The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Lon R. Hays - One of the best experts on this subject based on the ideXlab platform.
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Influence of tiagabine maintenance on cannabis effects and related behaviors in daily cannabis users.
Experimental and clinical psychopharmacology, 2018Co-Authors: Michael J. Wesley, Thomas H. Kelly, Lon R. Hays, William W. Stoops, Philip M. Westgate, Joshua A. LileAbstract:No medications are approved for cannabis use disorder (CUD). Gamma-aminobutyric acid (GABA) Reuptake is modulated by cannabinoid (CB) receptor agonists, and there are shared effects between CB agonists and the GABA Reuptake Inhibitor tiagabine. This overlapping neuropharmacology suggested that tiagabine might be useful for CUD. The study determined the ability of tiagabine maintenance to reduce cannabis self-administration using a placebo-controlled, double-blind, counterbalanced, within-subjects design. Nontreatment-seeking daily cannabis users (N = 12; 3 female, 9 male) completed two 12-day outpatient maintenance phases (0 or 12 mg of tiagabine/day). Each phase consisted of a safety session, 7 maintenance days, and 4 experimental sessions. During experimental sessions, maintenance continued and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% Δ9-tetrahydrocannabinol). Naturalistic cannabis use, the subjective, performance and physiological response to cannabis, as well as side effects, sleep quality, craving, other self-reported substance use, and observer ratings were also measured. Cannabis functioned as a reinforcer and produced prototypical effects (e.g., increased heart rate and ratings of "high"), but tiagabine generally did not impact the effects of cannabis, or alter naturalistic use. Furthermore, tiagabine produced small, but significant, increases on 2 subscales of a Marijuana Craving Questionnaire, and reductions in both the amount of time slept in the past 24 hr and ratings of positive mood upon awakening. These human laboratory results from a sample of nontreatment-seeking cannabis users do not support the potential efficacy of 12 mg of tiagabine as a stand-alone pharmacotherapy for CUD. (PsycINFO Database Record
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Separate and combined effects of the GABAB agonist baclofen and Δ9-THC in humans discriminating Δ9-THC
Drug and Alcohol Dependence, 2012Co-Authors: Joshua A. Lile, Thomas H. Kelly, Lon R. HaysAbstract:Background Our previous research with the GABA Reuptake Inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABAB receptor subtype by assessing the separate and combined effects of the GABAB-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures.
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Separate and combined effects of the GABA(B) agonist baclofen and Δ9-THC in humans discriminating Δ9-THC.
Drug and alcohol dependence, 2012Co-Authors: Joshua A. Lile, Thomas H. Kelly, Lon R. HaysAbstract:Our previous research with the GABA Reuptake Inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABA(B) receptor subtype by assessing the separate and combined effects of the GABA(B)-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures. Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received baclofen (25 and 50mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ9-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50 mg) substituted for the Δ9-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ9-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ9-THC-like subjective responses when administered alone. These results suggest that the GABA(B) receptor subtype is involved in the abuse-related effects of Δ9-THC, and that GABA(B) receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABA(A)) to determine the contribution of the different GABA receptors in the effects of Δ9-THC, and by extension cannabis, in humans. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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Separate and combined effects of the GABA Reuptake Inhibitor tiagabine and Δ9-THC in humans discriminating Δ9-THC
Drug and Alcohol Dependence, 2011Co-Authors: Joshua A. Lile, Thomas H. Kelly, Lon R. HaysAbstract:Background The involvement of non-cannabinoid neurotransmitter systems in the abuse-related behavioral effects of cannabis has not been well characterized in humans. GABAergic drugs have overlapping effects with cannabis and Δ9-tetrahydrocannabinol (Δ9-THC) on certain behavioral measures, but those measures lack the specificity to draw conclusions regarding the involvement of GABA in cannabinoid effects. The aim of this study was to assess the separate and combined effects of the GABA Reuptake Inhibitor tiagabine and Δ9-THC using more pharmacologically specific drug-discrimination procedures.
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Separate and combined effects of the GABA Reuptake Inhibitor tiagabine and Δ9-THC in humans discriminating Δ9-THC.
Drug and alcohol dependence, 2011Co-Authors: Joshua A. Lile, Thomas H. Kelly, Lon R. HaysAbstract:The involvement of non-cannabinoid neurotransmitter systems in the abuse-related behavioral effects of cannabis has not been well characterized in humans. GABAergic drugs have overlapping effects with cannabis and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) on certain behavioral measures, but those measures lack the specificity to draw conclusions regarding the involvement of GABA in cannabinoid effects. The aim of this study was to assess the separate and combined effects of the GABA Reuptake Inhibitor tiagabine and Δ(9)-THC using more pharmacologically specific drug-discrimination procedures. Eight cannabis users learned to discriminate 30 mg oral Δ(9)-THC from placebo and then received tiagabine (6 and 12 mg), Δ(9)-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ(9)-THC produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on psychomotor performance tasks. The higher tiagabine dose substituted for the Δ(9)-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of Δ(9)-THC when administered alone. In combination, tiagabine shifted the discriminative-stimulus effects of Δ(9)-THC leftward/upward and enhanced Δ(9)-THC effects on other outcomes. These results indicate that GABA is involved in the clinical effects of Δ(9)-THC, and by extension, cannabis. Future studies should test selective GABAergic compounds to determine which receptor subtype(s) are responsible for the effects observed when combined with cannabinoids. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Joshua A. Lile - One of the best experts on this subject based on the ideXlab platform.
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Influence of tiagabine maintenance on cannabis effects and related behaviors in daily cannabis users.
Experimental and clinical psychopharmacology, 2018Co-Authors: Michael J. Wesley, Thomas H. Kelly, Lon R. Hays, William W. Stoops, Philip M. Westgate, Joshua A. LileAbstract:No medications are approved for cannabis use disorder (CUD). Gamma-aminobutyric acid (GABA) Reuptake is modulated by cannabinoid (CB) receptor agonists, and there are shared effects between CB agonists and the GABA Reuptake Inhibitor tiagabine. This overlapping neuropharmacology suggested that tiagabine might be useful for CUD. The study determined the ability of tiagabine maintenance to reduce cannabis self-administration using a placebo-controlled, double-blind, counterbalanced, within-subjects design. Nontreatment-seeking daily cannabis users (N = 12; 3 female, 9 male) completed two 12-day outpatient maintenance phases (0 or 12 mg of tiagabine/day). Each phase consisted of a safety session, 7 maintenance days, and 4 experimental sessions. During experimental sessions, maintenance continued and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% Δ9-tetrahydrocannabinol). Naturalistic cannabis use, the subjective, performance and physiological response to cannabis, as well as side effects, sleep quality, craving, other self-reported substance use, and observer ratings were also measured. Cannabis functioned as a reinforcer and produced prototypical effects (e.g., increased heart rate and ratings of "high"), but tiagabine generally did not impact the effects of cannabis, or alter naturalistic use. Furthermore, tiagabine produced small, but significant, increases on 2 subscales of a Marijuana Craving Questionnaire, and reductions in both the amount of time slept in the past 24 hr and ratings of positive mood upon awakening. These human laboratory results from a sample of nontreatment-seeking cannabis users do not support the potential efficacy of 12 mg of tiagabine as a stand-alone pharmacotherapy for CUD. (PsycINFO Database Record
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Chapter 79 – The Role of γ-Aminobutyric Acid in the Interoceptive Effects of Oral Δ9-Tetrahydrocannabinol in Humans
Handbook of Cannabis and Related Pathologies, 2017Co-Authors: Joshua A. Lile, Jessica S. Fogel, T.h. KellyAbstract:This chapter focuses on the involvement of γ-aminobutyric acid (ie, GABA) in the interoceptive effects of Δ 9 -tetrahydrocannabinol (ie, Δ 9 -THC) in humans. The interoceptive effects of drugs can be assessed using drug discrimination methodology, which is a selective means to examine neuropharmacological interactions between neurotransmitter systems. In humans trained to discriminate oral Δ 9 -THC, the GABA Reuptake Inhibitor tiagabine substituted for Δ 9 -THC, and enhanced the discriminative stimulus effects of Δ 9 -THC. The GABA B agonist baclofen, but not the GABA A positive allosteric modulator diazepam, also substituted for Δ 9 -THC, and enhanced the discriminative stimulus effects of Δ 9 -THC. The results from these clinical drug-discrimination studies disagree with preclinical data, suggesting that the neuropharmacological interactions between GABA and CB systems differ between human and nonhuman species. The studies reviewed here indicate that GABA, particularly the GABA B receptor subtype, plays a significant part in the interoceptive effects produced by Δ 9 -THC, and by extension cannabis, in humans.
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Separate and combined effects of the GABAB agonist baclofen and Δ9-THC in humans discriminating Δ9-THC
Drug and Alcohol Dependence, 2012Co-Authors: Joshua A. Lile, Thomas H. Kelly, Lon R. HaysAbstract:Background Our previous research with the GABA Reuptake Inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABAB receptor subtype by assessing the separate and combined effects of the GABAB-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures.
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Separate and combined effects of the GABA(B) agonist baclofen and Δ9-THC in humans discriminating Δ9-THC.
Drug and alcohol dependence, 2012Co-Authors: Joshua A. Lile, Thomas H. Kelly, Lon R. HaysAbstract:Our previous research with the GABA Reuptake Inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABA(B) receptor subtype by assessing the separate and combined effects of the GABA(B)-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures. Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received baclofen (25 and 50mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ9-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50 mg) substituted for the Δ9-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ9-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ9-THC-like subjective responses when administered alone. These results suggest that the GABA(B) receptor subtype is involved in the abuse-related effects of Δ9-THC, and that GABA(B) receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABA(A)) to determine the contribution of the different GABA receptors in the effects of Δ9-THC, and by extension cannabis, in humans. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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Separate and combined effects of the GABA Reuptake Inhibitor tiagabine and Δ9-THC in humans discriminating Δ9-THC
Drug and Alcohol Dependence, 2011Co-Authors: Joshua A. Lile, Thomas H. Kelly, Lon R. HaysAbstract:Background The involvement of non-cannabinoid neurotransmitter systems in the abuse-related behavioral effects of cannabis has not been well characterized in humans. GABAergic drugs have overlapping effects with cannabis and Δ9-tetrahydrocannabinol (Δ9-THC) on certain behavioral measures, but those measures lack the specificity to draw conclusions regarding the involvement of GABA in cannabinoid effects. The aim of this study was to assess the separate and combined effects of the GABA Reuptake Inhibitor tiagabine and Δ9-THC using more pharmacologically specific drug-discrimination procedures.
Jim Myers - One of the best experts on this subject based on the ideXlab platform.
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Significant reductions in human visual gamma frequency by the GABA Reuptake Inhibitor tiagabine revealed by robust peak frequency estimation.
Human Brain Mapping, 2016Co-Authors: Lorenzo Magazzini, Suresh Daniel Muthukumaraswamy, Anne Eileen Campbell, Khalid Hamandi, Anne Lingford-hughes, Jim Myers, Petroc Sumner, Sue Wilson, David J. Nutt, Krish Devi SinghAbstract:The frequency of visual gamma oscillations is determined by both the neuronal excitation–inhibition balance and the time constants of GABAergic processes. The gamma peak frequency has been linked to sensory processing, cognitive function, cortical structure, and may have a genetic contribution. To disentangle the intricate relationship among these factors, accurate and reliable estimates of peak frequency are required. Here, a bootstrapping approach that provides estimates of peak frequency reliability, thereby increasing the robustness of the inferences made on this parameter was developed. The method using both simulated data and real data from two previous pharmacological MEG studies of visual gamma with alcohol and tiagabine was validated. In particular, the study by Muthukumaraswamy et al. [2013a] (Neuropsychopharmacology 38(6):1105–1112), in which GABAergic enhancement by tiagabine had previously demonstrated a null effect on visual gamma oscillations, contrasting with strong evidence from both animal models and very recent human studies was re-evaluated. After improved peak frequency estimation and additional exclusion of unreliably measured data, it was found that the GABA Reuptake Inhibitor tiagabine did produce, as predicted, a marked decrease in visual gamma oscillation frequency. This result demonstrates the potential impact of objective approaches to data quality control, and provides additional translational evidence for the mechanisms of GABAergic transmission generating gamma oscillations in humans.
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Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers
Neuropharmacology, 2015Co-Authors: D Nutt, Anastasios Papadopoulos, Anne Lingford-hughes, Jim Myers, Sue Wilson, Andreas Papadopoulos, Suresh MuthukumaraswamyAbstract:A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA Reuptake Inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here. This article is part of the Special Issue entitled 'GABAergic Signaling in Health and Disease'.
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Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers
Neuropharmacology, 2014Co-Authors: David J. Nutt, Anastasios Papadopoulos, Anne Lingford-hughes, Jim Myers, Sue Wilson, Suresh MuthukumaraswamyAbstract:A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA Reuptake Inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here.
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Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine
Synapse (New York N.Y.), 2014Co-Authors: Jim Myers, C. John Evans, Nicola J. Kalk, Richard A.e. Edden, Anne Lingford-hughesAbstract:Though GABA is the major Inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA Reuptake Inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations. MEGA-PRESS was used to obtain GABA-edited spectra in 10 male individuals, before and after a 15-mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self-reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)-derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission.
Anne Lingford-hughes - One of the best experts on this subject based on the ideXlab platform.
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Significant reductions in human visual gamma frequency by the GABA Reuptake Inhibitor tiagabine revealed by robust peak frequency estimation.
Human Brain Mapping, 2016Co-Authors: Lorenzo Magazzini, Suresh Daniel Muthukumaraswamy, Anne Eileen Campbell, Khalid Hamandi, Anne Lingford-hughes, Jim Myers, Petroc Sumner, Sue Wilson, David J. Nutt, Krish Devi SinghAbstract:The frequency of visual gamma oscillations is determined by both the neuronal excitation–inhibition balance and the time constants of GABAergic processes. The gamma peak frequency has been linked to sensory processing, cognitive function, cortical structure, and may have a genetic contribution. To disentangle the intricate relationship among these factors, accurate and reliable estimates of peak frequency are required. Here, a bootstrapping approach that provides estimates of peak frequency reliability, thereby increasing the robustness of the inferences made on this parameter was developed. The method using both simulated data and real data from two previous pharmacological MEG studies of visual gamma with alcohol and tiagabine was validated. In particular, the study by Muthukumaraswamy et al. [2013a] (Neuropsychopharmacology 38(6):1105–1112), in which GABAergic enhancement by tiagabine had previously demonstrated a null effect on visual gamma oscillations, contrasting with strong evidence from both animal models and very recent human studies was re-evaluated. After improved peak frequency estimation and additional exclusion of unreliably measured data, it was found that the GABA Reuptake Inhibitor tiagabine did produce, as predicted, a marked decrease in visual gamma oscillation frequency. This result demonstrates the potential impact of objective approaches to data quality control, and provides additional translational evidence for the mechanisms of GABAergic transmission generating gamma oscillations in humans.
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Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers
Neuropharmacology, 2015Co-Authors: D Nutt, Anastasios Papadopoulos, Anne Lingford-hughes, Jim Myers, Sue Wilson, Andreas Papadopoulos, Suresh MuthukumaraswamyAbstract:A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA Reuptake Inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here. This article is part of the Special Issue entitled 'GABAergic Signaling in Health and Disease'.
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Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers
Neuropharmacology, 2014Co-Authors: David J. Nutt, Anastasios Papadopoulos, Anne Lingford-hughes, Jim Myers, Sue Wilson, Suresh MuthukumaraswamyAbstract:A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA Reuptake Inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here.
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Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine
Synapse (New York N.Y.), 2014Co-Authors: Jim Myers, C. John Evans, Nicola J. Kalk, Richard A.e. Edden, Anne Lingford-hughesAbstract:Though GABA is the major Inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA Reuptake Inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations. MEGA-PRESS was used to obtain GABA-edited spectra in 10 male individuals, before and after a 15-mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self-reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)-derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission.
Sue Wilson - One of the best experts on this subject based on the ideXlab platform.
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Significant reductions in human visual gamma frequency by the GABA Reuptake Inhibitor tiagabine revealed by robust peak frequency estimation.
Human Brain Mapping, 2016Co-Authors: Lorenzo Magazzini, Suresh Daniel Muthukumaraswamy, Anne Eileen Campbell, Khalid Hamandi, Anne Lingford-hughes, Jim Myers, Petroc Sumner, Sue Wilson, David J. Nutt, Krish Devi SinghAbstract:The frequency of visual gamma oscillations is determined by both the neuronal excitation–inhibition balance and the time constants of GABAergic processes. The gamma peak frequency has been linked to sensory processing, cognitive function, cortical structure, and may have a genetic contribution. To disentangle the intricate relationship among these factors, accurate and reliable estimates of peak frequency are required. Here, a bootstrapping approach that provides estimates of peak frequency reliability, thereby increasing the robustness of the inferences made on this parameter was developed. The method using both simulated data and real data from two previous pharmacological MEG studies of visual gamma with alcohol and tiagabine was validated. In particular, the study by Muthukumaraswamy et al. [2013a] (Neuropsychopharmacology 38(6):1105–1112), in which GABAergic enhancement by tiagabine had previously demonstrated a null effect on visual gamma oscillations, contrasting with strong evidence from both animal models and very recent human studies was re-evaluated. After improved peak frequency estimation and additional exclusion of unreliably measured data, it was found that the GABA Reuptake Inhibitor tiagabine did produce, as predicted, a marked decrease in visual gamma oscillation frequency. This result demonstrates the potential impact of objective approaches to data quality control, and provides additional translational evidence for the mechanisms of GABAergic transmission generating gamma oscillations in humans.
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Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers
Neuropharmacology, 2015Co-Authors: D Nutt, Anastasios Papadopoulos, Anne Lingford-hughes, Jim Myers, Sue Wilson, Andreas Papadopoulos, Suresh MuthukumaraswamyAbstract:A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA Reuptake Inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here. This article is part of the Special Issue entitled 'GABAergic Signaling in Health and Disease'.
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Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers
Neuropharmacology, 2014Co-Authors: David J. Nutt, Anastasios Papadopoulos, Anne Lingford-hughes, Jim Myers, Sue Wilson, Suresh MuthukumaraswamyAbstract:A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA Reuptake Inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here.
