Discriminative Stimulus Effects of γ-Hydroxybutyrate in Pigeons: Role of Diazepam-Sensitive and -Insensitive GABA<sub>A</sub> and GABA<sub>B</sub> Receptors

Koek, Wouter; Flores, Lauren R.; Carter, Lawrence P.; Lamb, Richard; Chen, Weibin; Wu, Huifang; Coop, Andrew

doi:10.1124/jpet.103.056093

Cited by 32 publications

(46 citation statements)

References 36 publications

(54 reference statements)

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“…Taken together, these results suggest that the specific-GHB binding site contributes minimally to the above effects of GHB and its precursors. Alternatively, it can be hypothesized that NCS-382 may not be particularly selective for the specific-GHB binding site (15) or even possess agonistic properties at this binding site (28), leaving the contribution of this binding site on GHB, 1,4-BD, and GBL pharmacology an open issue. Accordingly, it is worthy of note that the recently cloned specific-GHB binding site was insensitive to NCS-382, suggesting the possible existence of different subtypes of this binding site (29).…”

Section: Discussionmentioning

confidence: 99%

γ-Aminobutyric AcidB (GABAB)-Receptor Mediation of Different In Vivo Effects of γ-Butyrolactone

et al. 2008

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Abstract. The endogenous brain constituent, γ-hydroxybutyric acid (GHB), as well as its prodrug, γ-butyrolactone (GBL), have recently gained interest in the drug addiction field due to their abuse potential and fatalities caused by overdose. It is known that GHB has two sites of actions: the γ-aminobutyric acid B (GABA B ) receptor and a specific-GHB binding site. The present study was designed to extend to GBL the investigations on the contribution of the GABA B receptor and the specific-GHB binding site to its in vivo effects. To this aim, DBA mice were pretreated either with GABA B -receptor antagonists, (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP 35348) and (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), or a putative antagonist of the specific-GHB binding site, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (NCS-382), prior to the administration of doses of GBL that induced hypothermia, motor-incoordination (measured as motor-impairment at the Rota-Rod task), and sedation / hypnosis. The capability of SCH 50911 and NCS-382 to protect against GBL-induced lethality was also investigated. Pretreatment with either GABA B -receptor antagonist completely prevented GBL-induced hypothermia, motor-incoordination, and sedation / hypnosis. SCH 50911 also provided complete protection against GBL-associated lethality. Vice versa, NCS-382 failed to exert any antagonistic or protective effect. These results suggest that the in vivo GBL effects tested in the present study are mediated by activation of the GABA B receptor.

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Section: Discussionmentioning

confidence: 99%

γ-Aminobutyric AcidB (GABAB)-Receptor Mediation of Different In Vivo Effects of γ-Butyrolactone

et al. 2008

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“…Increasing evidence (e.g., cross-substitution between GHB and baclofen) in rats and pigeons suggests that GABAergic activity is a major component of the discriminative stimulus effects of GHB (Colombo et al, 1998;Lobina et al, 1999;Carter et al, 2003Carter et al, , 2004aBaker et al, 2004;Koek et al, 2004). Thus, compounds that do not bind to GABA receptors might not be expected to produce or attenuate GHB-like discriminative stimulus effects, which is consistent with the relatively small amount of GHB-appropriate responding observed after administration of selective GHB receptor ligands current study) and the failure of UMB86, UMB72, or 3-HPA to fully antagonize the discriminative stimulus effects of the training dose in either rats or pigeons.…”

Section: Discussionmentioning

confidence: 99%

“…Adult white Carneau pigeons (Columbia livia; Palmetto, Sumter, SC) discriminating 100 mg/kg GHB i.m. (n ϭ 6; Koek et al, 2004) were maintained at 80 to 90% of their free-feeding weight, ranging from 590 to 620 g, by providing mixed grain in the home cage after daily sessions. Eighty male C57BL/6J mice (The Jackson Laboratory, Bar Harbor, ME) were used to examine directly observable effects; all mice had free access to food (rodent sterilizable diet; Harlan Teklad), weighed between 17 to 30 g, and were experimentally naive before testing.…”

Section: Methodsmentioning

confidence: 99%

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists

Carter

Chen

et al. 2005

J Pharmacol Exp Ther

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␥-Hydroxybutyrate (GHB), a therapeutic for narcolepsy and a drug of abuse, has several mechanisms of action that involve GHB and GABA B receptors, metabolism to GABA, and modulation of dopaminergic signaling. The aim of these studies was to examine the role of GHB and GABA B receptors in the behavioral effects of GHB. Three approaches were used to synthesize GHB analogs that bind selectively to GHB receptors and are not metabolized to GABA-active compounds. Radioligand binding assays identified UMB86 (4-hydroxy-4-napthylbutanoic acid, sodium salt), UMB72 [4-(3-phenylpropyloxy)butyric acid, sodium salt], UMB73 (4-benzyloxybutyric acid, sodium salt), 2-hydroxyphenylacetic acid, 3-hydroxyphenylacetic acid (3-HPA), and 4-hydroxy-4-phenylbutyric acid as compounds that displace In rats and pigeons, GHB discriminative stimulus effects were not mimicked or attenuated by UMB86, UMB72, or 3-HPA up to doses that decreased responding. In mice, GHB, GHB precursors (␥-butyrolactone and 1,4-butanediol) and GABA B receptor agonists [SKF97541 [3-aminopropyl(methyl)phosphinic acid hydrochloride] and baclofen] dose-dependently produced hypolocomotion, catalepsy, ataxia, and loss of righting. The GABA B receptor antagonist CGP35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) attenuated catalepsy and ataxia that was observed after GHB and GABA B receptor agonists SKF97541 and baclofen. UMB86, UMB72, UMB73, and 3-HPA, like GHB, produced hypolocomotion, ataxia, and loss of righting; however, catalepsy was never observed with these compounds, which is consistent with the cataleptic effects of GHB being

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“…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. NCS-382 has GHB-like effects on intestinal motility (Carai et al, 2002) and GHB-like discriminative stimulus effects .…”

Section: Discrimination Test Compound Dosementioning

confidence: 99%

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

Koek

Carter

Lamb³

et al. 2005

J Pharmacol Exp Ther

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␥-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.

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

Cited by 32 publications

References 36 publications

γ-Aminobutyric AcidB (GABAB)-Receptor Mediation of Different In Vivo Effects of γ-Butyrolactone

γ-Aminobutyric AcidB (GABAB)-Receptor Mediation of Different In Vivo Effects of γ-Butyrolactone

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists

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

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

Cited by 32 publications

References 36 publications

γ-Aminobutyric AcidB (GABAB)-Receptor Mediation of Different In Vivo Effects of γ-Butyrolactone

γ-Aminobutyric AcidB (GABAB)-Receptor Mediation of Different In Vivo Effects of γ-Butyrolactone

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABABReceptor Agonists

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

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

Novel γ-Hydroxybutyric Acid (GHB) Analogs Share Some, but Not All, of the Behavioral Effects of GHB and GABA_BReceptor Agonists