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Anne Lingford-hughes - One of the best experts on this subject based on the ideXlab platform.
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GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513.
Molecular Psychiatry, 2020Co-Authors: Tiago Reis Marques, Anne Lingford-hughes, Jim Myers, Federico Turkheimer, David J. Nutt, Abhishekh Hulegar Ashok, Ilinca Angelescu, Faith Borgan, Mattia Veronese, Oliver D. HowesAbstract:: A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case-control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p
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Decreased GABA-A Receptor Binding in Association With β-Lactam Antibiotic Use.
Clinical Nuclear Medicine, 2019Co-Authors: Anthime Flaus, Anne Lingford-hughes, Jim Myers, Alexander Hammers, Daniela A. Riaño Barros, Rainer Hinz, Matthias J. Koepp, Colm J. McginnityAbstract:: β-Lactam antibiotics are proconvulsive. In laboratory animals, this effect seems to be predominantly mediated through inhibition of GABA-A receptors, but it has not been demonstrated in humans in vivo. We report images of a [C]Ro15-4513 PET from a 40-year-old man who had completed a 1-week course of flucloxacillin before it. Relative to healthy controls, the participant had significantly lower mean gray matter binding. These novel data suggest that, in humans, the proconvulsive effect of β-lactam antibiotics is mediated via either competition for the same benzodiazepine-binding site as [C]Ro15-4513 or downregulation of GABA-A receptor expression.
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Using [(11)C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism.
NeuroImage, 2016Co-Authors: Anne Lingford-hughes, Jim Myers, Ben Watson, Alastair G. Reid, Nicola J. Kalk, Adrian Feeney, Alexander Hammers, Daniela A. Riaño-barros, Colm J. Mcginnity, L.g. TaylorAbstract:The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [11C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [11C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [11C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [11C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n = 12) underwent an [11C]Ro15 4513 PET scan and compared with matched healthy controls (n = 13). We found a significant reduction in [11C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [11C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [11C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [11C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates.
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Influence of agonist induced internalization on [3H]Ro15-4513 binding-an application to imaging fluctuations in endogenous GABA with positron emission tomography.
Synapse, 2014Co-Authors: Darren R. Quelch, Anne Lingford-hughes, Jim Myers, David J. Nutt, Vittorio De Santis, Annette Strege, Lisa Wells, Christine A. Parker, Robin J. TyackeAbstract:: Low affinity α1/α2 containing GABAA receptors are significantly less able to bind [(11) C]/[(3) H]Ro15-4513 following translocation to the endosomal environment. The alterations in [(11) C]Ro15-4513 binding observed in vivo following perturbations in endogenous GABA are likely driven by both alterations in receptor binding parameters following agonist induced internalisation and the GABA Shift.
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History of cigarette smoking is associated with higher limbic GABAA receptor availability
NeuroImage, 2012Co-Authors: Paul R. A. Stokes, Jim Myers, Nicola J. Kalk, Alexander Hammers, David J. Nutt, Aaf Benecke, David Erritzoe, Ben J. Watson, Daniela A. Riaño Barros, Anne Lingford-hughesAbstract:Abstract Cigarette smoking presents a significant worldwide healthcare challenge. Preclinical, genetic association and clinical trials studies provide considerable evidence for the involvement of the human γ-aminobutyric acid (GABA) system in the neurobiology of nicotine addiction. However there are few human GABA neurochemical imaging studies of nicotine addiction. We investigated limbic GABA A receptor availability in volunteers with a history of cigarette smoking using [ 11 C]Ro15 4513 positron emission tomography (PET). Eight [ 11 C]Ro15 4513 PET scans from volunteers with a history of cigarette smoking were compared to twelve scans from volunteers who were non-smokers. Total, α1 and α5 GABA A receptor subtype [ 11 C]Ro15 4513 V T values were quantified using spectral analysis of limbic regions implicated in nicotine addiction. Spectral analysis allows quantification of the overall [ 11 C]Ro15 4513 spectral frequency as well as α1 and α5 GABA A receptor subtype specific spectral frequency components. Volunteers with a history of cigarette smoking showed significantly higher total [ 11 C]Ro15 4513 V T values in the presubgenual cingulate and parahippocampal gyrus, and at a trend level in the insula, nucleus accumbens and subgenual cingulate. In six abstinent previous smokers (‘ex-smokers’), total [ 11 C]Ro15 4513 binding was significantly higher in all limbic regions studied, with higher α5 availability in the amygdala, anterior cingulate, nucleus accumbens and presubgenual cingulate. These results suggest that limbic GABA A receptor availability is higher in volunteers with a history of cigarette smoking which may reflect either higher expression of GABA A receptors or lower endogenous GABA levels. The findings in ex-smokers suggest that higher GABA A receptor availability continues with abstinence indicating that this may be a trait marker for nicotine addiction or that alterations in GABA function associated with cigarette smoking persist.
Jim Myers - One of the best experts on this subject based on the ideXlab platform.
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GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513.
Molecular Psychiatry, 2020Co-Authors: Tiago Reis Marques, Anne Lingford-hughes, Jim Myers, Federico Turkheimer, David J. Nutt, Abhishekh Hulegar Ashok, Ilinca Angelescu, Faith Borgan, Mattia Veronese, Oliver D. HowesAbstract:: A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case-control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p
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Decreased GABA-A Receptor Binding in Association With β-Lactam Antibiotic Use.
Clinical Nuclear Medicine, 2019Co-Authors: Anthime Flaus, Anne Lingford-hughes, Jim Myers, Alexander Hammers, Daniela A. Riaño Barros, Rainer Hinz, Matthias J. Koepp, Colm J. McginnityAbstract:: β-Lactam antibiotics are proconvulsive. In laboratory animals, this effect seems to be predominantly mediated through inhibition of GABA-A receptors, but it has not been demonstrated in humans in vivo. We report images of a [C]Ro15-4513 PET from a 40-year-old man who had completed a 1-week course of flucloxacillin before it. Relative to healthy controls, the participant had significantly lower mean gray matter binding. These novel data suggest that, in humans, the proconvulsive effect of β-lactam antibiotics is mediated via either competition for the same benzodiazepine-binding site as [C]Ro15-4513 or downregulation of GABA-A receptor expression.
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Evidence for GABA-A receptor dysregulation in gambling disorder: correlation with impulsivity.
Addiction Biology, 2016Co-Authors: Inge Mick, Jim Myers, Paul R. A. Stokes, David Erritzoe, Anna C. Ramos, Samantha Chandrasekera, Maria Andreina Mendez, Roger N. Gunn, Ea Rabiner, Graham E. SearleAbstract:As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11C]Ro15-4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of the ‘Negative Urgency’ construct of impulsivity in GD, and these were positively associated with higher [11C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.
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Using [(11)C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism.
NeuroImage, 2016Co-Authors: Anne Lingford-hughes, Jim Myers, Ben Watson, Alastair G. Reid, Nicola J. Kalk, Adrian Feeney, Alexander Hammers, Daniela A. Riaño-barros, Colm J. Mcginnity, L.g. TaylorAbstract:The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [11C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [11C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [11C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [11C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n = 12) underwent an [11C]Ro15 4513 PET scan and compared with matched healthy controls (n = 13). We found a significant reduction in [11C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [11C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [11C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [11C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates.
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Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans
Journal of Cerebral Blood Flow and Metabolism, 2016Co-Authors: Jim Myers, Robert A. Comley, Roger N. GunnAbstract:[11C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABAAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in viv...
Michael J. Lewis - One of the best experts on this subject based on the ideXlab platform.
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Ethanol self-administration in deprived rats: effects of Ro15-4513 alone, and in combination with flumazenil (Ro15-1788).
Alcoholism: Clinical and Experimental Research, 2006Co-Authors: Harry L. June, Richard E. Colker, Kevin R. Domangue, Lauren E. Perry, Leslie H. Hicks, Pamela L. June, Michael J. LewisAbstract:: Previous work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine agonist, decreases self-administration of ethanol (ETOH) in rats maintained on a two-bottle regmine of a saccharin ethanol solution (ES) and water over a 35-day consumption period. The present study extended the consumption period to 60 days and examined the effects of Ro15-4513 (2.5 mg/kg), flumazenil (Ro15-1788) (8.0 mg/kg), and Ro15-4513 in combination with Ro15-1788 on the time course of ETOH self-administration. High initial intake of ES observed during the first 4 weeks declined significantly over subsequent weeks. Ro15-4513 pretreatment, however, resulted in significant reduction of ES, while significantly preventing the "normal" reduction of consumption as was observed under control conditions. The antagonistic actions of Ro15-4513 were blocked/attenuated by the benzodiazepine receptor antagonist, Ro15-1788, independent of whether consumption of the ES was low or high. Both Ro15-4513 and Ro15-1788 affected water intake differentially compared with vehicle-injected controls. The results suggest that GABA-benzodiazepine mechanisms may be important in altering chronic ETOH drinking patterns depending upon experience with ETOH, tolerance, or learning.
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Interactions of Ro15-4513, Ro15-1788 (flumazenil) and ethanol on measures of exploration and locomotion in rats
Psychopharmacology, 1994Co-Authors: Harry L. June, Michael J. LewisAbstract:The present study investigated the role of the GABA_A-benzodiazepine (BDZ) receptor complex in mediating ethanol (ETOH)-induced increases in exploration (head-dipping) and locomotion of rats in a holeboard test. Male Sprague-Dawley rats were selected based on low basal exploratory rates to increase the likelihood that ETOH would increase these behaviors. The effects of the BDZ partial inverse agonist, Ro15-4513 (2.5 mg/kg), and the BDZ receptor antagonist, Ro15-1788 (flumazenil) (8.0 mg/kg), alone, and in combination with ETOH (0.25, 0.50 and 0.75 g/kg, IP) were investigated. The 0.25 and 0.50 g/kg doses of ETOH markedly increased both exploration and locomotion in low exploratory rats. The ETOH-induced increases were prevented by Ro15-4513 on both measures at a dose that produced no observable intrinsic action; however, this apparent lack of intrinsic activity on exploration may have been related to the low basal rates of responding in the subjects. The BDZ antagonist, flumazenil, completely reversed the antagonistic action produced by Ro15-4513 of the ETOH-induced stimulant effects on locomotion, however, flumazenil exerted only a marginal statistically significant effect on Ro15-4513's actions on head-dipping. When flumazenil was given alone, it increased head-dipping, but was without effect on locomotion. Flumazenil did not affect ETOH-induced increases in locomotion; however, ETOH and flumazenil appeared to show agonistic effects on exlporation. The different effects exerted by flumazenil alone, and in combination with ETOH on head-dipping and locomotion suggest that the actions of flumazenil on these behaviors are mediated through separate mechanisms. The research further suggests that both the anxiolytic and locomotor activational effects of ETOH are mediated through the GABA_A-BDZ receptor complex.
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Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone, and in combination with Ro15-1788 (flumazenil)
Psychopharmacology, 1994Co-Authors: Harry L. June, Roger W. Hughes, Holly L. Spurlock, Michael J. LewisAbstract:Recent work in our laboratory demonstrated that Ro15-4513, a partial inverse benzodiazepine (BDZ) agonist, decreases ethanol (ETOH) self-administration in rodents under fluid deprivation conditions. The present study further examined the effects of Ro15-4513 (2.5 and 5.0 mg/kg) alone and in combination with Ro15-1788, (flumazenil) (8.0 and 16.0 mg/kg), a BDZ receptor antagonist on ETOH self-administration in freely feeding and drinking rats. Animals were trained to consume ETOH (11% v/v) using a limited access procedure. Measurements were taken at 10- and 60-min intervals. Ro15-4513 (2.5 and 5.0 mg/kg) markedly attenuated ETOH consumption at both intervals. The antagonistic actions of Ro15-4513 were completely blocked by the higher dose of flumazenil at both intervals; the lower dose failed to antagonize the Ro15-4513-induced reduction of ETOH intake. When flumazenil was given alone, both doses reduced ETOH self-administration at 60 min; although the magnitude of the antagonism was comparable to that of Ro15-4513 only with the highest does of flumazenil (16.0 mg/kg). Neither Ro15-4513 nor flumazenil alone or in combination significantly altered water intake at any of the tested doses. Rats pretreated with Ro15-4513 showed a substantial reduction in blood ethanol concentration (BEC) compared with the Tween-80 vehicle condition at the 10-min interval. However, the BEC of animals given Ro15-4513 in combination with flumazenil were similar to rats given Tween-80 vehicle. The present study extends our previous research by demonstrating that Ro15-4513 and flumazenil attenuate ETOH self-administration in non-food or water deprived rats. These studies suggest that the suppressant effects of Ro15-4513 and flumazenil on ETOH self-administration are associated with actions at the BDZ site of the GABA_A receptor complex. These data are discussed in relation to the possible mechanism(s) by which Ro-15-4513 and flumazenil exert their antagonism on ETOH self-administration.
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Failure of Ro15-4513 to alter an ethanol-induced taste aversion.
Pharmacology Biochemistry and Behavior, 1992Co-Authors: Harry L. June, Kevin R. Domangue, Leslie H. Hicks, Pamela L. June, Guy Lummis, Michael J. LewisAbstract:Abstract The ability of Ro15-4513, an imidazobenzodiazepine inverse benzodiazepine agonist, to attenuate/block the acquisition of an ethanol (ETOH)-induced conditioned taste aversion (CTA) was investigated in two experiments. Experiment 1 examined the effects of Ro15-4513 (3 mg/kg) on rats' consumption of a novel saccharin solution under a traditional CTA paradigm. Experiment 2 examined the effects of Ro15-4513 (3 mg/kg) on rats' consumption of a novel saccharin solution under a preexposure CTA paradigm. Under the preexposure paradigm, rats were given Ro15-4513 immediately before each of five daily consecutive preexposure treatments prior to the initial conditioning day. To obtain maximal preexposure and unconditioned stimulus effects, a 2-g/kg dose of ETOH (20% v/v) was used in the present study. As previously reported, animals given ETOH following 20-min access to a novel saccharin solution established moderate to strong aversions, with the degree of aversion being directly related to the number of conditioning days. Experiment 1 showed that Ro15-4513 failed to alter the CTA induced by ETOH. Experiment 2 further showed that Ro15-4513 failed to block the preexposure effect exerted on the ETOH-mediated CTA. The results confirm previous reports regarding the failure of Ro15-4513 to disrupt an ETOH-induced CTA. These data are in agreement with a number of behavioral studies demonstrating the failure of Ro15-4513 to antagonize certain actions of ETOH. Moreover, the present study along with a previous report suggests that ETOH-induced CTA's do not appear to be mediated via actions at the GABA-BDZ receptor complex.
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Ro15-4513 attenuates the consumption of ethanol in deprived rats.
Alcoholism: Clinical and Experimental Research, 1991Co-Authors: Harry L. June, Richard E. Colker, Guy Lummis, Timothy O. Moore, Michael J. LewisAbstract:: This research investigated the effects of Ro15-4513 (Ro15), a partial inverse benzodiazepine agonist, on the drinking behavior of 23-1/2 hr fluid deprived rats. Water-deprived rats were maintained on a two-bottle regimen of a saccharin-ETOH solution along with tap water available for 30 min/day for several days. Following this acclimation period, animals were pretreated with either Ro15 (1.0, 2.5, and 5.0 mg/kg) or Tween-80 vehicle injections. Pretreatment with Ro15 at all doses tested resulted in a significant reduction of the saccharin-ETOH solution; however, Ro15 did not alter the rats' consumption of water. The effects of Ro15 on general fluid consumption was investigated in Experiment 2. Following acclimation to a two-bottle regimen of a saccharin-solution and tap water 30 min/day, naive animals were pretreated with Tween-80 vehicle or Ro15 injections. Ro15 failed to alter saccharin or water consumption. The results of this study support previous reports suggesting that Ro15 attenuates the oral consumption of ETOH; however, this effect does not appear to be due to a general suppression of fluid intake.
David J. Brooks - One of the best experts on this subject based on the ideXlab platform.
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attenuation of dopamine induced gaba release in problem gamblers
Brain and behavior, 2019Co-Authors: David J. Brooks, Arne Møller, Jakob Udby Blicher, Kristine Romer Thomsen, Kim Mouridsen, Kim V HansenAbstract:INTRODUCTION: We have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self-awareness via synchronizing oscillations in the gamma range. The synchronization of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA-ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self-awareness. METHODS: [11 C]Ro15-4513 PET, a marker of benzodiazepine α1/α5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L-dopa in a double-blind controlled study of male problem gamblers (N = 10) and age-matched healthy male controls (N = 10). RESULTS: The mean reduction of cortical gray matter GABA/BDZ receptor availability induced by L-dopa was significantly attenuated in the problem gambling group compared to the healthy control group (p = 0.0377). CONCLUSIONS: Our findings demonstrate that: (a) Exogenous dopamine can induce synaptic GABA release in healthy controls. (b) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.
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Exogenous dopamine reduces GABA receptor availability in the human brain.
Brain and behavior, 2016Co-Authors: Astrid Rosenstand, David J. Brooks, Dirk Bender, Steen Jakobsen, Jakob Udby Blicher, K. Hansen, Arne MøllerAbstract:Background While it has recently been shown that dopamine release stimulates conscious self-monitoring through the generation of gamma oscillations in medial prefrontal/anterior cingulate cortex, and that the GABAergic system is effective in producing such oscillations, interaction of the two transmitter systems has not been demonstrated in humans. We here hypothesize that dopamine challenge stimulates the GABA system directly in the medial prefrontal/anterior cingulate region in the human brain. Methods Positron emission tomography (PET) with the GABA receptor α1/α5 subtype ligand [11C] Ro15-4513 was used to detect changes in GABA receptor availability after clinical oral doses of levodopa in a double blind controlled study. Results We here provide the first direct evidence for such coupling in the cerebral cortex, in particular in the medial prefrontal anterior cingulate region, by showing that exogenous dopamine decreases [11C] Ro15-4513 binding widely in the human brain compatible with a fall in α1 subtype availability in GABA complexes due to increased GABA activity.
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Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [11C]Ro15-4513 PET Images:
Journal of Cerebral Blood Flow and Metabolism, 2012Co-Authors: Jim Myers, Nicola J. Kalk, Lula Rosso, Federico Turkheimer, David J. Brooks, David J. Nutt, Ben J. Watson, Sue Wilson, Nicoletta Clementi, Anne Lingford-hughesAbstract:This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zol...
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A [11c]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced α5 benzodiazepine receptors in limbic regions
Journal of Psychopharmacology, 2010Co-Authors: Anne Lingford-hughes, Jim Myers, Alastair G. Reid, Adrian Feeney, Alexander Hammers, L.g. Taylor, Lula Rosso, Federico Turkheimer, David J. Brooks, Paul M. GrasbyAbstract:Preclinical evidence suggests the α5 subtype of the GABA-benzodiazepine receptor is involved in some of the actions of alcohol and in memory. The positron emission tomography (PET) tracer, [11C]Ro15 4513 shows relative selectivity in labelling the α5 subtype over the other GABA-benzodiazepine receptor subtypes in limbic regions of the brain. We used this tracer to investigate the distribution of α5 subtype availability in human alcohol dependence and its relationship to clinical variables. Abstinent (>6 weeks) alcohol-dependent men and healthy male controls underwent an [11C]Ro15 4513 PET scan. We report [11C]Ro15 4513 brain uptake for 8 alcohol-dependent men and 11 healthy controls. We found a significant reduction in [11C]Ro15 4513 binding in the nucleus accumbens, parahippocampal gyri, right hippocampus and amygdala in the alcohol-dependent compared with the healthy control group. Levels of [11C]Ro15 4513 binding in both hippocampi were significantly and positively associated with performance on a dela...
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Imaging the GABA-Benzodiazepine Receptor Subtype Containing the α5-Subunit In Vivo With [11C]Ro15 4513 Positron Emission Tomography
Journal of Cerebral Blood Flow and Metabolism, 2002Co-Authors: Anne Lingford-hughes, Adrian Feeney, David J. Brooks, Susan P. Hume, Ella Hirani, Safiye Osman, Vincent J. Cunningham, Victor W. Pike, David J. NuttAbstract:There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The 5-containing subtype is highly expressed in the hippocampus, and selective 5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the 1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the 5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the 1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the 5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.
David J. Nutt - One of the best experts on this subject based on the ideXlab platform.
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GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513.
Molecular Psychiatry, 2020Co-Authors: Tiago Reis Marques, Anne Lingford-hughes, Jim Myers, Federico Turkheimer, David J. Nutt, Abhishekh Hulegar Ashok, Ilinca Angelescu, Faith Borgan, Mattia Veronese, Oliver D. HowesAbstract:: A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case-control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p
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Influence of agonist induced internalization on [3H]Ro15-4513 binding-an application to imaging fluctuations in endogenous GABA with positron emission tomography.
Synapse, 2014Co-Authors: Darren R. Quelch, Anne Lingford-hughes, Jim Myers, David J. Nutt, Vittorio De Santis, Annette Strege, Lisa Wells, Christine A. Parker, Robin J. TyackeAbstract:: Low affinity α1/α2 containing GABAA receptors are significantly less able to bind [(11) C]/[(3) H]Ro15-4513 following translocation to the endosomal environment. The alterations in [(11) C]Ro15-4513 binding observed in vivo following perturbations in endogenous GABA are likely driven by both alterations in receptor binding parameters following agonist induced internalisation and the GABA Shift.
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History of cigarette smoking is associated with higher limbic GABAA receptor availability
NeuroImage, 2012Co-Authors: Paul R. A. Stokes, Jim Myers, Nicola J. Kalk, Alexander Hammers, David J. Nutt, Aaf Benecke, David Erritzoe, Ben J. Watson, Daniela A. Riaño Barros, Anne Lingford-hughesAbstract:Abstract Cigarette smoking presents a significant worldwide healthcare challenge. Preclinical, genetic association and clinical trials studies provide considerable evidence for the involvement of the human γ-aminobutyric acid (GABA) system in the neurobiology of nicotine addiction. However there are few human GABA neurochemical imaging studies of nicotine addiction. We investigated limbic GABA A receptor availability in volunteers with a history of cigarette smoking using [ 11 C]Ro15 4513 positron emission tomography (PET). Eight [ 11 C]Ro15 4513 PET scans from volunteers with a history of cigarette smoking were compared to twelve scans from volunteers who were non-smokers. Total, α1 and α5 GABA A receptor subtype [ 11 C]Ro15 4513 V T values were quantified using spectral analysis of limbic regions implicated in nicotine addiction. Spectral analysis allows quantification of the overall [ 11 C]Ro15 4513 spectral frequency as well as α1 and α5 GABA A receptor subtype specific spectral frequency components. Volunteers with a history of cigarette smoking showed significantly higher total [ 11 C]Ro15 4513 V T values in the presubgenual cingulate and parahippocampal gyrus, and at a trend level in the insula, nucleus accumbens and subgenual cingulate. In six abstinent previous smokers (‘ex-smokers’), total [ 11 C]Ro15 4513 binding was significantly higher in all limbic regions studied, with higher α5 availability in the amygdala, anterior cingulate, nucleus accumbens and presubgenual cingulate. These results suggest that limbic GABA A receptor availability is higher in volunteers with a history of cigarette smoking which may reflect either higher expression of GABA A receptors or lower endogenous GABA levels. The findings in ex-smokers suggest that higher GABA A receptor availability continues with abstinence indicating that this may be a trait marker for nicotine addiction or that alterations in GABA function associated with cigarette smoking persist.
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The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [11C]Ro15-4513 positron emission tomography study
Neuropharmacology, 2012Co-Authors: Maria Andreina Mendez, Anne Lingford-hughes, Jim Myers, Paul R. A. Stokes, David Erritzoe, Oliver D. Howes, Jamie Horder, Suzanne Coghlan, Declan G. Murphy, David J. NuttAbstract:Abstract GABA (gamma-amino-butyric-acid) is the primary inhibitory neurotransmitter in the human brain. It has been proposed that the symptoms of autism spectrum disorders (ASDs) are the result of deficient GABA neurotransmission, possibly including reduced expression of GABAA receptors. However, this hypothesis has not been directly tested in living adults with ASD. In this preliminary investigation, we used Positron Emission Tomography (PET) with the benzodiazepine receptor PET ligand [11C]Ro15-4513 to measure α1 and α5 subtypes of the GABAA receptor levels in the brain of three adult males with well-characterized high-functioning ASD compared with three healthy matched volunteers. We found significantly lower [11C]Ro15-4513 binding throughout the brain of participants with ASD (p This article is part of the Special Issue entitled ‘Neurodevelopmental Disorders’.
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Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [11C]Ro15-4513 PET Images:
Journal of Cerebral Blood Flow and Metabolism, 2012Co-Authors: Jim Myers, Nicola J. Kalk, Lula Rosso, Federico Turkheimer, David J. Brooks, David J. Nutt, Ben J. Watson, Sue Wilson, Nicoletta Clementi, Anne Lingford-hughesAbstract:This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zol...
