Specific Reduction of Alcohol’s Motivational Properties by the Positive Allosteric Modulator of the GABA<sub>B</sub> Receptor, GS39783—Comparison With the Effect of the GABA<sub>B</sub> Receptor Direct Agonist, Baclofen

2012

In vivo effects of GABA B receptor-positive modulators suggest them to have therapeutic potential to treat central nervous system disorders such as anxiety and drug abuse. Although these effects are thought to be mediated by positive modulation of GABA B receptors, such modulation has been examined primarily in vitro. This study further examined the in vivo properties of the GABA B receptor-positive modulators 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). In pigeons discriminating baclofen from saline, ␥-hydroxybutyrate (GHB) produced 100% baclofen-appropriate responding, and the GABA B antagonist 3-aminopropyl(dimethoxymethyl) phosphinic acid (CGP35348) blocked the effects of both drugs. CGP7930 and rac-BHFF produced at most 41 and 74% baclofen-appropriate responding, respectively, and enhanced the discriminative stimulus effects of baclofen, but not of GHB. In pigeons discriminating GHB from saline, CGP7930 and rac-BHFF produced at most 1 and 49% GHB-appropriate responding, respectively, and enhanced the effects of baclofen, but not of GHB. Enhancement of the discriminative stimulus effects of baclofen by rac-BHFF and CGP7930 is further evidence of their effectiveness as GABA B receptor-positive modulators in vivo. Furthermore, lack of complete substitution of the positive modulators rac-BHFF and CGP7930 for baclofen and GHB suggests that their discriminative stimulus effects differ from those of GABA B receptor agonists. Finally, together with converging evidence that the GABA B receptor populations mediating the effects of baclofen and GHB are not identical, the present findings suggest that these populations differ in their susceptibility to positive modulatory effects. Such differences could allow for more selective therapeutic targeting of the GABA B system.

Section: Introductionmentioning

confidence: 99%

Effects of the GABA_B Receptor-Positive Modulators CGP7930 and rac-BHFF in Baclofen- and γ-Hydroxybutyrate-Discriminating Pigeons

Koek¹,

2012

“…In addition, positive modulators of GABA B receptors reduce self-administration of alcohol (Orrù et al, 2005;Liang et al, 2006;Maccioni et al, 2008Maccioni et al, , 2009, cocaine , and nicotine (Mombereau et al, 2007;Paterson et al, 2008). Although all of these effects generally are thought to be mediated by positive modulation of GABA B receptors, to date such modulation has been examined almost exclusively in vitro.…”

Section: Introductionmentioning

confidence: 99%

GABA_B Receptor-Positive Modulators: Enhancement of GABA_B Receptor Agonist Effects In Vivo

Koek

2010

In vivo effects of GABA B receptor-positive modulators suggest that they have therapeutic potential for treating central nervous system disorders such as anxiety, depression, and drug abuse. Although these effects generally are thought to be mediated by positive modulation of GABA B receptors, such modulation has been examined primarily in vitro. The present study was aimed at further examining the in vivo positive modulatory properties of the GABA B receptor-positive modulators, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). Both compounds enhanced loss of righting induced by baclofen in mice. However, CGP7930 was less effective and rac-BHFF was less potent for enhancing loss of righting induced by ␥-hydroxybutyrate (GHB), which, like baclofen, has GABA B receptor agonist properties. In contrast with baclofen-and GHB-induced loss of righting, the hypothermic effects of baclofen and GHB were not enhanced by rac-BHFF but were enhanced by CGP7930 only at doses that produced hypothermia when given alone. CGP7930-induced hypothermia was not attenuated by the GABA B receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348), at doses that blocked baclofen-induced hypothermia, and was not increased by the nitric-oxide synthase inhibitor N -nitro-L-arginine methyl ester, at doses that increased the hypothermic effects of baclofen and GHB. The results provide evidence that CGP7930 and rac-BHFF act in vivo as positive modulators at GABA B receptors mediating loss of righting, but not at GABA B receptors mediating hypothermia. Conceivably, CGP7930, but not rac-BHFF, acts as an allosteric agonist at these latter receptors. Taken together, the results provide further evidence of pharmacologically distinct GABA B receptor subtypes, possibly allowing for a more selective therapeutic interference with the GABA B system.

“…In addition, they reduce self-administration of alcohol (Orru et al, 2005(Orru et al, , 2012Liang et al, 2006;Maccioni et al, 2007Maccioni et al, , 2008Maccioni et al, , 2009Maccioni et al, , 2010aMaccioni et al, , b, 2012Agabio et al, 2012), cocaine , and nicotine (Mombereau et al, 2007;Paterson et al, 2008;Vlachou et al, 2011). GABA B receptorpositive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction, because they may have a better side-effect profile than GABA B receptor agonists, based on the notion that selective enhancement of activated receptors has effects that differ from indiscriminate activation of all receptors.…”

Section: Introductionmentioning

confidence: 99%

“…GABA B receptors, which are present throughout the central nervous system, are implicated in various central nervous system disorders (Cryan and Kaupmann, 2005;Bowery, 2006), including drug dependence (Maccioni et al, 2008;Addolorato et al, 2009;Vlachou and Markou, 2010). They couple through Ga i/o to inhibit adenylyl cyclase, close voltagedependent calcium channels, and open inwardly rectifying K 1 channels (Bowery et al, 2002;Bettler et al, 2004), and function as autoreceptors and heteroreceptors, modulating neurotransmitter release and neuronal firing, and influencing long-term changes in synaptic strength (Pinard et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Discriminative Stimulus Effects of the GABA_B Receptor-Positive Modulator rac-BHFF: Comparison with GABA_B Receptor Agonists and Drugs of Abuse

Koek

2012

GABA B receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction. They may have fewer side effects than GABA B 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 GABA B 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 GABA B receptor agonists baclofen and g-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose selfadministration has been reported to be attenuated by GABA B receptor-positive modulators. The discriminative stimulus effects of rac-BHFF were not antagonized by the GABA B receptor antagonist 3-aminopropyl (diethoxymethyl)phosphinic acid (CGP35348) but were attenuated by the less efficacious GABA B 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 GABA B2 subunits of GABA B 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 GABA B receptorpositive modulators are not identical to those of GABA B receptor agonists. In addition, the results suggest that positive modulation of GABA B 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 GABA B receptors mediating the effects of baclofen and GHB are not identical.