Effects of the GABAB receptor-positive modulators CGP7930 and rac-BHFF in baclofen- and γ-hydroxybutyrate-discriminating pigeons.
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, 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(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.
Departments of Psychiatry and Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7792, San Antonio, TX 78229-3900, USA. koek@uthscsa.edu
Wouter
W
Koek
Charles P
CP
France
Kejun
K
Cheng
Kenner C
KC
Rice
D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D010856:Columbidae; D003216:Conditioning, Operant / Q000187:drug effects*; D004192:Discrimination, Psychological; D018756:GABA Antagonists / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000378:metabolism; D012978:Sodium Oxybate / Q000494:pharmacology*
C532129:(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one; C438607:2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; D001572:Benzofurans; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D010636:Phenols; D010721:Phosphinic Acids; D018080:Receptors, GABA-B; D012978:Sodium Oxybate; D001418:Baclofen