TY - JOUR
T1 - Effects of the GABA B receptor-positive modulators CGP7930 and rac-BHFF in baclofen- and γ-hydroxybutyrate-discriminating pigeons
AU - Koek, Wouter
AU - France, Charles P.
AU - Cheng, Kejun
AU - Rice, Kenner C.
PY - 2012/5/1
Y1 - 2012/5/1
N2 - 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 Breceptors, such modulation has been examined primarily in vitro. This study further examined the in vivo properties of the GABA Breceptor-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, γ- 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 Breceptor-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.
AB - 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 Breceptors, such modulation has been examined primarily in vitro. This study further examined the in vivo properties of the GABA Breceptor-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, γ- 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 Breceptor-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.
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U2 - 10.1124/jpet.111.190975
DO - 10.1124/jpet.111.190975
M3 - Article
C2 - 22319197
AN - SCOPUS:84859952070
VL - 341
SP - 369
EP - 376
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 2
ER -