Effects of the putative antagonist NCS382 on the behavioral pharmacological actions of gammahydroxybutyrate in mice

Cook, Charles D.; Aceto, Mario D.; Coop, Andrew; Beardsley, Patrick M.

doi:10.1007/s00213-001-0951-8

Cited by 30 publications

(32 citation statements)

References 32 publications

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“…; Cook et al, 2002) have been shown to produce catalepsy (300 mg/kg i.p. ; Itzhak and Ali, 2002), ataxia (300 -1000 mg/kg i.g.…”

Section: Novel Ghb Analogs: Binding and Behavioral Effects 1321mentioning

confidence: 99%

“…; Itzhak and Ali, 2002), ataxia (300 -1000 mg/kg i.g. ; Cook et al, 2002), and loss of righting (560 -1000 mg/kg i.p. ; Carai et al, 2001).…”

Section: Novel Ghb Analogs: Binding and Behavioral Effects 1321mentioning

confidence: 99%

“…These latter studies were designed to compare the effects of a broad range of doses, up to and including doses that produced loss of righting or at which other limitations became apparent, of GHB and GHB precursors [␥-butyrolactone (GBL) and 1,4-butanediol (1,4-BDL)], conventional GABA B receptor agonists (SKF97541 and baclofen), and selective GHB analogs (UMB86, UMB72, UMB73, and 3-HPA) on several unconditioned behaviors that are known to be affected by GHB in mice (Carai et al, 2001;Cook et al, 2002;Itzhak and Ali, 2002). GHB precursors and GABA B receptor agonists were also examined in the observational assays in mice because they serve as important controls and have been studied in the same binding and discrimination procedures (Mehta et al, 2001;Carter et al, 2003).…”

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confidence: 99%

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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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“…; Cook et al, 2002) have been shown to produce catalepsy (300 mg/kg i.p. ; Itzhak and Ali, 2002), ataxia (300 -1000 mg/kg i.g.…”

Section: Novel Ghb Analogs: Binding and Behavioral Effects 1321mentioning

confidence: 99%

“…; Itzhak and Ali, 2002), ataxia (300 -1000 mg/kg i.g. ; Cook et al, 2002), and loss of righting (560 -1000 mg/kg i.p. ; Carai et al, 2001).…”

Section: Novel Ghb Analogs: Binding and Behavioral Effects 1321mentioning

confidence: 99%

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confidence: 99%

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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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“…Since that time, NCS-382 has been reported to antagonize some behavioral effects of GHB, such as self-administration in mice (Martellotta et al, 1998) and DS effects in rats (Colombo et al, 1995a). More recent studies, however, suggest that the antagonism by NCS-382 of the behavioral depressant effects of GHB is very limited (Carai et al, 2001;Cook et al, 2002;Lamb et al, 2003) and that NCS-382 can enhance certain effects of GHB, such as loss of righting (Carai et al, 2001). In a recent study of rats, NCS-382 partially attenuated the DS effects of GHB, but its antagonism was limited by partial GHB-like effects when given alone (Carter et al, 2003).…”

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confidence: 99%

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

Koek

Flores

Carter

et al. 2004

J Pharmacol Exp Ther

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␥-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.

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“…This appears unlikely, however, because in vivo studies with NCS-382 suggest that it interacts with a functional receptor; that is, NCS-382 administration diminishes the sedative and cataleptic effects of GHB and blocks the enhancing effects on the spontaneous firing rate of cortical neurons at low doses of GHB but not the depressant effects seen at higher doses (14,15). Because NCS-382 administration blocks neither GHB-induced ataxia nor its depressant effects on locomotor activity, learned and unlearned behavior, and operant responses (16,17), these actions are probably mediated by GHB activation of GABA B receptors.…”

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confidence: 99%

Extrasynaptic site of action for γ-hydroxybutyrate

Enna

2012

Proc. Natl. Acad. Sci. U.S.A.

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Effects of the putative antagonist NCS382 on the behavioral pharmacological actions of gammahydroxybutyrate in mice

Cited by 30 publications

References 32 publications

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

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 in Pigeons: Role of Diazepam-Sensitive and -Insensitive GABA_A and GABA_B Receptors

Extrasynaptic site of action for γ-hydroxybutyrate

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Effects of the putative antagonist NCS382 on the behavioral pharmacological actions of gammahydroxybutyrate in mice

Cited by 30 publications

References 32 publications

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

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 in Pigeons: Role of Diazepam-Sensitive and -Insensitive GABAA and GABAB Receptors

Extrasynaptic site of action for γ-hydroxybutyrate

Contact Info

Product

Resources

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

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 in Pigeons: Role of Diazepam-Sensitive and -Insensitive GABA_A and GABA_B Receptors