Intravenous self-administration of gamma-hydroxybutyric acid in drug-naive mice

et al. 2004

J Pharmacol Exp Ther

␥-Hydroxybutyrate (GHB) is an emerging drug of abuse with multiple mechanisms of action. This study is part of an effort to examine the role of GHB, GABA A , and GABA B receptors in the discriminative stimulus (DS) effects of GHB. In pigeons trained to discriminate 100 mg/kg GHB from saline, GHB and its precursors ␥-butyrolactone and 1,4-butanediol produced 80 to 100% GHB-appropriate responding, whereas other compounds such as morphine, naltrexone, cocaine, and haloperidol produced no more than 34%. Compounds interacting with GABA receptors produced different maximal levels of GHBappropriate responding. For example, the GABA A agonist muscimol produced 3%; the GABA A -positive modulators diazepam, pentobarbital, and ethanol, and the GABA B agonist baclofen produced levels ranging from 54 to 73%; and the benzodiazepine antagonist flumazenil and inverse agonist Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-␣]-[1,4]-benzodiazepine-3-carboxylate) both produced 96%. The putative GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a] [7]annulen-6-ylidene ethanoic acid (NCS-382) produced 70% GHB-appropriate responding. The GABA B antagonist (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) completely blocked the GHB-like DS effects of NCS-382 and baclofen at a dose of 56 mg/kg. CGP 35348 also blocked the DS effects of GHB, but incompletely and only at a dose of 560 mg/kg. Together, these results are consistent with a role for diazepam-sensitive and -insensitive GABA A and GABA B receptors in the DS effects of GHB. Together with previous findings, the present results suggest that diazepam-insensitive GABA A receptors are more prominently involved in the DS effects of GHB in pigeons than in rats, whereas GABA B receptors are less prominently involved. Exploring the role of GHB receptors with NCS-382 is hampered by its GABA B receptor-mediated, GHB-like agonist activity.

Section: Downloaded Frommentioning

confidence: 94%

Discriminative Stimulus Effects of γ-Hydroxybutyrate in Pigeons: Role of Diazepam-Sensitive and -Insensitive GABA_A and GABA_B Receptors

Koek

Flores

et al. 2004

J Pharmacol Exp Ther

“…In studies that have reported i.v. selfadministration of GHB in mice, the total dose of GHB that was self-administered was either not reported (Martellotta et al, 1998) or was relatively low (5-7 mg/kg; Fattore et al, 2001) and there was no additional evidence to suggest that the doses of GHB that were self-administered (0.05 and 0.1 mg/kg/inf) were discriminable or had other behavioral effects. Rats have been shown to consume more of a GHB (sodium salt) solution than water in a two-bottle choice procedure (Colombo et al, 1995); however, in the same procedure, rats consumed the same amount of sodium chloride solution as GHB solution, and did so in a (salt) concentration-dependent manner (Colombo et al, 1998).…”

Section: Introductionmentioning

confidence: 94%

Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB

Richards

Mintzer

et al. 2006

Neuropsychopharmacol

Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad range of GHB doses (2-18 g/70 kg), up to a dose that produced severe behavioral impairment in each participant, were compared to placebo and two abused sedative/hypnotic drugs, triazolam (0.5 and 1 mg/70 kg) and pentobarbital (200 and 400 mg/70 kg), under double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to triazolam and pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified triazolam and pentobarbital as such. On most measures of likelihood of abuse (eg ratings of liking, reinforcing effects), effects of pentobarbital were significantly greater than those of triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after triazolam and pentobarbital. Within participants, the dose-effect function for sedation was steeper for GHB than for triazolam and pentobarbital. Also, at higher doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest that the profile of effects of GHB only partially overlaps with that of triazolam and pentobarbital. Although the likelihood for GHB to be abused is intermediate to triazolam and pentobarbital, the possibility of accidental overdose (ie greater sedation than intended) with GHB appears to be greater.

“…NCS-382 was initially reported to antagonize several behavioral effects of GHB, such as self-administration in mice (Martellotta et al, 1998) and discriminative stimulus effects in rats (Colombo et al, 1995a). However, more recent studies suggest that the GHB antagonist effects of NCS-382 are limited (Carai et al, 2001;Cook et al, 2002;Lamb et al, 2003;Carter et al, 2003;Koek et al, 2004), perhaps by its own agonist effects.…”

Section: Discrimination Test Compound Dosementioning

confidence: 99%

Discriminative Stimulus Effects of γ-Hydroxybutyrate (GHB) in Rats Discriminating GHB from Baclofen and Diazepam

Koek

Lamb³

et al. 2005

J Pharmacol Exp Ther

␥-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.