Differential ontogeny of Type 1 and Type 2 benzodiazepine receptors
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GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABA<inf>A</inf> receptors
2022, Pharmacology and TherapeuticsCitation Excerpt :The advent of molecular biology enabled further refinement to the search for anxio-selective drugs. The concept of benzodiazepine type 1 and type 2 receptors (Klepner et al., 1979; Lippa et al., 1978, 1981, 1982) was integrated into the current understanding of the structure and function of the GABAAR. Basic and applied research in this area focused on the specific α-subunit comprising the GABAAR assembly since modifications of this subunit produced major changes in pharmacological activity.
The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders
2022, Pharmacology Biochemistry and BehaviorCitation Excerpt :There were multiple approaches to this discovery effort, a sequence guided, in part, by the currently available science (Fig. 1). The early discovery that a compound could produce anxiolytic-like activity but with reduced sedation liability (CL218,872) (Lippa et al., 1978, 1981, 1982; Klepner et al., 1979) encouraged compound screening to find other compounds with this preclinical profile. Although CL218,872 was never put into clinical development, a structural analog, ocinaplon (CL 273,547 or DOV 273,547), was developed years after the discovery of CL218,872 and was found to be anxiolytic without sedation (Lippa et al., 2005; Czobor et al., 2010).
To what extent is it possible to dissociate the anxiolytic and sedative/hypnotic properties of GABA<inf>A</inf> receptors modulators?
2016, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :The anxiogenic effects of FG-7142 were less marked in adolescent rats likely reflecting immature modulation of anxiety-like behavior by BZ-sensitive GABAARs in adolescents (Arrant et al., 2013). Although the mature expression of BZ-sensitive GABAR subtypes takes place by early adolescence (Candy and Martin, 1979; Fritschy et al., 1994; Lippa et al., 1981; Palacios et al., 1979), there are developmental differences in regulation of anxiety-like behavior affecting BZR function (Primus and Kellogg, 1991). FG-7142 has also been shown to be anxiogenic in a variety of animal models of anxiety (Agmo et al., 1991; Cole et al., 1995; Rodgers et al., 1995; Sulcova et al., 1992; Wettstein, 1989).
Use of the light/dark test for anxiety in adult and adolescent male rats
2013, Behavioural Brain ResearchCitation Excerpt :The similar suppression of locomotion in adolescents and adults is consistent with a previous report of similar reduction of locomotion in PN24 and adult rats after 15 mg/kg FG-7142 [48]. The expression of benzodiazepine-sensitive GABA receptor subtypes is mature by early adolescence [49–52]. However, exposure to the social interaction test for anxiety differentially affects benzodiazepine receptor function in adult and adolescent rats, suggesting developmental differences in GABAergic modulation of anxiety-like behavior [53].
The neurobiology of alcohol consumption and alcoholism: An integrative history
2013, Pharmacology Biochemistry and BehaviorCitation Excerpt :The GABA-A receptor is a pentameric (five subunit) protein which is composed of particular combinations of α (1–6), β (1–3), γ (1–3), δ, ε, and θ subunits (Hevers and Luddens, 1998; Mohler et al., 1998). It is currently believed that the Type 1 GABA-A receptors originally classified by Lippa et al. (1981) as receptors mediating sedation, correspond to receptors containing α1 subunits. The α1 subunit is often part of a receptor complex that also contains β2 and γ1 subunits.
Periadolescent exposure to ethanol and diazepam alters the aversive properties of ethanol in adult mice
2006, Pharmacology Biochemistry and Behavior