ncs-382 and 1-4-butanediol

Anecdotal reports indicate that GHB produces subjective effects similar to those of ethanol. However, recent investigations comparing the discriminative stimulus effects of GHB to those of ethanol suggest that the subjective effects of these substances may differ considerably. To explore further potential differences between GHB and ethanol, 16 male Sprague-Dawley rats were trained in a three-lever drug discrimination procedure to discriminate ethanol (1.0 g/kg, experiment 1; 1.5 g/kg, experiment 2) and GHB (300 mg/kg) from vehicle. Dose-response functions determined with both training compounds revealed a clear dissociation between the discriminative stimulus effects of these drugs. As expected, the GHB precursors gamma-butyrolactone and 1,4-butanediol produced full substitution for GHB. In addition, the GABA(B) receptor agonist baclofen substituted for GHB, whereas the benzodiazepine flunitrazepam and the NMDA receptor antagonist ketamine engendered greater responding on the ethanol-lever. GHB's discriminative stimulus effects were blocked by the GABA(B) receptor antagonist CGP-35348 but only partially blocked by the putative GHB receptor antagonist NCS 382. These findings are consistent with previous reports of GHB's discriminative stimulus effects in two-choice drug discrimination procedures and provide additional evidence that these effects are distinct from those of ethanol.

Topics: 4-Butyrolactone; Animals; Baclofen; Benzocycloheptenes; Butylene Glycols; Discrimination, Psychological; Ethanol; Flunitrazepam; GABA Agonists; GABA Antagonists; GABA Modulators; Ketamine; Male; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate; Sodium Oxybate

Pigeons trained to discriminate 0.1 mg/kg flumazenil, proposed as an in-vivo model to study interactions with diazepam-insensitive gamma-aminobutyric acid (GABA)A receptors, were tested with various GABAergic and non-GABAergic compounds. As a result of its pharmacological selectivity, the model was suitable for further examining previously reported flumazenil-like effects of gamma-hydroxybutyrate (GHB). Flumazenil and the GABAA negative modulator Ro 15-4513 produced 82-100% flumazenil-appropriate responding. Diazepam and the direct-acting GABAA agonists muscimol and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP) produced 38-64% flumazenil-appropriate responding. GHB, its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), and the GABAB agonists baclofen and SKF97541 produced 0-24% flumazenil-appropriate responding. Baclofen shifted the flumazenil dose-response curve to the right and down, possibly involving perceptual masking of the discriminative stimulus effects of flumazenil by agonist activity at GABAB receptors. These masking effects of baclofen were blocked by the GABAB antagonist CGP35348. When CGP35348 was given together with GHB to block its GABAB agonist effects, GHB did not produce flumazenil-appropriate responding. Conceivably, effects of GHB at non-GABAB receptors (e.g. diazepam-sensitive GABAA receptors and GHB receptors) may interfere with the expression of its flumazenil-like discriminative stimulus effects. The asymmetric substitution between GHB and flumazenil is consistent with the hypothesis that the discriminative stimulus effects of GHB consist of several components, not all of which are mimicked by flumazenil.

Topics: 4-Butyrolactone; Animals; Baclofen; Benzocycloheptenes; Butylene Glycols; Columbidae; Discrimination, Psychological; Dose-Response Relationship, Drug; Flumazenil; GABA Agonists; GABA Antagonists; GABA Modulators; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; Organophosphorus Compounds; Sodium Oxybate

Gamma-hydroxybutyrate (GHB) is a drug of abuse with actions at GHB and GABA receptors. This study tried to increase the selectivity of the discriminative stimulus effects of GHB by training animals to discriminate GHB from compounds that share pharmacological mechanisms with GHB. In comparison with a previous GHB versus saline discrimination (group 1), rats were trained to discriminate GHB (200 mg/kg) either from saline and the GABA(B) agonist baclofen (3.2 mg/kg) (group 2) or from saline, baclofen, and the positive GABA(A) modulator diazepam (1 mg/kg) (group 3). In all groups, GHB produced more than 80% GHB-appropriate responding. Baclofen produced 84% GHB-appropriate responding in group 1 but less than 30% in groups 2 and 3. Diazepam produced 68% GHB-appropriate responding in group 1, 30% in group 2, and only 5% in group 3. The GABA(B) receptor antagonists CGP35348 [3-[aminopropyl(diethoxymethyl)phosphinic acid] and CGP52432 [3-[[[((3,4-dichlorophenyl)methyl]amino]propyl]diethoxymethyl)phosphinic acid] attenuated the discriminative stimulus effects of GHB; CGP35348 did so with similar potency in all groups, but CGP52432 was significantly less potent in groups 2 and 3 than in group 1. In all groups, the GHB antagonist NCS-382 [(2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene ethanoic acid] partially attenuated the discriminative stimulus effects of GHB. The selective GHB receptor ligand UMB86 (4-hydroxy-4-napthylbutanoic acid sodium) tended to attenuate the discriminative stimulus effects of GHB more in group 3 than in the other groups. The finding that animals can discriminate GHB from baclofen is further evidence that the effects of GHB and baclofen are not identical. Effects that GHB does not share with baclofen may involve GHB receptors or differential interactions with GABA(B) receptors.

Topics: 4-Butyrolactone; Anesthetics, Intravenous; Animals; Baclofen; Benzocycloheptenes; Benzylamines; Butylene Glycols; Diazepam; Discrimination, Psychological; Dithiothreitol; Dose-Response Relationship, Drug; GABA Agonists; GABA Antagonists; GABA Modulators; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; Male; Organophosphorus Compounds; Phosphinic Acids; Rats; Rats, Sprague-Dawley; Sodium Oxybate