Abstract
γ-Hydroxybutyrate (GHB) is a drug of abuse with actions at GHB and GABA receptors. This study examined whether the relative importance of GABAA, 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, diazepam-insensitive 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.
Footnotes
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This work was supported by U.S. Public Health Service Grants DA15692 and DA14986, by Independent Scientist Award DA19634 (to A.C.), and by Senior Scientist Award DA17918 (to C.P.F.).
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doi:10.1124/jpet.105.096909.
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ABBREVIATIONS: GHB, γ-hydroxybutyrate; N-methyl-d-aspartate; CGP35348, 3-aminopropyl(diethoxymethyl)phosphinic acid; GBL, γ-butyrolactone; NCS-382, (2E)-5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid; SKF97541, 3-aminopropyl(methyl)phosphinic acid hydrochloride; THIP, 4,5,6,7-tetrahydroisoxazolo[5,4-c]epyridine-3-ol; Ro 15-4513, ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-α]-[1,4]-benzodiazepine-3-carboxylate; DTT, dithiothreitol.
- Received October 10, 2005.
- Accepted December 2, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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