The role of GABA in mediating the anticonvulsant properties of benzodiazepines

Lippa, Arnold S.; Klepner, Claire A.; Benson, Donald I.; Critchett, Donald J.; Sano, Mary; Beer, Bernard

doi:10.1016/0361-9230(80)90145-8

Cited by 64 publications

(11 citation statements)

References 33 publications

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“…Thus, CL 218,872 was most potent in displacing [3H]BZ from cerebellum, significantly less potent in hippocampus, and exhibited an intermediate potency in cortex. Like 1,4-BZ, CL 218,872 exhibited potent anticonflict actions [12–14] in preclinical models [15] predictive of anxiolytic activity. However, in contrast to BZ, much higher doses of CL 218,872 were required to produce sedation and muscle relaxation [12–14].…”

Section: Anxiolytics: Past Present and The Need For Anxioselective mentioning

confidence: 99%

“…Like 1,4-BZ, CL 218,872 exhibited potent anticonflict actions [12–14] in preclinical models [15] predictive of anxiolytic activity. However, in contrast to BZ, much higher doses of CL 218,872 were required to produce sedation and muscle relaxation [12–14]. The unique pharmacological profile of this molecule 2 provided the impetus for many companies to develop compounds with a similar profile, screening libraries based using the displacement of [ 3 H]BZ from brain tissue as the starting point.…”

Section: Anxiolytics: Past Present and The Need For Anxioselective mentioning

confidence: 99%

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Anxioselective anxiolytics: on a quest for the Holy Grail

Skolnick

2012

Trends in Pharmacological Sciences

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The discovery of “benzodiazepine receptors” provided the impetus to discover and develop anxioselective anxiolytics (“Valium® without the side effects”). The market potential for a GABAA receptor-based anxioselective resulted in multiple compounds entering clinical trials. In contrast to the anxioselective profile displayed in preclinical models, compounds such as bretazenil, TPA023, and MRK 409 produced benzodiazepine-like side effects (sedation, dizziness) in Phase I studies, whereas alpidem and ocinaplon exhibited many of the characteristics of an anxioselective in the clinic. Alpidem was briefly marketed for the treatment of anxiety, but withdrawn because of liver toxicity. Reversible elevations in liver enzymes halted development of ocinaplon in Phase III. The clinical profiles of these two molecules demonstrate that it is possible to develop GABAA receptor-based anxioselectives. However, despite the formidable molecular toolbox at our disposal, we are no better informed about the GABAA receptors responsible for an anxioselective profile in the clinic. Here, I discuss the evolution of a quest, spanning 4 decades, for molecules that retain the rapid and robust anti-anxiety actions of benzodiazepines absent the side effects that limit their usefulness.

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Section: Anxiolytics: Past Present and The Need For Anxioselective mentioning

confidence: 99%

Section: Anxiolytics: Past Present and The Need For Anxioselective mentioning

confidence: 99%

Anxioselective anxiolytics: on a quest for the Holy Grail

Skolnick

2012

Trends in Pharmacological Sciences

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“…If different mechanisms underlie these various effects it should be possible to design more specific drugs to minimize side effects. Although the specific mechanisms responsible for various BZ actions are not yet understood, there is evidence that not all BZ effects are mediated by GABA (Lippa et al 1980;Seppinwall and Cook 1980;Pellow 1985;Sanger 1985). Studies with these selectively-bred lines can provide another approach to this question.…”

Section: Discussionmentioning

confidence: 95%

Mouse lines selected for genetic differences in diazepam sensitivity

et al. 1987

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Selective breeding techniques were used to alter allelic frequencies responsible for diazepam sensitivity and resistance. We used the rotarod test to determine the duration of diazepam-induced neurologic deficit in genetically heterogeneous mice. Males were more sensitive than females in the initial population. We then selectively bred for diazepam resistance and sensitivity. A significant difference between the lines was apparent in both sexes after two generations, and divergence has continued over seven generations. Brain benzodiazepine assays indicated that absorption and distribution of diazepam do not differ in the two lines. Differences in brain benzodiazepine concentrations at recovery from ataxia indicated that the two lines differ in central nervous system sensitivity. We found diazepam-induced rotarod impairment to be blocked in a dose-dependent manner by the specific benzodiazepine antagonist Ro 15-1788, indicating that this effect is mediated through BZ receptors. A dose-response curve obtained from generations 6 and 7 indicates a 9- to 14-fold difference in dose required to obtain similar effects in the two lines. These mice are expected to be useful experimental subjects in studies of benzodiazepine mechanisms.

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“…Type 2 receptors play an important role in hypokinesic and sedative effects (Lippa et al 1979(Lippa et al , 1980. Recently, in the GABA/BZP receptor complex, it has been reported that only type 2 receptors couple with GABAA receptors (Burch et al 1983).…”

Section: Discussionmentioning

confidence: 98%

Involvement of GABAergic systems in benzodiazepine-induced impairment of passive avoidance learning in mice

et al. 1991

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The possible involvement of GABAergic neuronal systems in benzodiazepine (BZP)-induced impairment of a passive avoidance response was investigated. Chlordiazepoxide (CDP) impaired passive avoidance when administered prior to training. The CDP-induced impairment was antagonized by pretreatment with picrotoxin, but not by pretreatment with bicuculline or post-training administration of picrotoxin. On the contrary, when combined with muscimol, the dose at which CDP impaired the response was lower than the dose at which it did so alone. The synergy of muscimol and CDP was attenuated by pretreatment with flumazenil or bicuculline. From these results, we conclude that GABAergic systems play an important role in the BZP-induced impairment of passive avoidance.

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The role of GABA in mediating the anticonvulsant properties of benzodiazepines

Cited by 64 publications

References 33 publications

Anxioselective anxiolytics: on a quest for the Holy Grail

Anxioselective anxiolytics: on a quest for the Holy Grail

Mouse lines selected for genetic differences in diazepam sensitivity

Involvement of GABAergic systems in benzodiazepine-induced impairment of passive avoidance learning in mice

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