Reduction of Alcohol’s Reinforcing and Motivational Properties by the Positive Allosteric Modulator of the GABA_B Receptor, BHF177, in Alcohol‐Preferring Rats

Abstract

The present results extend to BHF177 the capacity of the 2 previously tested positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, to specifically suppress alcohol's reinforcing and motivational properties in alcohol-preferring rats.

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

“…In vivo results suggest positive GABA B receptor modulators to have anxiolyticand antidepressant-like properties in elevated-maze and forced-swimming tests, respectively (Cryan et al, 2004;Frankowska et al, 2007;Jacobson and Cryan, 2008). In addition, they 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 these effects are thought to be mediated by positive modulation of GABA B receptors, such modulation has been examined almost exclusively in vitro.…”

“…Several compounds have been shown to have positive GABA B modulatory activity in vitro [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930) (Urwyler et al, 2001;Adams and Lawrence, 2007), N, (Urwyler et al, 2003), (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) (Malherbe et al, 2008), N- [(1R,2R,4S)bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) (Guery et al, 2007;Maccioni et al, 2009), methyl-2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627), and methyl-2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628) (Castelli et al, 2012)], evidenced by enhancing GABA, and, for all compounds except BHF177, also by enhancing the GABA B receptor agonist baclofen. In vivo results suggest positive GABA B receptor modulators to have anxiolyticand antidepressant-like properties in elevated-maze and forced-swimming tests, respectively (Cryan et al, 2004;Frankowska et al, 2007;Jacobson and Cryan, 2008).…”

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

“…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.…”

“…Several compounds have been shown to have positive GABA B modulatory activity in vitro [e.g., 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930) (Urwyler et al, 2001;Adams and Lawrence, 2007), N,N9-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (Urwyler et al, 2003), (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran -2-one (rac-BHFF) (Malherbe et al, 2008), N-[(1R,2R,4S)-bicyclo [2.2.1]hept-2-yl]-2-m ethyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) (Guery et al, 2007;Maccioni et al, 2009), methyl-2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate and methyl-2-(cyclohexanecarboxamido)-4-ethyl-5-methyltiophene-3-carboxylate (Castelli et al, 2011), and 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (Perdona et al, 2011)]. Their positive GABA B modulatory activity in vitro was evidenced by enhancing GABA, and, for all compounds except BHF177, also by enhancing the GABA B receptor agonist baclofen.…”

Characterization of COR627 and COR628, Two Novel Positive Allosteric Modulators of the GABAB Receptor

“…PAMs display no or minimal agonist activity, but enhance both potency and efficacy of orthosteric agonists, and produce fewer side effects and less tolerance than orthosteric agonists (Gjoni and Urwyler, 2008;Urwyler, 2011) -methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177), and (R,S)-5,7-di-tertbutyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF), the most widely characterized GABA B PAMs, have been found to increase GABA potency and efficacy at both recombinant and native GABA B receptors in various in vitro assays (Urwyler et al, 2001(Urwyler et al, , 2003Olianas et al, 2005;Malherbe et al, 2008) and in vivo procedures (Carai et al, 2004;Gjoni et al, 2006;Malherbe et al, 2008;Koek et al, 2010). GABA B PAMs display anxiolytic (Cryan et al, 2004;Frankowska et al, 2007) and antidepressant properties and reduce self-administration of alcohol and different other behaviors motivated by alcohol (Liang et al, 2006;Maccioni et al, 2009Maccioni et al, , 2010, cocaine (Smith et al, 2004;Filip et al, 2007), and nicotine (Mombereau et al, 2007;Paterson et al, 2008) …”