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Wolfgang Froestl - One of the best experts on this subject based on the ideXlab platform.
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doi: 10.3389/fpsyt.2011.00076 Activation of the GABAB Receptor prevents nicotine-induced locomotor stimulation in mice
2011Co-Authors: Carla Lobina, Wolfgang Froestl, Mauro A. M. Carai, Claudia Mugnaini, Serena Pasquini, Federico Corelli, Gian Luigi Gessa, Giancarlo Colombo, Michela Marinelli, Giancarlo Colombo NeuroscienceAbstract:Recent studies demonstrated that activation of the GABAB Receptor, either by means of orthosteric agonists or positive allosteric modulators (PAMs), inhibited different nicotinerelated behaviors, including intravenous self-administration and conditioned place preference, in rodents. The present study investigated whether the anti-nicotine effects of the GABAB Receptor agonist, baclofen, and GABAB PAMs, CGP7930, and GS39783, extend to nicotine stimulant effects. To this end, CD1 mice were initially treated with baclofe
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Repeated administration of the GABAB Receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats.
Psychopharmacology, 2010Co-Authors: Styliani Vlachou, Wolfgang Froestl, Sebastien Guery, Deboshri Banerjee, Jessica Benedict, M. G. Finn, Athina MarkouAbstract:Rationale γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABAB Receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABAB Receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse side effects compared with GABAB Receptor agonists, GABAB Receptor positive modulators are potentially improved therapeutic compounds for the treatment of drug dependence compared with agonists.
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mutagenesis and modeling of the GABAB Receptor extracellular domain support a venus flytrap mechanism for ligand binding
Journal of Biological Chemistry, 1999Co-Authors: Thierry Galvez, Wolfgang Froestl, Marielaure Parmentier, Cecile Joly, Barbara Malitschek, Klemens Kaupmann, Rainer Kuhn, Helmut Bittiger, Bernhard Bettler, Jeanphilippe PinAbstract:The gamma-aminobutyric acid type B (GABAB) Receptor is distantly related to the metabotropic glutamate Receptor-like family of G-protein-coupled Receptors (family 3). Sequence comparison revealed that, like metabotropic glutamate Receptors, the extracellular domain of the two GABAB Receptor splice variants possesses an identical region homologous to the bacterial periplasmic leucine-binding protein (LBP), but lacks the cysteine-rich region common to all other family 3 Receptors. A three-dimensional model of the LBP-like domain of the GABAB Receptor was constructed based on the known structure of LBP. This model predicts that four of the five cysteine residues found in this GABAB Receptor domain are important for its correct folding. This conclusion is supported by analysis of mutations of these Cys residues and a decrease in the thermostability of the binding site after dithiothreitol treatment. Additionally, Ser-246 was found to be critical for CGP64213 binding. Interestingly, this residue aligns with Ser-79 of LBP, which forms a hydrogen bond with the ligand. The mutation of Ser-269 was found to differently affect the affinity of various ligands, indicating that this residue is involved in the selectivity of recognition of GABAB Receptor ligands. Finally, the mutation of two residues, Ser-247 and Gln-312, was found to increase the affinity for agonists and to decrease the affinity for antagonists. Such an effect of point mutations can be explained by the Venus flytrap model for Receptor activation. This model proposes that the initial step in the activation of the Receptor by agonist results from the closure of the two lobes of the binding domain.
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effects of GABAB Receptor antagonism on the development of pentylenetetrazol induced kindling in mice
Brain Research, 1998Co-Authors: D Getova, Wolfgang Froestl, N G BoweryAbstract:Abstract Pentylenetetrazol (PTZ) administered chronically in rodents induces kindling which is considered to be a model of chronic epilepsy mediated through a specific interaction with the GABA-gated chloride ionophore. PTZ kindling also impairs shuttle-box learning indicating a possible modulation of memory storage [A. Becker, G. Grecksch, H. Mathies. The influence of diazepam on learning processes impaired by pentylenetetrazol kindling. Naunyn-Schmiedeberg's Arch. Pharmacol. 349 (1994) 429-496]. Since GABAB Receptor antagonism has been shown to improve cognitive performance in rodents and primates we have examined the effects of 3 antagonists: CGP 36742 (3-amino-propyl-n-butyl-phosphinic acid), CGP 56433 ([3-{1-(S)-[{3-(cyclohexylmethyl) hydroxyphosphinyl]-2-(S)-hydroxypropyl]-amino]ethyl]benzoic acid) and CGP 61334 ([3-{[3[(diethoxymethyl)hydroxyphosphinyl]-propyl]-amino}methyl]-benzoic acid) on the induction of PTZ kindling in mice at 48 h intervals for 8 weeks. Subsequently the mice were tested in an active avoidance paradigm. At the end of the experiment GABAB Receptor autoradiography was performed on brain sections from these animals. Seizure intensity increased progressively in control mice reaching by 8 weeks a mean score which corresponded to clonic seizures. The GABAB antagonists suppressed kindling during the first 4 weeks and after that restored the seizure intensity to the level of control animals. The level of kindling was proportional to the avoidance score. The density of GABAB Receptor binding in brain sections from PTZ kindled mice was significantly greater than in controls. This was not altered by pretreatment with the GABAB antagonists except in the cerebellum.
Tomoyuki Takahashi - One of the best experts on this subject based on the ideXlab platform.
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gtp binding protein βγ subunits mediate presynaptic calcium current inhibition by GABAB Receptor
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Yoshinao Kajikawa, Naoto Saitoh, Tomoyuki TakahashiAbstract:A variety of GTP-binding protein (G protein)-coupled Receptors are expressed at the nerve terminals of central synapses and play modulatory roles in transmitter release. At the calyx of Held, a rat auditory brainstem synapse, activation of presynaptic γ-aminobutyric acid type B Receptors (GABAB Receptors) or metabotropic glutamate Receptors inhibits presynaptic P/Q-type Ca2+ channel currents via activation of G proteins, thereby attenuating transmitter release. To identify the heterotrimeric G protein subunits involved in this presynaptic inhibition, we loaded G protein βγ subunits (Gβγ) directly into the calyceal nerve terminal through whole-cell patch pipettes. Gβγ slowed the activation of presynaptic Ca2+ currents (IpCa) and attenuated its amplitude in a manner similar to the externally applied baclofen, a GABAB Receptor agonist. The effects of both Gβγ and baclofen were relieved after strong depolarization of the nerve terminal. In addition, Gβγ partially occluded the inhibitory effect of baclofen on IpCa. In contrast, guanosine 5′-O-(3-thiotriphosphate)-bound Goα loaded into the calyx had no effect. Immunocytochemical examination revealed that the subtype of G proteins Go, but not the Gi, subtype, is expressed in the calyceal nerve terminal. These results suggest that presynaptic inhibition mediated by G protein-coupled Receptors occurs primarily by means of the direct interaction of Go βγ subunits with presynaptic Ca2+ channels.
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g protein coupled modulation of presynaptic calcium currents and transmitter release by a GABAB Receptor
The Journal of Neuroscience, 1998Co-Authors: Tomoyuki Takahashi, Yoshinao Kajikawa, Tetsuhiro TsujimotoAbstract:Presynaptic GABAB Receptors play a regulatory role in central synaptic transmission. To elucidate their underlying mechanism of action, we have made whole-cell recordings of calcium and potassium currents from a giant presynaptic terminal, the calyx of Held, and EPSCs from its postsynaptic target in the medial nucleus of the trapezoid body of rat brainstem slices. The GABAB Receptor agonist baclofen suppressed EPSCs and presynaptic calcium currents but had no effect on voltage-dependent potassium currents. The calcium current-EPSC relationship measured during baclofen application was similar to that observed on reducing [Ca2+]o, suggesting that the presynaptic inhibition generated by baclofen is caused largely by the suppression of presynaptic calcium influx. Presynaptic loading of the GDP analog guanosine-5'-O-(2-thiodiphosphate) (GDPbetaS) abolished the effect of baclofen on both presynaptic calcium currents and EPSCs. The nonhydrolyzable GTP analog guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) suppressed presynaptic calcium currents and occluded the effect of baclofen on presynaptic calcium currents and EPSCs. Photoactivation of GTPgammaS induced an inward rectifying potassium current at the calyx of Held, whereas baclofen had no such effect. We conclude that presynaptic GABAB Receptors suppress transmitter release through G-protein-coupled inhibition of calcium currents.
David A Colby - One of the best experts on this subject based on the ideXlab platform.
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activation of the γ aminobutyric acid type b GABAB Receptor by agonists and positive allosteric modulators
Journal of Medicinal Chemistry, 2015Co-Authors: Katie M Brown, Kuldeep K Roy, Gregory H Hockerman, Robert J Doerksen, David A ColbyAbstract:Since the discovery of the GABAB agonist and muscle relaxant baclofen, there have been substantial advancements in the development of compounds that activate the GABAB Receptor as agonists or positive allosteric modulators. For the agonists, most of the existing structure–activity data apply to understanding the role of substituents on the backbone of GABA as well as replacing the carboxylic acid and amine groups. In the cases of the positive allosteric modulators, the allosteric binding site(s) and structure–activity relationships are less well-defined; however, multiple classes of molecules have been discovered. The recent report of the X-ray structure of the GABAB Receptor with bound agonists and antagonists provides new insights for the development of compounds that bind the orthosteric site of this Receptor. From a therapeutic perspective, these data have enabled efforts in drug discovery in areas of addiction-related behavior, the treatment of anxiety, and the control of muscle contractility.
Giancarlo Colombo - One of the best experts on this subject based on the ideXlab platform.
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inhibition of alcohol self administration by positive allosteric modulators of the GABAB Receptor in rats lack of tolerance and potentiation of baclofen
Psychopharmacology, 2015Co-Authors: Paola Maccioni, Claudia Mugnaini, Federico Corelli, Gian Luigi Gessa, Daniela Vargiolu, Thomas Andrew William, Pari Malherbe, Kimberly A Leitemorris, Giancarlo ColomboAbstract:Treatment with positive allosteric modulators (PAMs) of the GABAB Receptor (GABAB PAMs) inhibits several alcohol-motivated behaviors in rodents, including operant, oral alcohol self-administration. The present study assessed the effects of (a) repeated administration of the GABAB PAMs, GS39783, and rac-BHFF and (b) a combination of an ineffective dose of either GS39783, or rac-BHFF, and an ineffective dose of the prototypic GABAB Receptor agonist, baclofen, on operant, oral alcohol self-administration. Studies were conducted using selectively bred Sardinian alcohol-preferring (sP) rats exposed to a standard procedure of fixed ratio (FR) 4 (FR4) schedule of reinforcement for 15 % (v/v) alcohol. Repeated treatment with GS39783 (50 mg/kg, i.g.) or rac-BHFF (50 mg/kg, i.g.) produced an initial 40 % reduction in number of lever responses for alcohol and amount of self-administered alcohol that was maintained unaltered throughout the 10-day period of the GS39783 treatment and increased throughout the 5-day period of the rac-BHFF treatment. Combination of per se ineffective doses of GS39783 (5 mg/kg, i.g.), or rac-BHFF (5 mg/kg, i.g.), and baclofen (1 mg/kg, i.p.) reduced, by 35–45 %, both number of lever responses for alcohol and amount of self-administered alcohol. GS39783 and rac-BHFF (a) reduced alcohol reinforcing properties when given repeatedly, with no development of tolerance, and (b) potentiated baclofen effect. Both sets of data possess translational interest, as they suggest potential effectiveness of GABAB PAMs under chronic treatment and selective potentiation of baclofen effect.
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doi: 10.3389/fpsyt.2011.00076 Activation of the GABAB Receptor prevents nicotine-induced locomotor stimulation in mice
2011Co-Authors: Carla Lobina, Wolfgang Froestl, Mauro A. M. Carai, Claudia Mugnaini, Serena Pasquini, Federico Corelli, Gian Luigi Gessa, Giancarlo Colombo, Michela Marinelli, Giancarlo Colombo NeuroscienceAbstract:Recent studies demonstrated that activation of the GABAB Receptor, either by means of orthosteric agonists or positive allosteric modulators (PAMs), inhibited different nicotinerelated behaviors, including intravenous self-administration and conditioned place preference, in rodents. The present study investigated whether the anti-nicotine effects of the GABAB Receptor agonist, baclofen, and GABAB PAMs, CGP7930, and GS39783, extend to nicotine stimulant effects. To this end, CD1 mice were initially treated with baclofe
Wouter Koek - One of the best experts on this subject based on the ideXlab platform.
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Discriminative stimulus effects of the GABAB Receptor-positive modulator rac-BHFF: comparison with GABAB Receptor agonists and drugs of abuse.
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Wouter Koek, Kejun Cheng, Kenner C. RiceAbstract:GABAB Receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction. They may have fewer side effects than GABAB Receptor agonists, because selective enhancement of activated Receptors could have effects different from nonselective activation of all Receptors. To examine this, pigeons were trained to discriminate the GABAB Receptor-positive modulator (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) from its vehicle. The discriminative stimulus effects of rac-BHFF were not mimicked by the GABAB Receptor agonists baclofen and γ-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose self-administration has been reported to be attenuated by GABAB Receptor-positive modulators. The discriminative stimulus effects of rac-BHFF were not antagonized by the GABAB Receptor antagonist 3-aminopropyl (diethoxymethyl)phosphinic acid (CGP35348) but were attenuated by the less efficacious GABAB Receptor-positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930), suggesting the possibility that rac-BHFF produces its discriminative stimulus effects by directly activating GABAB2 subunits of GABAB Receptors. At a dose 10-fold lower than the training dose, rac-BHFF enhanced the discriminative stimulus effects of baclofen, but not of GHB. This study provides evidence that the effects of GABAB Receptor-positive modulators are not identical to those of GABAB Receptor agonists. In addition, the results suggest that positive modulation of GABAB Receptors does not produce discriminative stimulus effects similar to those of benzodiazepines, alcohol, cocaine, and nicotine. Finally, the finding that rac-BHFF enhanced effects of baclofen but not of GHB is consistent with converging evidence that the populations of GABAB Receptors mediating the effects of baclofen and GHB are not identical.
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cataleptic effects of γ hydroxybutyrate ghb its precursor γ butyrolactone gbl and GABAB Receptor agonists in mice differential antagonism by the GABAB Receptor antagonist cgp35348
Psychopharmacology, 2007Co-Authors: Wouter Koek, Susan L Mercer, Andrew CoopAbstract:Rationale Gamma-hydroxybutyrate (GHB) is used to treat narcolepsy but is also abused. GHB has many actions in common with the GABAB Receptor agonist baclofen.
