Discriminative stimulus effects of γ-hydroxybutyrate: Role of training dose

Wouter Koek, Weibin Chen, Susan L. Mercer, Andrew Coop, Charles P France

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

γ-Hydroxybutyrate (GHB) is a drug of abuse with actions at GHB and GABA receptors. This study examined whether the relative importance of GABA A, GABAB, and GHB receptors in the discriminative stimulus effects of GHB depends on the training dose. In comparison with a previous 100 mg/kg GHB-saline discrimination, pigeons were trained to discriminate either 178 or 56 mg/kg GHB from saline. Increasing the training dose shifted the GHB gradient to the right, and decreasing it shifted the gradient to the left. Similar shifts occurred with the GHB precursor γ-butyrolactone, which substituted for GHB, and with the GABAB agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) and the benzodiazepine diazepam, each of which produced at most 54 to 68% GHB-appropriate responding. The benzodiazepine antagonist flumazenil, the benzodiazepine inverse agonist ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H- imidazo[1,5-α]-[1,4]-benzodiazepine-3-carboxylate (Ro 15-4513), and the GHB receptor antagonist (2E)-5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen- 6-ylidene ethanoic acid (NCS-382) produced a maximum of 66 to 97% GHB-appropriate responding in animals discriminating 56 or 100 mg/kg GHB and a maximum of 1 to 49% in animals discriminating 178 mg/kg. NCS-382 did not attenuate the effects of GHB. The GABAB antagonist 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP35348) blocked GHB at all training doses. The results suggest that increasing the training dose of GHB increases the pharmacological selectivity of its discriminative stimulus effects. At a high training dose, diazepaminsensitive GABAA receptors, for which flumazenil and Ro 15-4513 have affinity, may no longer be involved. Diazepam-sensitive GABAA receptors and GABAB receptors appear to play a similar role at all training doses. There was no evidence for GHB receptor involvement.

Original languageEnglish (US)
Pages (from-to)409-417
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume317
Issue number1
DOIs
StatePublished - Apr 2006

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Hydroxybutyrates
Benzodiazepines
Flumazenil
GABA-A Receptors
Diazepam
Baclofen
GABA Receptors
Columbidae
Street Drugs
gamma-Aminobutyric Acid
Pharmacology
Acids
NCS 382
3-aminopropyl(methyl)phosphinic acid
Ro 15-4513

ASJC Scopus subject areas

  • Pharmacology

Cite this

Discriminative stimulus effects of γ-hydroxybutyrate : Role of training dose. / Koek, Wouter; Chen, Weibin; Mercer, Susan L.; Coop, Andrew; France, Charles P.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 317, No. 1, 04.2006, p. 409-417.

Research output: Contribution to journalArticle

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abstract = "γ-Hydroxybutyrate (GHB) is a drug of abuse with actions at GHB and GABA receptors. This study examined whether the relative importance of GABA A, GABAB, and GHB receptors in the discriminative stimulus effects of GHB depends on the training dose. In comparison with a previous 100 mg/kg GHB-saline discrimination, pigeons were trained to discriminate either 178 or 56 mg/kg GHB from saline. Increasing the training dose shifted the GHB gradient to the right, and decreasing it shifted the gradient to the left. Similar shifts occurred with the GHB precursor γ-butyrolactone, which substituted for GHB, and with the GABAB agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) and the benzodiazepine diazepam, each of which produced at most 54 to 68{\%} GHB-appropriate responding. The benzodiazepine antagonist flumazenil, the benzodiazepine inverse agonist ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H- imidazo[1,5-α]-[1,4]-benzodiazepine-3-carboxylate (Ro 15-4513), and the GHB receptor antagonist (2E)-5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen- 6-ylidene ethanoic acid (NCS-382) produced a maximum of 66 to 97{\%} GHB-appropriate responding in animals discriminating 56 or 100 mg/kg GHB and a maximum of 1 to 49{\%} in animals discriminating 178 mg/kg. NCS-382 did not attenuate the effects of GHB. The GABAB antagonist 3-aminopropyl(diethoxymethyl) phosphinic acid (CGP35348) blocked GHB at all training doses. The results suggest that increasing the training dose of GHB increases the pharmacological selectivity of its discriminative stimulus effects. At a high training dose, diazepaminsensitive GABAA receptors, for which flumazenil and Ro 15-4513 have affinity, may no longer be involved. Diazepam-sensitive GABAA receptors and GABAB receptors appear to play a similar role at all training doses. There was no evidence for GHB receptor involvement.",
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