Abstract
In vivo effects of GABAB 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 GABAB receptors, such modulation has been examined primarily in vitro. This study further examined the in vivo properties of the GABAB 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 GABAB 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 GABAB 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 GABAB receptor agonists. Finally, together with converging evidence that the GABAB 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 GABAB system.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA15692, DA17918]; the Intramural Research Programs of the National Institute on Drug Abuse; and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- CGP7930
- 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol
- rac-BHFF
- (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one
- CGP35348
- 3-aminopropyl(diethoxymethyl)phosphinic acid
- GHB
- γ-hydroxybutyrate
- GS39783
- N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine
- BHF177
- N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine
- COR627
- methyl-2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate
- COR628
- methyl-2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate
- CL
- confidence level
- NCS-382
- (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid.
- Received December 12, 2011.
- Accepted February 6, 2012.
- U.S. Government work not protected by U.S. copyright
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|