ChemInform Abstract: Bz1 Receptor Subtype Specific Ligands. Synthesis and Biological Properties of βCCt, a Bz1 Receptor Subtype Specific Antagonist.

Cox, Eric; Hagen, Timothy J.; McKernan, Ruth M.; Cook, J. M.

doi:10.1002/chin.199621165

Cited by 16 publications

(17 citation statements)

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“…Thus, the nonspecific effects of 3-PBC on sucrose drinking in previous studies at high doses may be due to action at α2/3/5GABA A receptors. However, the results reported in the present study agree with the reported selectivity data for both compounds (Yin et al, 2010, Cox et al, 1995). Importantly, we did not observe any signs of ataxia following 3-PBC or βCCT administration at the doses that increased latency in alcohol drinkers in the present study, suggesting that the observed effects are not due to nonspecific muscle-relaxant or motor-sedative effects (Tan et al, 2011, Licata et al, 2005, Rowlett et al, 2005).…”

Section: Discussionsupporting

confidence: 93%

“…The short-acting, nonselective benzodiazepine agonist triazolam (Huang et al, 2000, Ziegler et al, 1983), and the α1GABA A -preferring agonist zolpidem (Crestani et al, 2000) were obtained from Sigma/RBI., St. Louis, MO. The nonselective benzodiazepine antagonist flumazenil (Hunkeler et al, 1981), α1GABA A -preferring antagonist b-carboline-3-carboxylate-tert-butyl ester (βCCT)(Yin et al, 2010, Cox et al, 1995), and nonselective benzodiazepine inverse agonist ethyl β-carboline carboxylate (βCCE)(Cowen et al, 1981) were either purchased from Sigma/RBI or provided by Dr. Jim Cook. The α1GABA A -preferring antagonist 3-propoxy-β-carboline hydrochloride (3-PBC) was provided by Dr. Cook (Yin et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

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Little Evidence of a Role for the α1GABA_A Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

Moran

Sirbu

Szafir

et al. 2013

Alcoholism Clin & Exp Res

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Background Alcohol potentiates GABAergic neurotransmission via action at the GABAA receptor. α1 subunit-containing GABAA receptors have been implicated as mediators, in part, of the behavioral and abuse-related effects of alcohol in rodents. Methods We systematically investigated the effects of one α1-preferring benzodiazepine agonist, zolpidem, and two antagonists, βCCT and 3-PBC, on oral self-administration of alcohol (2% w/v) or sucrose solution and observable behavior in rhesus macaques. We compared these effects to those of the nonselective benzodiazepine agonist triazolam, antagonist flumazenil, and inverse agonist βCCE. Results Alcohol and sucrose solutions maintained reliable baseline drinking behavior across the study. The α1-preferring compounds did not affect intake, number of sipper extensions, or blood alcohol levels at any of the doses tested. Zolpidem, βCCT, and 3-PBC increased latency to first sipper extension in animals self-administering alcohol, but not sucrose, solution. Triazolam exerted biphasic effects on alcohol drinking behavior, increasing intake at low doses but decreasing BAL and increasing latency at higher doses. At doses higher than those effective in alcohol-drinking animals, triazolam increased sucrose intake and latency. Flumazenil non-systematically increased number of extensions for alcohol but decreased BAL, with no effects on sucrose drinking. βCCE decreased sipper extensions for alcohol and increased latency for first sucrose sipper extension, but full dose-effect relationships could not be determined due to seizures at higher doses. Conclusions Alcohol-drinking animals appeared more sensitive to the effects of GABAergic compounds on drinking behavior. However, these results do not support a strong contribution of α1GABA receptors to the reinforcing effects of alcohol in primates.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Little Evidence of a Role for the α1GABA_A Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

Moran

Sirbu

Szafir

et al. 2013

Alcoholism Clin & Exp Res

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“…In the present study, diazepam- and zolpidem-induced ataxia on the rotarod in rats were successfully antagonized with the α 1 -selective antagonist ßCCt. Because of its 20-fold selectivity for α 1 -GABA A receptors compared with α 2 -GABA A and α 3 -GABA A receptors, ßCCt is one of the most selective BZ-site ligands identified to date (Cox et al 1995; Huang et al 2000). In many behavioral studies, ßCCt successfully reversed effects of BZs related to the α 1 -GABA A receptor subtype, such as ataxia, sedation and anticonvulsant activity (Griebel et al 1999; Platt et al 2002; Savić et al 2009).…”

Section: Discussionmentioning

confidence: 99%

The role of α1 and α5 subunit-containing GABAA receptors in motor impairment induced by benzodiazepines in rats

Milić

Divljaković

Rallapalli

et al. 2012

Behavioural Pharmacology

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Benzodiazepines negatively affect motor coordination and balance and produce myorelaxation. The aim of the present study was to examine the extent to which populations of GABAA receptors containing α1 and α5 subunit contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the α1-selective agonist zolpidem, as well as nonselective, α1- and α5-subunit-selective antagonists flumazenil, βCCt and XLi093, respectively. Ataxia and muscle relaxation were assessed by rotarod and grip strength tests performed 20 minutes after i.p. treatment. Diazepam (2 mg/kg) induced significant ataxia and muscle relaxation which were completely prevented by pretreatment with flumazenil (10 mg/kg) and βCCt (20 mg/kg). XLi093 antagonized the myorelaxant, but not ataxic actions of diazepam. All three doses of zolpidem (1, 2 and 5 mg/kg) produced ataxia, but only the highest dose (5mg/kg) significantly decreased the grip strength. These effects of zolpidem were reversed by ßCCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that α1 GABAA receptors mediate ataxia and indirectly contribute to myorelaxation in rats, while α5 GABAA receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia.

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“…Different effects of allosteric positive modulators of GABA A receptors may be explained by targeting different subunits of the GABA A receptor complex. The α1 subunit protein and its role in aggressive behavior was investigated pharmacologically due to the availability of α1-preferring agonists, such as zolpidem and antagonists such as β-CCt and 3-PBC (Cox et al 1995; Huang et al 2000). The α1 subunit appears relevant in the aggression-heightening effects of midazolam and alcohol, since these effects can be attenuated by the alpha1 subunit-preferring antagonists (de Almeida et al 2004; Gourley et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Flunitrazepam in combination with alcohol engenders high levels of aggression in mice and rats

Almeida¹,

Saft²,

Rosa³

et al. 2010

Pharmacology Biochemistry and Behavior

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Rationale Higher doses of benzodiazepines and alcohol induce sedation and sleep; however, in low to moderate doses these drugs can increase aggressive behavior. Objectives To assess firstly the effects of ethanol, secondly the effects of flunitrazepam, a so-called club drug, and thirdly the effects of flunitrazepam plus alcohol on aggression in mice and rats. Methods Exhaustive behavioral records of confrontations between a male resident and a male intruder were obtained twice a week, using CF-1 mice and Wistar rats. The salient aggressive and non-aggressive elements in the resident´s reperetoire were analyzed. Initially, the effects of ethanol (1.0 g/kg), and secondly flunitrazepam (0; 0.01; 0.1; and 0.3 mg/kg) were determined in all mice and rats; subsequently, flunitrazepam or vehicle, given intraperitoneally (0; 0.01; 0.1; and 0.3 mg/kg) was administered plus ethanol 1.0 g/kg or vehicle via gavage. Results The most significant finding is the escalation of aggression after a moderate dose of ethanol, and a low dose of flunitrazepam. The largest increase in aggressive behaviour occurred after combined flunitrazepam plus ethanol treatment in mice and rats. Conclusions Ethanol can heighten aggressive behavior and flunitrazepam further increases this effect in male mice and rats.

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ChemInform Abstract: Bz1 Receptor Subtype Specific Ligands. Synthesis and Biological Properties of βCCt, a Bz1 Receptor Subtype Specific Antagonist.

Cited by 16 publications

References 0 publications

Little Evidence of a Role for the α1GABA_A Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

Little Evidence of a Role for the α1GABA_A Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

The role of α1 and α5 subunit-containing GABAA receptors in motor impairment induced by benzodiazepines in rats

Flunitrazepam in combination with alcohol engenders high levels of aggression in mice and rats

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ChemInform Abstract: Bz1 Receptor Subtype Specific Ligands. Synthesis and Biological Properties of βCCt, a Bz1 Receptor Subtype Specific Antagonist.

Cited by 16 publications

References 0 publications

Little Evidence of a Role for the α1GABAA Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

Little Evidence of a Role for the α1GABAA Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

The role of α1 and α5 subunit-containing GABAA receptors in motor impairment induced by benzodiazepines in rats

Flunitrazepam in combination with alcohol engenders high levels of aggression in mice and rats

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Little Evidence of a Role for the α1GABA_A Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

Little Evidence of a Role for the α1GABA_A Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking