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Wouter Koek - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2012
    Co-Authors: Wouter Koek, Kejun Cheng, Kenner C. Rice
    Abstract:

    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.

  • Behavioral Effects of γ-Hydroxybutyrate, Its Precursor γ-Butyrolactone, and GABAB Receptor Agonists: Time Course and Differential Antagonism by the GABAB Receptor Antagonist 3-Aminopropyl(diethoxymethyl)phosphinic Acid (CGP35348)
    Journal of Pharmacology and Experimental Therapeutics, 2009
    Co-Authors: Wouter Koek, Susan L Mercer, Andrew Coop
    Abstract:

    γ-Hydroxybutyrate (GHB) is used therapeutically and recreationally. The mechanism by which GHB produces its therapeutic and recreational effects is not entirely clear, although GABAB Receptors seem to play an important role. This role could be complex, because there are indications that different GABAB Receptor mechanisms mediate the effects of GHB and the prototypical GABAB Receptor agonist baclofen. To further explore possible differences in underlying GABAB Receptor mechanisms, the present study examined the effects of GHB and baclofen on operant responding and their antagonism by the GABAB Receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348). Pigeons were trained to peck a key for access to food during response periods that started at different times after the beginning of the session. In these pigeons, GHB, its precursor γ-butyrolactone (GBL), and the GABAB Receptor Agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) decreased the rate of responding in a dose- and time-dependent manner. CGP35348 shifted the dose-response curve of each agonist to the right, but the magnitude of the shift differed among the Agonists. Schild analysis yielded a pA2 value of CGP35348 to antagonize GHB and GBL [i.e., 3.9 (3.7–4.2)] that was different (P = 0.0011) from the pA2 value to antagonize baclofen and SKF97541 [i.e., 4.5 (4.4–4.7)]. This finding is further evidence that the GABAB Receptor mechanisms mediating the effects of GHB and prototypical GABAB Receptor Agonists are not identical. A better understanding of the similarities and differences between these mechanisms, and their involvement in the therapeutic effects of GHB and baclofen, could lead to more effective medications with fewer adverse effects.

  • 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, 2007
    Co-Authors: Wouter Koek, Susan L Mercer, Andrew Coop
    Abstract:

    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.

  • Discriminative stimulus effects of GHB and GABAB Agonists are differentially attenuated by CGP35348
    European Journal of Pharmacology, 2006
    Co-Authors: Lawrence P. Carter, Andrew Coop, Weibin Chen, Wouter Koek
    Abstract:

    Abstract The aim of this study was to examine the possible heterogeneity of mechanisms that contribute to the discriminative stimulus and rate-decreasing effects of γ-hydroxybutyrate (GHB). Dose effect curves were determined for GHB and two GABAB Receptor Agonists (baclofen and SKF97541) alone and together with the selective GABAB Receptor antagonist CGP35348 in rats discriminating GHB. In a second study, GHB and SKF97541 dose effect curves were determined alone and together with baclofen. CGP35348 attenuated the discriminative stimulus and rate-decreasing effects of SKF97541 and baclofen to a greater extent than those of GHB. In the second study, baclofen enhanced the discriminative stimulus and rate-decreasing effects of GHB and SKF97541; however, the GHB dose effect curve was not shifted in a parallel manner. Taken together, these data suggest that multiple mechanisms, possibly including GHB Receptors and GABAB Receptor subtypes, are involved in the discriminative stimulus and rate-decreasing effects of GHB.

  • novel γ hydroxybutyric acid ghb analogs share some but not all of the behavioral effects of ghb and GABAB Receptor Agonists
    Journal of Pharmacology and Experimental Therapeutics, 2005
    Co-Authors: Lawrence P. Carter, Andrew Coop, Weibin Chen, Huifang Wu, Marilyn Matthews, Ashok K Mehta, Jason R Hernandez, Jennifer A Thomson, Maharaj K Ticku, Wouter Koek
    Abstract:

    γ-Hydroxybutyrate (GHB), a therapeutic for narcolepsy and a drug of abuse, has several mechanisms of action that involve GHB and GABA B Receptors, metabolism to GABA, and modulation of dopaminergic signaling. The aim of these studies was to examine the role of GHB and GABA B Receptors in the behavioral effects of GHB. Three approaches were used to synthesize GHB analogs that bind selectively to GHB Receptors and are not metabolized to GABA-active compounds. Radioligand binding assays identified UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid (3-HPA), and 4-hydroxy-4-phenylbutyric acid as compounds that displace [ 3 H]NCS-382 [5-[ 3 H]-(2 E )-(5-hydroxy-5,7,8,9-tetrahydro-6 H -benzo[ a ][7] annulen-6-ylidene) ethanoic acid] from GHB Receptors at concentrations that do not markedly affect [ 3 H]GABA binding to GABA B Receptors. In rats and pigeons, GHB discriminative stimulus effects were not mimicked or attenuated by UMB86, UMB72, or 3-HPA up to doses that decreased responding. In mice, GHB, GHB precursors (γ-butyrolactone and 1,4-butanediol) and GABA B Receptor Agonists [SKF97541 [3-aminopropyl(methyl)phosphinic acid hydrochloride] and baclofen] dose-dependently produced hypolocomotion, catalepsy, ataxia, and loss of righting. The GABA B Receptor antagonist CGP35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) attenuated catalepsy and ataxia that was observed after GHB and GABA B Receptor Agonists SKF97541 and baclofen. UMB86, UMB72, UMB73, and 3-HPA, like GHB, produced hypolocomotion, ataxia, and loss of righting; however, catalepsy was never observed with these compounds, which is consistent with the cataleptic effects of GHB being mediated by GABA B Receptors. Ataxia that was observed with UMB86, UMB72, UMB73, and 3-HPA was not antagonized by CGP35348, suggesting that ataxia induced by these analogs is not mediated by GABA B Receptors and might involve GHB Receptors.

Anders Lehmann - One of the best experts on this subject based on the ideXlab platform.

  • Targeting the GABAB Receptors for the Treatment of Gastroesophageal Reflux Disease and Chronic Cough
    GABAB Receptor, 2016
    Co-Authors: Anders Lehmann, L. Ashley Blackshaw, Brendan J. Canning
    Abstract:

    Transient lower esophageal sphincter relaxation (TLESR) is the dominating motor event behind gastroesophageal reflux (GER) and therefore an important factor in gastroesophageal reflux disease (GERD). TLESR is a reflex dependent on the vagus and as such, it shares many similarities with the cough reflex. Moreover, GER is a known cause of chronic cough in some patients, and agents inhibiting both TLESR and cough may be useful antitussives. There is no effective therapy for GERD patients whose symptoms are not fully resolved by proton pump inhibitor (PPI) therapy and marketed antitussives have poor effects in most patients suffering from chronic cough. The observations that GABA type B (GABAB) Receptor Agonists reduce TLESR and inhibit cough regardless of stimulus open new inroads to the treatment of PPI-resistant GERD as well as GER-related cough. The present review focuses on these aspects and discusses the findings of GABAB Receptor Agonists on TLESR, GER, GERD, and cough in both the preclinical setting, healthy individuals and patients. Special attention is devoted to the role of the vagus in mediating these pharmacological effects.

  • Different in vitro and in vivo profiles of substituted 3‐aminopropylphosphinate and 3‐aminopropyl(methyl)phosphinate GABAB Receptor Agonists as inhibitors of transient lower oesophageal sphincter relaxation
    British Journal of Pharmacology, 2012
    Co-Authors: Anders Lehmann, Lena Brändén, Lillevi Kärrberg, Madeleine Antonsson, Ann Aurell-holmberg, L A Blackshaw, Thomas Elebring, Jörgen Jensen, Jan P. Mattsson, Karolina Nilsson
    Abstract:

    BACKGROUND AND PURPOSE Gastro-oesophageal reflux is predominantly caused by transient lower oesophageal sphincter relaxation (TLOSR) and GABAB Receptor stimulation inhibits TLOSR. Lesogaberan produces fewer CNS side effects than baclofen, which has been attributed to its affinity for the GABA transporter (GAT), the action of which limits stimulation of central GABAB Receptors. To understand the structure–activity relationship for analogues of lesogaberan (3-aminopropylphosphinic acids), and corresponding 3-aminopropyl(methyl)phosphinic acids, we have compared representatives of these classes in different in vitro and in vivo models. EXPERIMENTAL APPROACH The compounds were characterized in terms of GABAB agonism in vitro. Binding to GATs and cellular uptake was done using rat brain membranes and slices respectively. TLOSR was measured in dogs, and CNS side effects were evaluated as hypothermia in mice and rats. KEY RESULTS 3-Aminopropylphosphinic acids inhibited TLOSR with a superior therapeutic index compared to 3-aminopropyl(methyl)phosphinic acids. This difference was most likely due to differential GAT-mediated uptake into brain cells of the former but not latter. In agreement, 3-aminopropyl(methyl)phosphinic acids were much more potent in producing hypothermia in rats even when administered i.c.v. CONCLUSIONS AND IMPLICATIONS An enhanced therapeutic window for 3-aminopropylphosphinic acids compared with 3-aminopropyl(methyl)phosphinic acids with respect to inhibition of TLOSR was observed and is probably mechanistically linked to neural cell uptake of the former but not latter group of compounds. These findings offer a platform for discovery of new GABAB Receptor Agonists for the treatment of reflux disease and other conditions where selective peripheral GABAB Receptor agonism may afford therapeutic effects.

  • Antitussive effects of the peripherally restricted GABAB Receptor agonist lesogaberan in guinea pigs: comparison to baclofen and other GABAB Receptor-selective Agonists.
    Cough, 2012
    Co-Authors: Brendan J. Canning, Nanako Mori, Anders Lehmann
    Abstract:

    Background Gastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABAB Receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux therapy that reduces the frequency of transient lower esophageal sphincter relaxations (TLESR; the major cause of reflux) in animals and in patients with GERD. GABAB Receptor Agonists have also been shown to possess antitussive effects in patients and in animals independent of their effects on TLESR, suggesting that lesogaberan may be a promising treatment for chronic cough.

  • m1877 two functional categories of reflux inhibiting GABAB Receptor Agonists defined by their affinity for the gaba transporter
    Gastroenterology, 2009
    Co-Authors: Anders Lehmann, Thomas Elebring, Jörgen Jensen, Karolina Nilsson, Pirjo Saransaari, Sverker Von Unge, Jan P. Mattsson
    Abstract:

    Background: Proton pump inhibitors (PPI) are the drug of first choice for treating patients with gastroesophageal reflux disease (GERD). However, about 50% of non-erosive reflux disease (NERD) patients have a poor response to PPI treatment. It is reported that esophageal motility disorder involving a decline in esophageal clearance contributes to the poor PPI response. Accordingly, a drug capable of enhancing esophageal motility would be beneficial in the treatment of NERD patients. Rikkunshito, a gastrointestinal prokinetic agent, is known to improve esophageal clearance in GERD patients and gastric emptying in functional dyspepsia patients and to increase secretion of ghrelin in rats. Aim: To clarify the efficacy of rikkunshito in NERD patients, we evaluated the effects of rikkunshito on esophageal and lower esophageal sphincter (LES) motility and symptoms. Methods: Fifteen patients were enrolled in the study. They were diagnosed as having NERD according to endoscopic testing and the score (6 points or more) obtained on the questionnaire for the diagnosis of reflux disease (QUEST). All patients stopped taking all gastrointestinal-related drugs for over 1 week prior to rikkunshito treatment, and were administered rikkunshito (7.5 g per day, orally) for 8 weeks. Esophageal and LES functions during liquid or semisolid swallow were evaluated using MII-EM following gold standard methods before and after rikkunshitotreatment. Symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS) before, 4 weeks after, and 8 weeks after treatment. Results: Rikkunshito-treatment significantly improved the mean of complete bolus transit (CBT) during liquid or semisolid swallow from 60.7±7.7% to 90.0±5.8% (p 79%, semisolid: >69%) for CBT decreased from 53.3% to 16.7% and from 60.0% to 33.3% after treatment, respectively. In manometry evaluation, rikkunshito significantly improved the mean of LES residual pressure during liquid swallow from 6.0±1.3 mmHg to 3.8±1.4 mmHg (p<0.05). In addition, rikkunshito significantly ameliorated total GI symptom scores in GSRS (from 2.1±0.2 to 1.6±0.1: (p<0.05)) and showed a tendency toward improvement of subscales for reflux symptoms, abdominal pain and dyspeptic symptoms. Conclusion: We found that rikkunshito improved the esophageal clearance and symptoms in NERD patients through the amelioration of esophageal and LES motility disorder. Thus, rikkunshito may become a useful drug for treating NERD patients.

  • Inhibitory effects of GABAB Receptor Agonists on swallowing in the dog
    European Journal of Pharmacology, 2002
    Co-Authors: Anders Lehmann, Marianne Bremner-danielsen, Lena Brändén, Lillevi Kärrberg
    Abstract:

    Abstract The effects of the GABAB Receptor Agonists baclofen (1.4 and 7 μmol/kg i.v.) and CGP 44532 ([(2S)-3-amino-2-hydroxypropyl]methyl phosphinic acid], 0.2 and 0.7 μmol/kg i.v.) on transient lower esophageal sphincter relaxations and spontaneous and pharyngeally stimulated swallowing were investigated in conscious dogs. Both compounds inhibited transient lower esophageal sphincter relaxations dose-dependently, CGP 44532 being approximately fivefold more potent. In experiments designed to measure transient lower esophageal sphincter relaxations, spontaneous swallowing was suppressed by both compounds. When swallowing was evoked by intrapharyngeal water injection, both baclofen and CGP 44532 reduced the occurrence of primary peristalsis. It is concluded that centrally acting GABAB Receptor Agonists inhibit spontaneous and stimulated swallowing probably through an action in the central pattern generator for swallowing.

Athina Markou - One of the best experts on this subject based on the ideXlab platform.

  • KK-92A, a novel GABAB Receptor positive allosteric modulator, attenuates nicotine self-administration and cue-induced nicotine seeking in rats.
    Psychopharmacology, 2017
    Co-Authors: Emmanuel Sturchler, M. G. Finn, Katarzyna Kaczanowska, Michael D. Cameron, Patrick R. Griffin, Patricia Mcdonald, Athina Markou
    Abstract:

    Rationale GABAB Receptors (GABABR) play a critical role in GABAergic neurotransmission in the brain and are thought to be one of the most promising targets for the treatment of drug addiction. GABABR positive allosteric modulators (PAMs) have shown promise as potential anti-addictive therapies, as they lack the sedative and muscle relaxant properties of full GABAB Receptor Agonists such as baclofen.

  • 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, 2010
    Co-Authors: Styliani Vlachou, Wolfgang Froestl, Sebastien Guery, Deboshri Banerjee, Jessica Benedict, M. G. Finn, Athina Markou
    Abstract:

    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.

  • GABAB Receptors in reward processes.
    GABABReceptor Pharmacology - A Tribute to Norman Bowery, 2010
    Co-Authors: Styliani Vlachou, Athina Markou
    Abstract:

    Abstract γ-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the brain which acts through different Receptor subtypes. Metabotropic GABAB Receptors are widely distributed throughout the brain. Alterations in GABA signaling through pharmacological activation or deactivation of the GABAB Receptor regulate behavior and brain reward processes. GABAB Receptor Agonists and, most recently, positive modulators have been found to inhibit the reinforcing effects of drugs of abuse, such as cocaine, amphetamine, nicotine, ethanol, and opiates. This converging evidence of the effects of GABAB compounds on the reinforcing properties of addictive drugs is based on behavioral studies that used a variety of procedures with relevance to reward processes and drug abuse liability, including intracranial self-stimulation, intravenous self-administration under both fixed- and progressive-ratio schedules of reinforcement, reinstatement, and conditioned place preference. GABAB Receptor Agonists and positive modulators block the reinforcing effects of drugs of abuse in these animal models. However, GABAB Receptor Agonists also have undesirable side-effects. GABAB Receptor modulators have potential advantages as medications for drug addiction. These compounds have a better side-effect profile than GABAB Agonists because they are devoid of intrinsic agonistic activity in the absence of GABA. They only exert their modulatory actions in concert with endogenous GABAergic activity. Thus, GABAB Receptor positive modulators are promising therapeutics for the treatment of various aspects of dependence (e.g., initiation, maintenance, and relapse) on various drugs of abuse, such as cocaine, nicotine, heroin, and alcohol.

  • The GABAB Receptor-positive modulator GS39783 and the GABAB Receptor agonist baclofen attenuate the reward-facilitating effects of cocaine: intracranial self-stimulation studies in the rat.
    Neuropsychopharmacology, 2005
    Co-Authors: David A. Slattery, Wolfgang Froestl, Athina Markou, John F. Cryan
    Abstract:

    There is an increasing interest in the development of nondopaminergic pharmacotherapies for cocaine abuse. Emerging preclinical and clinical data with the metabotropic GABAB Receptor agonist baclofen support a role for the modulation of GABAB Receptors in the treatment of drug addiction. Nevertheless, the muscle relaxant, hypothermic, and sedative properties of baclofen somewhat limit its widespread potential therapeutic utility. Recently, positive modulators of the GABAB Receptor such as GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) have been identified. These positive modulators enhance the effects of GABA (gamma-aminobutyric acid) through actions at an allosteric site and are devoid of intrinsic agonistic efficacy. The aim of the present study was to assess the ability of the novel GABAB-positive modulator GS39873 or baclofen to modulate the behavioral effects of cocaine. Drugs of abuse such as cocaine lower brain reward thresholds obtained using intracranial self-stimulation (ICSS). We demonstrate here that GS39783 had no intrinsic effects on ICSS reward thresholds (10-100 mg/kg p.o.) in rats, whereas the full GABAB Receptor agonist baclofen (2.5-5 mg/kg p.o.) dose dependently elevated thresholds. Moreover, both GS39783 and baclofen attenuated the threshold lowering effect of cocaine administration (10 mg/kg intraperitoneally) in a dose-related manner. These data strongly suggest that activation of GABAB Receptors attenuates the rewarding effects of acute cocaine. Therefore, GABAB-positive modulation may represent a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse without the side effects of full GABAB Receptor Agonists.

  • The GABAB Receptor Agonists baclofen and CGP44532 decreased nicotine self-administration in the rat.
    Psychopharmacology, 2004
    Co-Authors: Neil E. Paterson, Wolfgang Froestl, Athina Markou
    Abstract:

    Rationale Previous work has indicated a potential role for γ-aminobutyric acid-B (GABAB) Receptor Agonists in treating drug addiction in humans. Specifically, GABAB Receptor Agonists decreased cocaine, heroin and nicotine self-administration in rats.

Wolfgang Froestl - One of the best experts on this subject based on the ideXlab platform.

  • The Development of Medications for Alcohol-Use Disorders Targeting the GABAB Receptor System
    Recent Patents on CNS Drug Discovery, 2012
    Co-Authors: Roberta Agabio, Wolfgang Froestl, Paola Maccioni, Mauro A.m. Carai, Gian Luigi Gessa, Giancarlo Colombo
    Abstract:

    The present paper summarizes experimental and clinical data suggesting the therapeutic potential of the prototypic GABAB Receptor agonist, baclofen, for the treatment of alcohol-use disorders (AUDs). Numerous studies have reported baclofen-induced suppression of alcohol drinking, relapse-like drinking, and alcohol reinforcing, rewarding, stimulating, and motivational properties in rats and mice. The majority of clinical surveys conducted to date have demonstrated the capacity of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. More recently, the discovery of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, provided a new tool for pharmacological manipulations of the GABAB Receptor. Accumulating lines of preclinical evidence suggest that positive allosteric modulators of the GABAB Receptor (GABAB PAMs), such as GS39783, display a high therapeutic index and retain baclofen's capacity to suppress alcohol consumption and alcohol reinforcing and motivational properties. The present paper also summarizes the most relevant patents on GABAB Receptor Agonists and GABAB PAMs as possible pharmacotherapies for AUDs.

  • 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, 2010
    Co-Authors: Styliani Vlachou, Wolfgang Froestl, Sebastien Guery, Deboshri Banerjee, Jessica Benedict, M. G. Finn, Athina Markou
    Abstract:

    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.

  • attenuation of cocaine seeking by GABAB Receptor Agonists baclofen and cgp44532 but not the gaba reuptake inhibitor tiagabine in baboons
    Drug and Alcohol Dependence, 2007
    Co-Authors: Elise M Weerts, Wolfgang Froestl, Barbara J Kaminski, Roland R Griffiths
    Abstract:

    The current study evaluated the effects of drugs that increase GABA levels by activation of GABAB Receptors (baclofen and {"type":"entrez-protein","attrs":{"text":"CGP44532","term_id":"875097404","term_text":"CGP44532"}}CGP44532) or by inhibition of GABA reuptake (tiagabine) on the reinstatement of extinguished lever responding produced by priming doses of cocaine in baboons (i.e., cocaine-seeking). Cocaine self-injection was established and maintained under a fixed ratio (FR10) schedule of reinforcement during daily 2-h sessions. Lever responding was extinguished by substituting vehicle (saline) for cocaine until the number of self-injections decreased to 10 or less per session for 2 consecutive sessions (defined as extinction). Once extinction occurred, priming doses of cocaine (0.1-3.2 mg/kg, IV) were administered during extinction conditions. Administration of priming doses of cocaine significantly increased cocaine-seeking in a dose dependent manner. Cocaine-seeking produced by priming doses of cocaine were attenuated by pretreatment with baclofen (N=5) or {"type":"entrez-protein","attrs":{"text":"CGP44532","term_id":"875097404","term_text":"CGP44532"}}CGP44532 (N=5) but not tiagabine (N=3). The doses of baclofen (0.32 mg/kg), and CGP445532 (0.32 mg/kg) that reduced cocaine-seeking produced by cocaine priming doses did not reinstate cocaine-seeking and did not produce overt effects when administered alone. These data indicate that GABAB Agonists may reduce relapse to cocaine taking.

  • The GABAB Receptor-positive modulator GS39783 and the GABAB Receptor agonist baclofen attenuate the reward-facilitating effects of cocaine: intracranial self-stimulation studies in the rat.
    Neuropsychopharmacology, 2005
    Co-Authors: David A. Slattery, Wolfgang Froestl, Athina Markou, John F. Cryan
    Abstract:

    There is an increasing interest in the development of nondopaminergic pharmacotherapies for cocaine abuse. Emerging preclinical and clinical data with the metabotropic GABAB Receptor agonist baclofen support a role for the modulation of GABAB Receptors in the treatment of drug addiction. Nevertheless, the muscle relaxant, hypothermic, and sedative properties of baclofen somewhat limit its widespread potential therapeutic utility. Recently, positive modulators of the GABAB Receptor such as GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) have been identified. These positive modulators enhance the effects of GABA (gamma-aminobutyric acid) through actions at an allosteric site and are devoid of intrinsic agonistic efficacy. The aim of the present study was to assess the ability of the novel GABAB-positive modulator GS39873 or baclofen to modulate the behavioral effects of cocaine. Drugs of abuse such as cocaine lower brain reward thresholds obtained using intracranial self-stimulation (ICSS). We demonstrate here that GS39783 had no intrinsic effects on ICSS reward thresholds (10-100 mg/kg p.o.) in rats, whereas the full GABAB Receptor agonist baclofen (2.5-5 mg/kg p.o.) dose dependently elevated thresholds. Moreover, both GS39783 and baclofen attenuated the threshold lowering effect of cocaine administration (10 mg/kg intraperitoneally) in a dose-related manner. These data strongly suggest that activation of GABAB Receptors attenuates the rewarding effects of acute cocaine. Therefore, GABAB-positive modulation may represent a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse without the side effects of full GABAB Receptor Agonists.

  • The GABAB Receptor Agonists baclofen and CGP44532 decreased nicotine self-administration in the rat.
    Psychopharmacology, 2004
    Co-Authors: Neil E. Paterson, Wolfgang Froestl, Athina Markou
    Abstract:

    Rationale Previous work has indicated a potential role for γ-aminobutyric acid-B (GABAB) Receptor Agonists in treating drug addiction in humans. Specifically, GABAB Receptor Agonists decreased cocaine, heroin and nicotine self-administration in rats.

Giambattista Bonanno - One of the best experts on this subject based on the ideXlab platform.

  • in vitro activation of gat1 transporters expressed in spinal cord gliosomes stimulates glutamate release that is abnormally elevated in the sod1 g93a mouse model of amyotrophic lateral sclerosis
    Journal of Neurochemistry, 2010
    Co-Authors: Marco Milanese, Simona Zappettini, Emanuela Jacchetti, Tiziana Bonifacino, Chiara Cervetto, Cesare Usai, Giambattista Bonanno
    Abstract:

    J. Neurochem. (2010) 113, 489–501. Abstract The effect of GABA on glutamate release from astrocytes has been studied in healthy mice and in a murine transgenic model of amyotrophic lateral sclerosis (ALS), using mouse spinal cord gliosomes labeled with [3H]d-aspartate ([3H]d-ASP). GABA concentration-dependently evoked the release of [3H]d-ASP. The effect of GABA was not mimicked by GABAA or GABAB Receptor Agonists or counteracted by antAgonists, excluding Receptor involvement. However, it was prevented by the GABA transport inhibitor N-(4,4-phenyl-3-butenyl)-nipecotic acid (SKF 89976A), suggesting participation of GABA transporters type 1 (GAT1) placed on glutamate-releasing astrocyte-derived gliosomes. Accordingly, GAT1 co-expressed with glutamate–aspartate transporter (GLAST) and glutamate transporter type 1 (GLT1) in the majority of glial particles. [3H]d-aspartate release was Ca2+-independent and not blocked by the glutamate uptake inhibitor dl-threo-b-benzyloxyaspartic acid (dl-TBOA); instead, it was abrogated by the anion channel blockers niflumic acid and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). The GAT1-mediated release of [3H]d-ASP was significantly enhanced in spinal cord gliosomes from the mouse model of ALS. This excessive [3H]d-ASP release was very precocious, largely preceding the onset of the disease symptoms. These data indicate that GAT1, GLAST and GLT1 coexist on the same gliosome in mouse spinal cord and that activation of GAT1 transporters elicits glutamate release by anion channel opening. This phenomenon might have pathological relevance, because [3H]d-ASP release is enhanced in experimental ALS.

  • GABAB Receptors as potential targets for drugs able to prevent excessive excitatory amino acid transmission in the spinal cord
    European Journal of Pharmacology, 1998
    Co-Authors: Giambattista Bonanno, Anna Fassio, Roberta Sala, Giovanna Schmid, Maurizio Raiteri
    Abstract:

    The effects of GABAB Receptor activation on the Ca2+-dependent depolarization-induced overflow of endogenous glutamic acid and γ-aminobutyric acid (GABA) was studied in rat spinal cord nerve terminals exposed in superfusion to 15 mM KCl. The GABAB Receptor agonist (−)-baclofen inhibited the K+-evoked overflow of glutamate (EC50=0.098 μM) but was almost inactive against that of GABA. The overflow of both transmitters could be quite similarly inhibited by two other GABAB Receptor Agonists, 3-APPA (3-aminopropylphosphonous acid; EC50=0.087 and 0.050 μM in the case of GABA and glutamate, respectively) and CGP 44532 (3-amino-2(S)-hydroxypropyl)methylphosphinic acid; EC50=0.81 and 0.50 μM). The GABAB Receptor antagonist CGP 35348 [3-amino-propyl(diethoxymethyl)phosphinic acid] blocked the effect of 3-APPA (1 μM) at the autoReceptors (IC50≃1 μM), but not at the heteroReceptors. In contrast, the effects of 3-APPA at both autoReceptors and heteroReceptors could be similarly prevented by another GABAB Receptor antagonist, CGP 52432 [3-[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl) phosphinic acid (IC50≃10 μM). The data suggest that, in the spinal cord, GABAB autoReceptors on GABA-releasing terminals differ pharmacologically from GABAB heteroReceptors on glutamatergic terminals. Selective GABAB Receptor ligands may be helpful for conditions characterized by excessive glutamatergic transmission in the spinal cord.