The Experts below are selected from a list of 282 Experts worldwide ranked by ideXlab platform
Vincenzo Crunelli - One of the best experts on this subject based on the ideXlab platform.
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GABAB receptor-mediated activation of astrocytes by Gamma-Hydroxybutyric Acid
Philosophical transactions of the Royal Society of London. Series B Biological sciences, 2014Co-Authors: Timothy M. Gould, Zsuzsa Emri, Vincenzo Crunelli, Lixin Chen, Tiina Pirttimäki, Adam C. Errington, H. Rheinallt ParriAbstract:The gamma-aminobutyric Acid (GABA) metabolite Gamma-Hydroxybutyric Acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABAB receptors (GABABRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABAA and GABABRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABABR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca2+ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABABRs and mediated by Ca2+ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.
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Unravelling the brain targets of Gamma-Hydroxybutyric Acid.
Current Opinion in Pharmacology, 2006Co-Authors: Vincenzo Crunelli, Zsuzsa Emri, N. LerescheAbstract:Gamma-Hydroxybutyric Acid (GHB) is a naturally occurring gamma-aminobutyric Acid (GABA) metabolite that has been proposed as a neurotransmitter/neuromodulator that acts via its own receptor (GHBR). Its exogenous administration, however, elicits central nervous system-dependent effects (e.g. memory impairment, increase in sleep stages 3 and 4, dependence, seizures and coma) that are mostly mediated by GABAB receptors. The past few years have seen important developments in our understanding of GHB neurobiology: a putative GHBR has been cloned; a transgenic model of GHB Aciduria has been developed; GABAB receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABAB receptors; and some of the cellular mechanisms underlying the dependence/abuse properties of GHB, and its ability to elicit absence seizures and an increase in sleep stages 3 and 4, have been clarified. Nevertheless, the physiological significance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABAB receptor-mediated actions of GHB are caused by GHB itself acting directly on GABAB receptors or by a GHB-derived GABA pool (or both).
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Gamma-Hydroxybutyric Acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABAB receptors.
Neuroscience Letters, 1996Co-Authors: Zsuzsa Emri, Károly Antal, Vincenzo CrunelliAbstract:Abstract The effect of Gamma-Hydroxybutyric Acid (GHB) on the excitatory postsynaptic potential (EPSP) evoked in thalamocortical neurones of the rat dorsal lateral geniculate nucleus and ventrobasal thalamus was investigated in vitro. GHB (0.1–5 mM) dose-dependently and reversibly decreased (36–78%) the amplitude of the sensory EPSP. This effect of GHB was blocked by the GABA B receptor antagonist CGP 35348 (1 mM). NCS 382 (1–3 mM), a putative GHB receptor antagonist, did not antagonise but weakly potentiated both the GHB- and baclofen-mediated decrease of the EPSP amplitude.
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Gamma-Hydroxybutyric Acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABAB receptors.
Neuroscience Letters, 1996Co-Authors: Zsuzsa Emri, Károly Antal, Vincenzo CrunelliAbstract:Abstract The effect of Gamma-Hydroxybutyric Acid (GHB) on the excitatory postsynaptic potential (EPSP) evoked in thalamocortical neurones of the rat dorsal lateral geniculate nucleus and ventrobasal thalamus was investigated in vitro. GHB (0.1–5 mM) dose-dependently and reversibly decreased (36–78%) the amplitude of the sensory EPSP. This effect of GHB was blocked by the GABA B receptor antagonist CGP 35348 (1 mM). NCS 382 (1–3 mM), a putative GHB receptor antagonist, did not antagonise but weakly potentiated both the GHB- and baclofen-mediated decrease of the EPSP amplitude.
Zsuzsa Emri - One of the best experts on this subject based on the ideXlab platform.
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GABAB receptor-mediated activation of astrocytes by Gamma-Hydroxybutyric Acid
Philosophical transactions of the Royal Society of London. Series B Biological sciences, 2014Co-Authors: Timothy M. Gould, Zsuzsa Emri, Vincenzo Crunelli, Lixin Chen, Tiina Pirttimäki, Adam C. Errington, H. Rheinallt ParriAbstract:The gamma-aminobutyric Acid (GABA) metabolite Gamma-Hydroxybutyric Acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABAB receptors (GABABRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABAA and GABABRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABABR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca2+ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABABRs and mediated by Ca2+ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.
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Unravelling the brain targets of Gamma-Hydroxybutyric Acid.
Current Opinion in Pharmacology, 2006Co-Authors: Vincenzo Crunelli, Zsuzsa Emri, N. LerescheAbstract:Gamma-Hydroxybutyric Acid (GHB) is a naturally occurring gamma-aminobutyric Acid (GABA) metabolite that has been proposed as a neurotransmitter/neuromodulator that acts via its own receptor (GHBR). Its exogenous administration, however, elicits central nervous system-dependent effects (e.g. memory impairment, increase in sleep stages 3 and 4, dependence, seizures and coma) that are mostly mediated by GABAB receptors. The past few years have seen important developments in our understanding of GHB neurobiology: a putative GHBR has been cloned; a transgenic model of GHB Aciduria has been developed; GABAB receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABAB receptors; and some of the cellular mechanisms underlying the dependence/abuse properties of GHB, and its ability to elicit absence seizures and an increase in sleep stages 3 and 4, have been clarified. Nevertheless, the physiological significance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABAB receptor-mediated actions of GHB are caused by GHB itself acting directly on GABAB receptors or by a GHB-derived GABA pool (or both).
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Gamma-Hydroxybutyric Acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABAB receptors.
Neuroscience Letters, 1996Co-Authors: Zsuzsa Emri, Károly Antal, Vincenzo CrunelliAbstract:Abstract The effect of Gamma-Hydroxybutyric Acid (GHB) on the excitatory postsynaptic potential (EPSP) evoked in thalamocortical neurones of the rat dorsal lateral geniculate nucleus and ventrobasal thalamus was investigated in vitro. GHB (0.1–5 mM) dose-dependently and reversibly decreased (36–78%) the amplitude of the sensory EPSP. This effect of GHB was blocked by the GABA B receptor antagonist CGP 35348 (1 mM). NCS 382 (1–3 mM), a putative GHB receptor antagonist, did not antagonise but weakly potentiated both the GHB- and baclofen-mediated decrease of the EPSP amplitude.
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Gamma-Hydroxybutyric Acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABAB receptors.
Neuroscience Letters, 1996Co-Authors: Zsuzsa Emri, Károly Antal, Vincenzo CrunelliAbstract:Abstract The effect of Gamma-Hydroxybutyric Acid (GHB) on the excitatory postsynaptic potential (EPSP) evoked in thalamocortical neurones of the rat dorsal lateral geniculate nucleus and ventrobasal thalamus was investigated in vitro. GHB (0.1–5 mM) dose-dependently and reversibly decreased (36–78%) the amplitude of the sensory EPSP. This effect of GHB was blocked by the GABA B receptor antagonist CGP 35348 (1 mM). NCS 382 (1–3 mM), a putative GHB receptor antagonist, did not antagonise but weakly potentiated both the GHB- and baclofen-mediated decrease of the EPSP amplitude.
Gian Luigi Gessa - One of the best experts on this subject based on the ideXlab platform.
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Protection by the GABAB receptor antagonist, SCH 50911, of Gamma-Hydroxybutyric Acid-induced mortality in mice.
European journal of pharmacology, 2004Co-Authors: Mauro A.m. Carai, Giancarlo Colombo, Gian Luigi GessaAbstract:Different effects of moderate to high doses of Gamma-Hydroxybutyric Acid, including sedation/hypnosis, have been found to be blocked by gamma-aminobutyric AcidB (GABAB) receptor antagonists. The present study investigated whether the protective effect of GABAB receptor antagonists extends also to Gamma-Hydroxybutyric Acid-induced mortality. To this aim, the present study investigated the effect of the GABAB receptor antagonist, (2S)(+)-5,5-dimethyl-2-morpholineacetic Acid (SCH 50911; 100 mg/kg, ip), on mortality induced by Gamma-Hydroxybutyric Acid (1-6 g/kg, ip) in DBA mice. Pretreatment with SCH 50911 resulted in a significant shift to the right of the dose-response curve of Gamma-Hydroxybutyric Acid-induced mortality. Accordingly, the LD50 in SCH 50911-pretreated mice was significantly higher than that obtained in water-pretreated mice. The results of the present study support the hypothesis that (a) the GABAB receptor is a relevant site of action of Gamma-Hydroxybutyric Acid, and (b) GABAB receptor antagonists may constitute potentially effective therapeutic interventions for Gamma-Hydroxybutyric Acid intoxication.
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Gamma-Hydroxybutyric Acid and baclofen decrease extracellular acetylcholine levels in the hippocampus via GABA(B) receptors.
European journal of pharmacology, 2001Co-Authors: F Nava, Marco Bortolato, Gianna Carta, Gian Luigi GessaAbstract:The effect of Gamma-Hydroxybutyric Acid (GHB) and baclofen, a GABA(B) receptor agonist, on extracellular hippocampal acetylcholine levels was studied in freely moving rats by microdialysis. GHB (200 and 500 mg/kg, i.p.) reduced in a dose-dependent manner, extracellular hippocampal acetylcholine concentrations and this effect was prevented by the GABA(B) receptor antagonist (2S)(+)-5,5-Dimethyl-2-morpholineacetic Acid (SCH 50911), at the dose of 20 mg/kg (i.p.), while the putative GHB receptor antagonist 6,7,8,9-Tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic Acid (NCS 382) was ineffective. Similar to GHB, the GABA(B) agonist baclofen (10 and 20 mg/kg, i.p.) produced a dose-related reduction in extracellular acetylcholine concentrations which was prevented by SCH 50911. These findings indicate that GHB-induced reduction of hippocampal acetylcholine release is mediated by GABA(B) receptors and support a possible involvement of hippocampal GABA(B) receptors in the control of cognitive processes and in the claimed amnesic effect of GHB intoxication.
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Gamma-Hydroxybutyric Acid in alcohol preference, dependence and withdrawal.
Addiction biology, 2000Co-Authors: Giancarlo Colombo, Gian Luigi GessaAbstract:Gamma-Hydroxybutyric Acid (GHB) is an endogenous constituent of the mammalian brain, where it likely functions as a neurotransmitter or a neuromodulator. Its exogenous administration exerts a number of pharmacological effects, including reduction of intensity of alcohol withdrawal syndrome and alcohol consumption in both laboratory animals and human alcoholics.The clinical studies conducted to date, although often testing samples of limited size, feature GHB as an effective, well-tolerated and safe drug for the treatment of alcohol dependence. Behavioural data in rats suggest that GHB may produce alcohol-like effects. This similarity may explain why GHB produces positively reinforcing properties, being subsequently self-administered by rodents and sometimes abused by humans (although episodes of self-directed intake of GHB appear to be a limited phenomenon in alcoholics); in addition it provides support to the hypothesis that GHB constitutes for alcoholism a replacement therapy similar to methadone in heroin addiction.
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Characterization of the discriminative stimulus effects of Gamma-Hydroxybutyric Acid as a means for unraveling the neurochemical basis of Gamma-Hydroxybutyric Acid actions and its similarities to those of ethanol☆
Alcohol (Fayetteville N.Y.), 2000Co-Authors: Giancarlo Colombo, Roberta Agabio, Mauro A.m. Carai, Carla Lobina, Marialaura Pani, Roberta Reali, Gian Luigi GessaAbstract:The present paper reviews the drug discrimination studies, both from the literature and from this laboratory, conducted to investigate the pharmacological profile of the discriminative stimulus effects of Gamma-Hydroxybutyric Acid. Collectively, the results of these studies suggest that: (1) the discriminative stimulus effects of Gamma-Hydroxybutyric Acid are composed of different cues, each one being the effect of Gamma-Hydroxybutyric Acid on a specific receptor system; (2) the proportion of each component cue varies as the training dose of Gamma-Hydroxybutyric Acid is increased; (3) the gamma-aminobutyric Acid B-mediated cue is a major ingredient of the mixed stimulus of Gamma-Hydroxybutyric Acid, but it is more prominent at high training doses than at low training doses of Gamma-Hydroxybutyric Acid; and (4) positive modulation of the gamma-aminobutyric Acid A receptor is a relevant part of the discriminative stimulus effects of low Gamma-Hydroxybutyric Acid doses. Finally, data indicating symmetrical generalization between the discriminative stimulus effects of a specific range of doses of Gamma-Hydroxybutyric Acid and those of ethanol are discussed in regard to their further support of the hypothesis that Gamma-Hydroxybutyric Acid may exert its antialcohol effects through a substitution mechanism.
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Mechanism of the antialcohol effect of Gamma-Hydroxybutyric Acid.
Alcohol (Fayetteville N.Y.), 2000Co-Authors: Gian Luigi Gessa, Roberta Agabio, Mauro A.m. Carai, Carla Lobina, Marialaura Pani, Roberta Reali, Giancarlo ColomboAbstract:Treatment with Gamma-Hydroxybutyric Acid has been reported to effectively decrease alcohol craving and consumption as well as alcohol withdrawal symptoms in alcoholics. We describe the results of animal studies demonstrating the ability of Gamma-Hydroxybutyric Acid to reduce (1) the severity of ethanol withdrawal signs in rats rendered physically dependent on ethanol and (2) voluntary ethanol intake in selectively bred Sardinian alcohol-preferring rats. Furthermore, we review experimental data suggesting that Gamma-Hydroxybutyric Acid and ethanol have several pharmacological effects in common. Relevant similarities are: (1) stimulation of firing rate of dopaminergic neurons and dopamine release in specific rat brain areas; (2) development of cross-tolerance to the motor-impairing effects after repeated administration in rats; 3) abuse potential, as indicated by self-administration of pharmacologically relevant doses of Gamma-Hydroxybutyric Acid in rats and mice; (4) induction of anxiolytic effects in rats; and (5) induction of similar discriminative stimulus effects, as evidenced by symmetrical generalization in a drug discrimination study in rats. These lines of evidence are discussed in relation to Gamma-Hydroxybutyric Acid exerting its antialcohol effects by a substitution mechanism.
Károly Antal - One of the best experts on this subject based on the ideXlab platform.
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Gamma-Hydroxybutyric Acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABAB receptors.
Neuroscience Letters, 1996Co-Authors: Zsuzsa Emri, Károly Antal, Vincenzo CrunelliAbstract:Abstract The effect of Gamma-Hydroxybutyric Acid (GHB) on the excitatory postsynaptic potential (EPSP) evoked in thalamocortical neurones of the rat dorsal lateral geniculate nucleus and ventrobasal thalamus was investigated in vitro. GHB (0.1–5 mM) dose-dependently and reversibly decreased (36–78%) the amplitude of the sensory EPSP. This effect of GHB was blocked by the GABA B receptor antagonist CGP 35348 (1 mM). NCS 382 (1–3 mM), a putative GHB receptor antagonist, did not antagonise but weakly potentiated both the GHB- and baclofen-mediated decrease of the EPSP amplitude.
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Gamma-Hydroxybutyric Acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABAB receptors.
Neuroscience Letters, 1996Co-Authors: Zsuzsa Emri, Károly Antal, Vincenzo CrunelliAbstract:Abstract The effect of Gamma-Hydroxybutyric Acid (GHB) on the excitatory postsynaptic potential (EPSP) evoked in thalamocortical neurones of the rat dorsal lateral geniculate nucleus and ventrobasal thalamus was investigated in vitro. GHB (0.1–5 mM) dose-dependently and reversibly decreased (36–78%) the amplitude of the sensory EPSP. This effect of GHB was blocked by the GABA B receptor antagonist CGP 35348 (1 mM). NCS 382 (1–3 mM), a putative GHB receptor antagonist, did not antagonise but weakly potentiated both the GHB- and baclofen-mediated decrease of the EPSP amplitude.
Paolo Palatini - One of the best experts on this subject based on the ideXlab platform.
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Effects of single dose of Gamma-Hydroxybutyric Acid and lorazepam on psychomotor performance and subjective feelings in healthy volunteers.
European journal of clinical pharmacology, 1999Co-Authors: Santo Davide Ferrara, Rocco Orlando, R. Giorgetti, S. Zancaner, Adriano Tagliabracci, F. Cavarzeran, Paolo PalatiniAbstract:Objective: This study investigated the possible effects of Gamma-Hydroxybutyric Acid (GHB) on human psychomotor performance and subjective feelings important for the safety of skilled performance.
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therapeutic gamma hydroxybutyric Acid monitoring in plasma and urine by gas chromatography mass spectrometry
Journal of Pharmaceutical and Biomedical Analysis, 1993Co-Authors: Santo Davide Ferrara, Luigi Gallimberti, Gian Luigi Gessa, L. Tedeschi, Giampietro Frison, Paolo Palatini, R. Giorgetti, F CastagnaAbstract:A gas chromatographic-mass spectrometric (GC-MS) method for the determination of therapeutic levels of Gamma-Hydroxybutyric Acid (GHB) in plasma and urine samples is described. GHB is converted to its lactonic form gamma-butyrolactone (GBL) which is extracted from biological fluids after the addition of the internal standard delta-valerolactone. Final GC-MS analysis is obtained under electron impact selected ion monitoring (SIM) conditions. Mean relative recoveries of GHB from plasma and urine are 75.5% (RSD% = 2.2) and 76.4% (RSD% = 2.4), respectively. The assay is linear over a plasma GHB range of 2-200 micrograms ml-1 (r = 0.999) and a urine GHB range of 2-150 micrograms ml-1 (r = 0.998). Intra- and inter-assay relative standard deviations (n = 5) determined at 10 and 100 micrograms ml-1 are below 5%. The method is simple, specific and accurate, and may be applied for analytical purposes related to pharmacokinetic studies and therapeutic drug monitoring.
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dose dependent absorption and elimination of gamma hydroxybutyric Acid in healthy volunteers
European Journal of Clinical Pharmacology, 1993Co-Authors: Paolo Palatini, Luigi Gallimberti, Gian Luigi Gessa, L. Tedeschi, Giampietro Frison, Rocco Orlando, R. Zordan, Roberto Padrini, Santo Davide FerraraAbstract:Gamma-Hydroxybutyric Acid (GHB) is effective in treatment of the alcohol and opiate withdrawal syndromes. Its absorption and disposition kinetics have been studied in 8 healthy male volunteers following oral administration of single doses of 12.5, 25 and 50 mg kg−1.
