 test retest reproducibility and head to head comparison with the antagonist 18 f Altanserin
    NeuroImage, 2016
    Co-Authors: Anders Ettrup, Claus Svarer, Szabolcs Lehel, Brenda Mcmahon, Sofi Da Cunhabang, Kirsten Moller, Agnete Dyssegaard
    Abstract:

    Abstract Introduction [11C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test–retest variability of cerebral [11C]Cimbi-36 PET and compare [11C]Cimbi-36 and the 5-HT2A receptor antagonist [18F]Altanserin. Methods Sixteen healthy volunteers (mean age 23.9 ± 6.4 years, 6 males) were scanned twice with a high resolution research tomography PET scanner. All subjects were scanned after a bolus of [11C]Cimbi-36; eight were scanned twice to determine test–retest variability in [11C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [18F]Altanserin. Regional differences in the brain distribution of [11C]Cimbi-36 and [18F]Altanserin were assessed with a correlation of regional binding measures and with voxel-based analysis. Results Test–retest variability of [11C]Cimbi-36 non-displaceable binding potential (BPND) was consistently Conclusions Excellent test–retest reproducibility highlights the potential of [11C]Cimbi-36 for PET imaging of 5-HT2A receptor agonist binding in vivo. Our data suggest that Cimbi-36 and Altanserin both bind to 5-HT2A receptors, but in regions with high 5-HT2C receptor density, choroid plexus and hippocampus, the [11C]Cimbi-36 binding likely represents binding to both 5-HT2A and 5-HT2C receptors.

  • in vivo imaging of cerebral serotonin transporter and serotonin2a receptor binding in 3 4 methylenedioxymethamphetamine mdma or ecstasy and hallucinogen users
    Archives of General Psychiatry, 2011
    Co-Authors: David Erritzoe, Vibe G. Frokjaer, Claus Svarer, Jacob Madsen, Klaus K. Holst, Maria Christoffersen, Sys Stybe Johansen, Peter Rasmussen, Thomas Z Ramsoy, Terry L Jernigan
    Abstract:

    Context Both hallucinogens and 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) have direct agonistic effects on postsynaptic serotonin 2A receptors, the key site for hallucinogenic actions. In addition, MDMA is a potent releaser and reuptake inhibitor of presynaptic serotonin. Objective To assess the differential effects of MDMA and hallucinogen use on cerebral serotonin transporter (SERT) and serotonin 2A receptor binding. Design A positron emission tomography study of 24 young adult drug users and 21 nonusing control participants performed with carbon 11 ( 11 C)–labeled 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile (DASB) and fluorine 18 ( 18 F)–labeled Altanserin, respectively. Scans were performed in the user group after a minimum drug abstinence period of 11 days, and the group was subdivided into hallucinogen-preferring users (n = 10) and MDMA-preferring users (n = 14). Participants Twenty-four young adult users of MDMA and/or hallucinogenic drugs and 21 nonusing controls. Main Outcome Measures In vivo cerebral SERT and serotonin 2A receptor binding. Results Compared with nonusers, MDMA-preferring users showed significant decreases in SERT nondisplaceable binding potential (neocortex, −56%; pallidostriatum, −19%; and amygdala, −32%); no significant changes were seen in hallucinogen-preferring users. Both cortical and pallidostriatal SERT nondisplaceable binding potential was negatively correlated with the number of lifetime MDMA exposures, and the time of abstinence from MDMA was positively correlated with subcortical, but not cortical, SERT binding. A small decrease in neocortical serotonin 2A receptor binding in the serotonin 2A receptor agonist users (both user groups) was also detected. Conclusions We found evidence that MDMA but not hallucinogen use is associated with changes in the cerebral presynaptic serotonergic transmitter system. Because hallucinogenic drugs primarily have serotonin 2A receptor agonistic actions, we conclude that the negative association between MDMA use and cerebral SERT binding is mediated through a direct presynaptic MDMA effect rather than by the serotonin 2A agonistic effects of MDMA. Our cross-sectional data suggest that subcortical, but not cortical, recovery of SERT binding might take place after several months of MDMA abstinence.

  • a nonlinear relationship between cerebral serotonin transporter and 5 ht 2a receptor binding an in vivo molecular imaging study in humans
    The Journal of Neuroscience, 2010
    Co-Authors: David Erritzoe, Vibe G. Frokjaer, Finn Årup Nielsen, Claus Svarer, Jacob Madsen, Klaus K. Holst, Jan Kalbitzer, Cecilie Loe Licht, Gitte M Knudsen
    Abstract:

    Serotonergic neurotransmission is involved in the regulation of physiological functions such as mood, sleep, memory, and appetite. Within the serotonin transmitter system, both the postsynaptically located serotonin 2A (5-HT(2A)) receptor and the presynaptic serotonin transporter (SERT) are sensitive to chronic changes in cerebral 5-HT levels. Additionally, experimental studies suggest that alterations in either the 5-HT(2A) receptor or SERT level can affect the protein level of the counterpart. The aim of this study was to explore the covariation between cerebral 5-HT(2A) receptor and SERT in vivo in the same healthy human subjects. Fifty-six healthy human subjects with a mean age of 36 +/- 19 years were investigated. The SERT binding was imaged with [(11)C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) and 5-HT(2A) receptor binding with [(18)F]Altanserin using positron emission tomography. Within each individual, a regional intercorrelation for the various brain regions was seen with both markers, most notably for 5-HT(2A) receptor binding. An inverted U-shaped relationship between the 5-HT(2A) receptor and the SERT binding was identified. The observed regional intercorrelation for both the 5-HT(2A) receptor and the SERT cerebral binding suggests that, within the single individual, each marker has a set point adjusted through a common regulator. A quadratic relationship between the two markers is consistent with data from experimental studies of the effect on SERT and 5-HT(2A) receptor binding of chronic changes in 5-HT levels. That is, the observed association between the 5-HT(2A) receptor and SERT binding could be driven by the projection output from the raphe nuclei, but other explanations are also at hand.

  • Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder
    Biological psychiatry, 2007
    Co-Authors: Vibe G. Frokjaer, Erik Lykke Mortensen, Finn Årup Nielsen, Steven Haugbøl, Lars H. Pinborg, Karen H. Adams, Claus Svarer, Steen G. Hasselbalch, S. Holm, Olaf B. Paulson
    Abstract:

    Background Serotonergic dysfunction has been associated with affective disorders. High trait neuroticism, as measured on personality inventories, is a risk factor for major depression. In this study we investigated whether neuroticism is associated with serotonin 2A receptor binding in brain regions of relevance for affective disorders. Methods Eighty-three healthy volunteers completed the standardized personality questionnaire NEO-PI-R (Revised NEO Personality Inventory) and underwent [ 18 F]Altanserin positron emission tomography imaging for assessment of serotonin 2A receptor binding. The correlation between the neuroticism score and frontolimbic serotonin 2A receptor binding was evaluated by multiple linear regression analysis with adjustment for age and gender. Results Neuroticism correlated positively with frontolimbic serotonin 2A receptor binding [ r (79) = .24, p = .028]. Post hoc analysis of the contributions from the six constituent traits of neuroticism showed that the correlation was primarily driven by two of them: vulnerability and anxiety. Indeed, vulnerability, defined as a person's difficulties in coping with stress, displayed the strongest positive correlation, which remained significant after correction for multiple comparisons ( r = .35, p = .009). Conclusions In healthy subjects the personality dimension neuroticism and particularly its constituent trait, vulnerability, are positively associated with frontolimbic serotonin 2A binding. Our findings point to a neurobiological link between personality risk factors for affective disorder and the serotonergic transmitter system and identify the serotonin 2A receptor as a biomarker for vulnerability to affective disorder.

Olaf B. Paulson - One of the best experts on this subject based on the ideXlab platform.

  • acute serotonin 2a receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala
    Journal of Psychopharmacology, 2013
    Co-Authors: Bettina Hornboll, Olaf B. Paulson, Julian Macoveanu, James B Rowe, Rebecca Elliott, Hartwig R Siebner, Gitte M Knudsen
    Abstract:

    Background:The serotonin 2A (5-HT2A) receptor has been implicated in neural-processing of emotionally salient information. To elucidate its role in processing of fear and anger, healthy individuals were studied with functional magnetic resonance imaging (fMRI) after 5-HT2A receptor blockade, while judging the gender of neutral, fearful and angry faces.Methods:5-HT2A receptors were blocked with ketanserin to a variable degree across subjects by adjusting the time between ketanserin-infusion and onset of the fMRI protocol. Neocortical 5-HT2A receptor binding in terms of the binding potential (BPp) was assessed prior to fMRI with 18F-Altanserin positron emission tomography (PET) and subsequently integrated in the fMRI data analysis. Also functional connectivity analysis was employed to evaluate the effect of ketanserin blocking on connectivity.Results:Compared to a control session, 5-HT2A receptor blockade reduced the neural response to fearful faces in the medial orbitofrontal cortex (OFC), independently of...

  • Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder
    Biological psychiatry, 2007
    Co-Authors: Vibe G. Frokjaer, Erik Lykke Mortensen, Finn Årup Nielsen, Steven Haugbøl, Lars H. Pinborg, Karen H. Adams, Claus Svarer, Steen G. Hasselbalch, S. Holm, Olaf B. Paulson
    Abstract:

    Background Serotonergic dysfunction has been associated with affective disorders. High trait neuroticism, as measured on personality inventories, is a risk factor for major depression. In this study we investigated whether neuroticism is associated with serotonin 2A receptor binding in brain regions of relevance for affective disorders. Methods Eighty-three healthy volunteers completed the standardized personality questionnaire NEO-PI-R (Revised NEO Personality Inventory) and underwent [ 18 F]Altanserin positron emission tomography imaging for assessment of serotonin 2A receptor binding. The correlation between the neuroticism score and frontolimbic serotonin 2A receptor binding was evaluated by multiple linear regression analysis with adjustment for age and gender. Results Neuroticism correlated positively with frontolimbic serotonin 2A receptor binding [ r (79) = .24, p = .028]. Post hoc analysis of the contributions from the six constituent traits of neuroticism showed that the correlation was primarily driven by two of them: vulnerability and anxiety. Indeed, vulnerability, defined as a person's difficulties in coping with stress, displayed the strongest positive correlation, which remained significant after correction for multiple comparisons ( r = .35, p = .009). Conclusions In healthy subjects the personality dimension neuroticism and particularly its constituent trait, vulnerability, are positively associated with frontolimbic serotonin 2A binding. Our findings point to a neurobiological link between personality risk factors for affective disorder and the serotonergic transmitter system and identify the serotonin 2A receptor as a biomarker for vulnerability to affective disorder.

  • MR-based automatic delineation of volumes of interest in human brain PET images using probability maps
    NeuroImage, 2004
    Co-Authors: Claus Svarer, Vibe G. Frokjaer, Steven Haugbøl, Lars H. Pinborg, Steen G. Hasselbalch, Olaf B. Paulson, Karine Madsen, Soren Holm, Gitte M Knudsen
    Abstract:

    Abstract 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-HT2A receptor binding PET-images (in terms of 18F-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-HT2A 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.

  • 18f Altanserin binding to human 5ht2a receptors is unaltered after citalopram and pindolol challenge
    Journal of Cerebral Blood Flow and Metabolism, 2004
    Co-Authors: Lars H. Pinborg, Karen H. Adams, Steen G. Hasselbalch, Olaf B. Paulson, Stig Yndgaard, Soren Holm, Heidi Kristiansen, Gitte M Knudsen
    Abstract:

    The aim of the present study was to develop an experimental paradigm for the study of serotonergic neurotransmission in humans using positron emission tomography and the 5-HT2A selective radioligand [18F]Altanserin. [18F]Altanserin studies were conducted in seven subjects using the bolus/infusion approach designed for attaining steady state in blood and brain 2 hours after the initial [18F]Altanserin administration. Three hours after commencement of radiotracer administration, 0.25 mg/kg of the selective serotonin reuptake inhibitor, citalopram (Lundbeck, Valby, Denmark), was administered to all subjects as a constant infusion for 20 minutes. To reduce 5-HT1A-mediated autoinhibition of cortical 5-HT release, four of the seven subjects were pretreated with the partial 5-HT1A agonist pindolol for 3 days at an increasing oral dose (25 mg on the day of scanning). In each subject, the baseline condition (120 to 180 minutes) was compared with the stimulated condition (195 to 300 minutes). Despite a pronounced increase in plasma prolactin and two subjects reporting hot flushes compatible with an 5-HT-induced adverse effect, cortical [18F]Altanserin binding was insensitive to the citalopram challenge, even after pindolol pretreatment. The biochemical and cellular events possibly affecting the unsuccessful translation of the citalopram/pindolol challenge into a change in 5-HT2A receptor binding of [18F]Altanserin are discussed.

  • a database of 18 f Altanserin binding to 5 ht 2a receptors in normal volunteers normative data and relationship to physiological and demographic variables
    NeuroImage, 2004
    Co-Authors: Karen H. Adams, Vibe G. Frokjaer, Steven Haugbøl, Lars H. Pinborg, Claus Svarer, Steen G. Hasselbalch, Karine Madsen, Soren Holm, Lars Martiny, Olaf B. Paulson
    Abstract:

    Abstract This study presents the results of an analysis of 5-hydroxytryptamine (5-HT) 2A receptors in 52 healthy subjects. Thirty men and twenty-two women aged between 21 and 79 years were investigated with magnetic resonance imaging (MRI) and [ 18 F]-Altanserin positron emission tomography (PET). The distribution volumes of specific tracer binding (DV 3 ′) was calculated for 15 brain regions using either cerebellum or pons as reference regions and correlations between DV 3 ′ and physiological and demographic variables were made. The regional distribution of [ 18 F]-Altanserin binding in the healthy human brain was in agreement with existing in vitro post-mortem human 5-HT 2A data. Apart from nonspecific cerebellar binding (DV 2 ), there was no gender difference in 5-HT 2A binding. A positive correlation between cerebellar binding and age was observed and negative correlations between age and DV 3 ′ were found in all cortical regions, except occipital cortex, corresponding to a decrease in DV 3 ′ of 6% or 4% per decade with cerebellum or pons as reference regions, respectively. In several temporal and frontal cortical regions, positive correlations were found between body mass index (BMI) and DV 3 ′. Our findings provide a resource to aid design of clinical studies of the 5-HT 2A receptors. [ 18 F]-Altanserin binding appears to be unaffected by gender, but the effects of ageing must be considered for clinical studies. The correlations between different cortical regions' 5-HT 2A binding and BMI should be explored in future studies.

Julie C Price - One of the best experts on this subject based on the ideXlab platform.

  • age sex and reproductive hormone effects on brain serotonin 1a and serotonin 2a receptor binding in a healthy population
    Neuropsychopharmacology, 2011
    Co-Authors: Eydie L Moseskolko, Sarah Berga, Carl Becker, Rhaven L Coleman, Scott N Mason, Susan M Sereika, Julie C Price, Patrick M Fisher, Nilesh Shah, Tammy Loucks
    Abstract:

    There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20–80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [11C]WAY100635 and [18F]Altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (VT) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age2, sex, and hormone concentrations, with post hoc regional significance set at p<0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004–0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05–0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03–0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p<0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults <50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex–hormone–serotonin receptor relationships.

  • gender personality and serotonin 2a receptor binding in healthy subjects
    Psychiatry Research-neuroimaging, 2010
    Co-Authors: Paul H Soloff, Carl Becker, Julie C Price, N S Mason, Carolyn C Meltzer
    Abstract:

    Abstract The vulnerability to mood disorders, impulsive-aggression, eating disorders, and suicidal behavior varies greatly with gender, and may reflect gender differences in central serotonergic function. We investigated the relationships of gender, mood, impulsivity, aggression and temperament to 5HT 2A receptor binding in 21 healthy subjects using [ 18 F]Altanserin and PET neuroimaging. Binding potentials in pre-defined regions-of-interest (ROI) were calculated using the Logan graphical method, corrected for partial volume effects, and compared by gender with age co-varied. SPM analysis was used for voxel level comparisons. Altanserin binding (BP P ) was greater in male than female subjects in the following nine ROIs: hippocampus (HIP) and Lt. HIP, lateral orbital frontal cortex (LOF) and Lt.LOF, left medial frontal cortex (Lt.MFC), left medial temporal cortex (Lt. MTC), left occipital cortex (Lt. OCC), thalamus (THL) and Lt. THL. Differences in Lt. HIP and Lt. MTL remained significant after Bonferroni correction. Gender differences were noted in the co-variation of psychological traits with BP P values in specific ROIs. Among males alone, aggression was negatively correlated with BP P values in Lt. LOF and Lt. MFC, and Suspiciousness positively correlated in LOF, Lt. LOF and Lt. MFC. Among female subjects alone, Negativism was positively correlated with BP P values in HIP, and Verbal Hostility in Lt. HIP. Altanserin binding in Lt. MTC was positively correlated with Persistence, with no significant gender effect. Gender differences in 5HT 2A receptor function in specific ROIs may mediate expression of psychological characteristics such as aggression, suspiciousness and negativism. Future studies of 5HT 2A receptor function and its relationship to behavior should control for gender.

  • medial prefrontal cortex 5 ht2a density is correlated with amygdala reactivity response habituation and functional coupling
    Cerebral Cortex, 2009
    Co-Authors: Patrick M Fisher, Sarah Berga, Carl Becker, Eydie L Moseskolko, Rhaven L Coleman, Julie C Price, Carolyn C Meltzer, Scott K Ziolko, Ahmad R Hariri
    Abstract:

    Feedback inhibition of the amygdala via medial prefrontal cortex (mPFC) is an important component in the regulation of complex emotional behaviors. The functional dynamics of this corticolimbic circuitry are, in part, modulated by serotonin (5-HT). Serotonin 2A (5-HT2A) receptors within the mPFC represent a potential molecular mechanism through which 5-HT can modulate this corticolimbic circuitry. We employed a multimodal neuroimaging strategy to explore the relationship between threat-related amygdala reactivity, assessed using blood oxygen level--dependent functional magnetic resonance imaging, and mPFC 5-HT2A density, assessed using [ 18 F]Altanserin positron emission tomography in 35 healthy adult volunteers. We observed a significant inverse relationship wherein greater mPFC 5-HT2A density was associated with reduced threat-related right amygdala reactivity. Remarkably, 25--37% of the variability in amygdala reactivity was explained by mPFC 5-HT2A density. We also observed a positive correlation between mPFC 5HT2A density and the magnitude of right amygdala habituation. Furthermore, functional coupling between the amygdala and mPFC was positively correlated with 5-HT2A density suggesting that effective integration of emotionally salient information within this corticolimbic circuitry may be modulated, at least in part, by mPFC 5-HT2A. Collectively, our results indicate that mPFC 5-HT2A is strongly associated with threat-related amygdala reactivity as well as its temporal habituation and functional coupling with prefrontal regulatory regions.

  • analyses of 18f Altanserin bolus injection pet data ii consideration of radiolabeled metabolites in humans
    Synapse, 2001
    Co-Authors: Julie C Price, Gwenn S Smith, Brian J Lopresti, Carolyn C Meltzer, N S Mason, Yiyun Huang, Daniel Holt, Roger N Gunn, Chester A Mathis
    Abstract:

    Imaging serotonin-2A (5-HT2A) neuroreceptors with positron emission tomography (PET) and [18F]Altanserin has been the focus of a series of PET studies, as [18F]Altanserin is one of the most selective 5-HT2A antagonist radiotracers. Previous animal studies showed that radiolabeled metabolites (radiometabolites) of [18F]Altanserin crossed the blood–brain barrier (BBB) to localize nonspecifically in brain, consistent with a constant radioactivity “background.” In this work, we evaluated human bolus injection [18F]Altanserin PET data with detailed consideration of the impact of BBB-permeable metabolites on the specific binding parameters. Data were quantified using either single (parent radiotracer), dual (parent radiotracer and radiometabolites), or no arterial input function(s) (cerebellum as reference tissue input function). A step-gradient high-performance liquid chromatography (HPLC) analysis provided distinct separation of [18F]Altanserin and four radiolabeled components in plasma. After [18F]Altanserin injection, the step-gradient data showed that the major BBB-permeable radiometabolites approached constant levels in plasma (>50 min), consistent with a constant metabolite “background.” The single-input Logan graphical results were highly correlated with the dual-input results and its bias was fairly constant across regions and subjects, as similarly observed for a nongraphical reference tissue method. The most comprehensive and quantitatively valid analysis for bolus [18F]Altanserin PET data was the dual-input method that specifically accounted for BBB-permeable metabolites, although the Logan analysis was preferred because it provided a good compromise between validity, sensitivity, and reliability of implementation. Further study is needed to better understand how the cerebellar kinetics of [18F]Altanserin and its radiometabolites impact the reference tissue measures. Synapse 41:11–21, 2001. © 2001 Wiley-Liss, Inc.

  • altered serotonin 2a receptor activity in women who have recovered from bulimia nervosa
    American Journal of Psychiatry, 2001
    Co-Authors: Walter H Kaye, Julie C Price, Carolyn C Meltzer, Guido K W Frank, Claire Mcconaha, Penelope J Crossan, Kelly L Klump, Leigh Rhodes
    Abstract:

    Results: The healthy volunteers, but not the women who had recovered from bulimia nervosa, had an age-related decline in 5HT2A binding. Women who had recovered from bulimia nervosa had a reduction of medial orbital frontal cortex 5-HT2A binding. Conclusions: The lack of age-related changes in 5-HT activity is further evidence of 5-HT alterations in subjects who have recovered from bulimia nervosa. In addition, vulnerabilities for eating disorders, impulse dyscontrol, and mood disturbances may involve 5-HT and frontal lobe activity. (Am J Psychiatry 2001; 158:1152–1155) Bulimia nervosa usually has an onset in adolescent women who are of normal body weight. It is characterized by restrictive eating alternating with binge eating and purging and body image distortions. Mood disturbances and extremes of impulse control such as impulsive and obsessive behaviors are common (1). Physiological and pharmacological studies support the possibility that altered central nervous system serotonin (5-HT) neurotransmitter activity could contribute to a susceptibility to develop appetitive and behavioral alterations in bulimia nervosa (1). Altered 5-HT activity in bulimia nervosa could be a consequence of pathological dietary behaviors. However, people who have recovered from bulimia nervosa also have 5-HT alterations as well as behavioral symptoms consistent with a dysregulation of 5-HT neuronal pathways (2, 3), raising the possibility that such alterations are trait-related and contribute to the pathogenesis of this disorder. To further understand 5-HT activity in women who have recovered from bulimia nervosa, we used the radioligand [ 18 F]Altanserin, a specific 5-HT2A receptor antagonist, and positron emission tomography (PET) imaging. The 5HT2A receptor system has been implicated in the modulation of feeding, mood, and anxiety as well as in antidepressant efficacy (4).