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Research ArticleBehavioral Pharmacology

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

Wouter Koek, Kejun Cheng and Kenner C. Rice
Journal of Pharmacology and Experimental Therapeutics March 2013, 344 (3) 553-560; DOI: https://doi.org/10.1124/jpet.112.202226
Wouter Koek
Departments of Psychiatry and Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (W.K.); and Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland (K.C., K.C.R.)
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Kejun Cheng
Departments of Psychiatry and Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (W.K.); and Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland (K.C., K.C.R.)
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Kenner C. Rice
Departments of Psychiatry and Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (W.K.); and Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland (K.C., K.C.R.)
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Abstract

GABAB receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction. They may have fewer side effects than GABAB 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 GABAB 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 GABAB receptor agonists baclofen and γ-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose self-administration has been reported to be attenuated by GABAB receptor-positive modulators. The discriminative stimulus effects of rac-BHFF were not antagonized by the GABAB receptor antagonist 3-aminopropyl (diethoxymethyl)phosphinic acid (CGP35348) but were attenuated by the less efficacious GABAB 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 GABAB2 subunits of GABAB 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 GABAB receptor-positive modulators are not identical to those of GABAB receptor agonists. In addition, the results suggest that positive modulation of GABAB 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 GABAB receptors mediating the effects of baclofen and GHB are not identical.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA15692]; and also, in part, by the Intramural Research Programs of the National Institutes of Health National Institute on Drug Abuse and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism.

  • dx.doi.org/10.1124/jpet.112.202226.

  • Received November 28, 2012.
  • Accepted December 27, 2012.
  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 344 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 3
1 Mar 2013
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Research ArticleBehavioral Pharmacology

Discriminative Stimulus Effects of rac-BHFF

Wouter Koek, Kejun Cheng and Kenner C. Rice
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 553-560; DOI: https://doi.org/10.1124/jpet.112.202226

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Research ArticleBehavioral Pharmacology

Discriminative Stimulus Effects of rac-BHFF

Wouter Koek, Kejun Cheng and Kenner C. Rice
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 553-560; DOI: https://doi.org/10.1124/jpet.112.202226
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