Selective Antagonism of GABAA Receptor Subtypes: An In Vivo Approach to Exploring the Therapeutic and Side Effects of Benzodiazepine–Type Drugs

Rowlett, James K.; Cook, James M.; Duke, Angela N.; Platt, Donna M.

doi:10.1017/s1092852900009895

Cited by 34 publications

(27 citation statements)

References 37 publications

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“…Although it was suggested that the reason for this was that the triazolam cue was mediated via GABA A -␣ 1 receptors at which L-838,417 has no efficacy (McKernan et al, 2000), assessing that the discriminative profile of L-838,417 in animals trained to discriminate zolpidem may have been more conclusive (Rowlett et al, 1999. Nonetheless, our data with L-838,417 concur with the conclusions of Rowlett et al (2005b) and demonstrate that its selective generalization to the chlordiazepoxide cue over the zolpidem cue mimics the receptor selectivity seen with this compound in vitro (McKernan et al, 2000).…”

Section: Discussionsupporting

confidence: 83%

“…Recently, Rowlett et al (2005b) showed that zolpidem and diazepam fully generalized to the triazolam cue in squirrel monkeys, whereas L-838,417 showed no generalization up to 10 mg/kg. Although it was suggested that the reason for this was that the triazolam cue was mediated via GABA A -␣ 1 receptors at which L-838,417 has no efficacy (McKernan et al, 2000), assessing that the discriminative profile of L-838,417 in animals trained to discriminate zolpidem may have been more conclusive (Rowlett et al, 1999.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Licata et al (2005) demonstrated that SL651498 partially generalized to the triazolam-discriminative cue in squirrel monkeys and that this effect could be blocked by the GABA A -␣ 1 -selective antagonist ␤-CCT. By contrast, as discussed above, L-838,417 does not generalize to the triazolam cue in squirrel monkeys (Rowlett et al, 2005b).…”

mentioning

confidence: 81%

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Comparative Cue Generalization Profiles of L-838, 417, SL651498, Zolpidem, CL218,872, Ocinaplon, Bretazenil, Zopiclone, and Various Benzodiazepines in Chlordiazepoxide and Zolpidem Drug Discrimination

Mirza

Rodgers²,

Mathiasen³

2005

J Pharmacol Exp Ther

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The zolpidem discriminative cue is mediated by GABA A -␣ 1 receptors, whereas the chlordiazepoxide cue may be mediated via non-␣ 1 GABA A receptors because compounds with selective affinity for GABA A -␣ 1 receptors fully generalize to the former cue. We predicted that L-838,417 [7-tert-butyl-3-(2,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine], a partial agonist at non-␣ 1 GABA A receptors and an antagonist at GABA A -␣ 1 receptors, would generalize to the chlordiazepoxide but not the zolpidem-discriminative cue. SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one] is a full agonist at GABA A -␣ 2 receptors, with lower efficacy at GABA A -␣ 3 receptors and least efficacy at GABA A -␣ 1 and GABA A -␣ 5 receptors. Because SL651498 has efficacy at GABA A -␣ 1 receptors, we anticipated that it would generalize to both discriminative cues. Rats were trained to discriminate either zolpidem (3 mg/kg) or chlordiazepoxide (5 mg/kg) from vehicle using a two-lever operant procedure. The generalization profiles of L-838,417 and SL651498 were compared with nonselective full agonists, GABA A -␣ 1 -selective ligands zolpidem and CL218,872 [3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine], the nonselective partial agonist bretazenil, and the novel anxioselective drug ocinaplon. A nonselective partial agonist was included because L-838,417 and SL651498 are partial agonists at some GABA A receptors, and this property may influence their generalization profiles. All nonselective full agonists and ocinaplon fully generalized to both cues. CL218,872 and zolpidem generalized to zolpidem only, whereas L-838,417 fully generalized to chlordiazepoxide only. SL651498 fully generalized to chlordiazepoxide and occasioned significant zolpidem-appropriate responding. Bretazenil was similar to SL651498. In conclusion, at this training dose, the chlordiazepoxide-discriminative stimulus is mediated primarily via non-␣ 1 GABA A receptors and the generalization profiles of the ligands tested seem to correspond with their in vitro profiles at GABA A receptor subtypes.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Comparative Cue Generalization Profiles of L-838, 417, SL651498, Zolpidem, CL218,872, Ocinaplon, Bretazenil, Zopiclone, and Various Benzodiazepines in Chlordiazepoxide and Zolpidem Drug Discrimination

Mirza

Rodgers²,

Mathiasen³

2005

J Pharmacol Exp Ther

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“…Assessment of the ability of 10 mg/kg ßCCt (i.p.) to displace the radio-labeled flumazenil in mice indicates that ßCCt at the given dose level preferentially targets the cerebellum, while it binds to less than 40% of GABA A receptors, mainly of the α 2 -subtype, in the spinal cord (Rowlett et al 2005). Given the doses of zolpidem and ßCCt that we used, we hypothesize that under our experimental conditions the actions of these ligands may, to a small extent, have involved the α 2 -, in addition to the predominantly affected α 1 -GABA A receptor subtype.…”

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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“…However, pharmacological studies with GABA A -␣ 1 selective antagonists are also inconsistent with gene knock-in mouse data in implicating GABA A -␣ 1 receptors in anxiolytic efficacy (Shannon et al, 1984;Griebel et al, 1999b;Huang et al, 1999;Paronis et al, 2001;Rowlett et al, 2005). Indeed, ocinaplon, an arguably GABA A -␣ 1 selective molecule, demonstrates anxiolytic efficacy in GAD patients without engendering sedation (Basile et al, 2006).…”

Section: Routementioning

confidence: 99%

NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABA_A Receptor Positive Allosteric Modulator: In Vitro Actions, Pharmacokinetic Properties and in Vivo Anxiolytic Efficacy

Mirza

Larsen²,

Mathiasen³

et al. 2008

J Pharmacol Exp Ther

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The novel positive allosteric modulator NS11394 [3Ј-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] possesses a functional selectivity profile at GABA A receptors of ␣ 5 Ͼ ␣ 3 Ͼ ␣ 2 Ͼ ␣ 1 based on oocyte electrophysiology with human GABA A receptors. Compared with other subtype-selective ligands, NS11394 is unique in having superior efficacy at GABA A -␣ 3 receptors while maintaining low efficacy at GABA A -␣ 1 receptors. NS11394 has an excellent pharmacokinetic profile, which correlates with pharmacodynamic endpoints (CNS receptor occupancy), yielding a high level of confidence in deriving in vivo conclusions anchored to an in vitro selectivity profile and allowing for translation to higher species. Specifically, we show that NS11394 is potent and highly effective in rodent anxiety models. The anxiolytic efficacy of NS11394 is most probably mediated through its high efficacy at GABA A -␣ 3 receptors, although a contributory role of GABA A -␣ 2 receptors cannot be excluded. Compared with benzodiazepines, NS11394 has a significantly reduced side effect profile in rat (sedation, ataxia, and ethanol interaction) and mouse (sedation), even at full CNS receptor occupancy. We attribute this benign side effect profile to very low efficacy of NS11394 at GABA A -␣ 1 receptors and an overall partial agonist profile across receptor subtypes. However, NS11394 impairs memory in both rats and mice, which is possibly attributable to its efficacy at GABA A -␣ 5 receptors, albeit activity at this receptor might be relevant to its antinociceptive effects (J Pharmacol Exp Ther 327:doi;10.1124/jpet.108.144, 2008). In conclusion, NS11394 has a unique subtype-selective GABA A receptor profile and represents an excellent pharmacological tool to further our understanding on the relative contributions of GABA A receptor subtypes in various therapeutic areas.Preclinical studies using genetically modified mice suggest that GABA A -␣ 1 (Rudolph et al., 1999;McKernan et al., 2000), ␣ 2 (Low et al., 2000), and ␣ 5 (Collinson et al., 2002;Crestani et al., 2002)-containing receptors mediate the sedative/ motor-impairing, anxiolytic, and memory impairing effects of benzodiazepines, respectively. Pharmacologically, various nonbenzodiazepine compounds have been described that show either selective affinity (e.g., zolpidem and indiplon) or selective efficacy (e.g., L-838,417, SL651498, TP003, TPA023) for subtypes of GABA A receptors (Sanger et al., 1987;McKernan et al., 2000;Griebel et al., 2001;Dias et al., 2005;Atack et al., 2006). Such selectivity profiles have been argued to be the basis for selective behavioral profiles of these compounds in rodents and in some cases man. For example, zolpidem is selective for GABA A -␣ 1 -containing receptors, has a preferential sedative-hypnotic profile in animals, and is marketed as a sleep aid zolpidem tartrate (Ambien). Although additional compounds with various selectivity profiles have emerged, limited clinical data in patient populations exist to date (but see Basile...

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Selective Antagonism of GABAA Receptor Subtypes: An In Vivo Approach to Exploring the Therapeutic and Side Effects of Benzodiazepine–Type Drugs

Cited by 34 publications

References 37 publications

Comparative Cue Generalization Profiles of L-838, 417, SL651498, Zolpidem, CL218,872, Ocinaplon, Bretazenil, Zopiclone, and Various Benzodiazepines in Chlordiazepoxide and Zolpidem Drug Discrimination

Comparative Cue Generalization Profiles of L-838, 417, SL651498, Zolpidem, CL218,872, Ocinaplon, Bretazenil, Zopiclone, and Various Benzodiazepines in Chlordiazepoxide and Zolpidem Drug Discrimination

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

NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABA_A Receptor Positive Allosteric Modulator: In Vitro Actions, Pharmacokinetic Properties and in Vivo Anxiolytic Efficacy

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Selective Antagonism of GABAA Receptor Subtypes: An In Vivo Approach to Exploring the Therapeutic and Side Effects of Benzodiazepine–Type Drugs

Cited by 34 publications

References 37 publications

Comparative Cue Generalization Profiles of L-838, 417, SL651498, Zolpidem, CL218,872, Ocinaplon, Bretazenil, Zopiclone, and Various Benzodiazepines in Chlordiazepoxide and Zolpidem Drug Discrimination

Comparative Cue Generalization Profiles of L-838, 417, SL651498, Zolpidem, CL218,872, Ocinaplon, Bretazenil, Zopiclone, and Various Benzodiazepines in Chlordiazepoxide and Zolpidem Drug Discrimination

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

NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABAA Receptor Positive Allosteric Modulator: In Vitro Actions, Pharmacokinetic Properties and in Vivo Anxiolytic Efficacy

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Product

Resources

About

NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABA_A Receptor Positive Allosteric Modulator: In Vitro Actions, Pharmacokinetic Properties and in Vivo Anxiolytic Efficacy