Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys

Shinday, Nina M.; Sawyer, Eileen K; Fischer, Bradford D.; Platt, Donna M.; Licata, Stephanie C.; Atack, John; Dawson, Gerard R.; Reynolds, David S.; Rowlett, James K.

doi:10.1038/npp.2012.265

Cited by 22 publications

(33 citation statements)

References 35 publications

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“…Regarding α3GABA A receptors, the imidazopyridine compound TP003 has been recognized as the primary research tool used for exploring the function of this receptor subtype (Fischer et al, 2011; Marowski et al, 2012; Shinday et al, 2013). TP003 has been described as having comparatively high agonist efficacy at α3GABA A receptors but essentially no efficacy at α1GABA A , α2GABA A , and α5GABA A receptors (Dias et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABA A receptor ligand MP-III-024

Fischer

Schlitt

Hamade

et al. 2017

Brain Research Bulletin

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γ-aminobutyric acid type A (GABAA) receptors are located in spinal nociceptive circuits where they mediate the transmission of pain sensory signals from the periphery to higher centers. Benzodiazepine-type drugs bind GABAA, receptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAA, and α5GABAA receptors, respectively) through which they inhibit the transmission of these signals. However, the role of these different GABAA receptor subtypes in the antihyperalgisic properties of benzodiazepine-type drugs has not been characterized fully and is limited by currently available compounds. In the present study we describe the novel benzodiazepine site positive allosteric modulator modulator methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024). MP-III-024 displayed preference for α2GABAA and α3GABAA receptors relative to α1GABAA and α5GABAA receptors as well as an improved metabolic profile relative to subtype-selective positive modulators that are available currently. MP-III-024 produced a dose- and time-dependent reversal of mechanical sensitivity. On locomotor activity and schedule-controlled responding, MP-III-024 was ineffective across the doses tested. These data provide further evidence that α2GABAA and α3GABAA receptors play an important role in the antihyperalgiesic effects and may not be involved in some of the off target effects of benzodiazepine-like drugs. Further, these findings suggest that MP-III-024 is an ideal research tool for investigating the role of α2GABAA and α3GABAA receptors in the behavioral properties of benzodiazepine-like drugs in mice.

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Section: Discussionmentioning

confidence: 99%

Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABA A receptor ligand MP-III-024

Fischer

Schlitt

Hamade

et al. 2017

Brain Research Bulletin

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“…And activated IL-6 receptor recruits JAK1, JAK2, and Tyk2 tyrosine kinases which can phosphorylate STAT1 and STAT3 [18,19]. Midazolam is a potent benzodiazepine derivative with powerful hypnotic, sedative, anxiolytic, amnestic, anticonvulsant and muscle-relaxant properties by modulating the GABA A receptor in the central nervous system [20] . Recent study has demonstrated that astrocytic activation, maturation, and differentiation are involved in the expression of central type benzodiazepine receptors coupled to GABA A receptors in astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Midazolam Inhibits the Apoptosis of Astrocytes Induced by Oxygen Glucose Deprivation via Targeting JAK2-STAT3 Signaling Pathway

Liu

You²,

Tu³

et al. 2015

Cell Physiol Biochem

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Background: There is an increasing interest in the role of astrocytes contributing to the intrinsic bioremediation of ischemic brain injury. The purpose of this study was to disclose the effects and mechanism of midazolam (MDZ) on the proliferation and apoptosis of astrocytes under oxygen glucose deprivation (OGD) condition. Methods: The astrocytes were assigned randomly into four groups: control group, OGD group, OGD+MDZ group, and OGD+MDZ+IL-6 group. The astrocytes were treated with MDZ at dose of 10 μmol/L in OGD+MDZ group. And in OGD+MDZ+IL-6 group, the astrocytes were treated with MDZ at dose of 10μmol/L and IL-6 at dose of 50 ng/mL. MTT assay was used to assess cell proliferation, and cell apoptosis was analyzed by TUNEL apoptosis assay kit and flow cytometry. Furthermore, the expression of JAK2, p-JAK2, STAT3, p-STAT3, Bcl-2, Bax and Caspase-3 proteins were determined by western blotting assay. Results: Astrocytes proliferation was decreased obviously in OGD group, while MDZ could increase astrocytes proliferation under OGD condition. Moreover, OGD could induce apoptosis in astrocytes and MDZ could play an anti-apoptotic role. However, IL-6, a JAK2 activator, could attenuate cell proliferation and anti-apoptotic effects of MDZ in astrocytes. In addition, the expression of Bcl-2 protein in MDZ group increased markedly, while the JAK2/STAT3 signal proteins, Bax and Caspase-3 proteins decreased relative to OGD group. But IL-6 could counteract the anti-apoptotic effects of MDZ. Conclusion: Midazolam has protective effects on the proliferation and apoptosis of astrocytes via JAK2/STAT3 signal pathway in vitro. We firstly disclose the beneficial roles of midazolam in astrocytes under ischemic condition, which may be a rational treatment selection for ischemic cerebral protection.

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“…While strong conclusions are precluded because of the underpowered regression analyses (and consequent lack of statistical significance), these findings raise the possibility that the binding sites that 3-PBC, βCCT and flumazenil antagonized were more likely to be the α2-and/or α3GABA A receptor sites than either α1- or α5GABA A sites. This possibility is bolstered by our previous work with subtype-selective agonists, which implicated the α3GABA A , and potentially the α2GABA A , receptor subtype in the reinforcing effects of benzodiazepines (Rowlett et al, 2005; Shinday et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

“…Monkeys were trained to self-administer the benzodiazepine midazolam (0.03 mg/kg/infusion) under a PR schedule of i.v. drug injection (Shinday et al, 2013). At the beginning of each session, a set of two white stimulus lights above a response lever was illuminated (Med Associates, St Albans, VT).…”

Section: Methodsmentioning

confidence: 99%

“…, low-to-zero intrinsic efficacy at α1GABA A receptors) compound TPA023 up to doses that maximally occupy CNS benzodiazepine binding sites (Ator et al, 2010). However, we have demonstrated that α1GABA A receptor-sparing compounds are reliably self-administered in rhesus monkeys trained with GABA A positive modulators (midazolam, methohexital) but not the monoamine transport blocker cocaine (Rowlett et al, 2005; Shinday et al, 2013). Overall, these findings suggest that α1GABA A receptors are critical for the reinforcing effects of benzodiazepines only under certain conditions ( e.g.…”

Section: Introductionmentioning

confidence: 94%

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Antagonism of triazolam self-administration in rhesus monkeys responding under a progressive-ratio schedule: In vivo apparent pA2 analysis

Fischer

Platt

Rallapalli

et al. 2016

Drug and Alcohol Dependence

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Background Conventional benzodiazepines bind non-selectively to GABAA receptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAA, and α5GABAA receptors, respectively), and the role of these different GABAA receptor subtypes in the reinforcing effects of benzodiazepines has not been characterized fully. We used a pharmacological antagonist approach with available subtype-selective ligands to evaluate the role of GABAA receptor subtypes in the reinforcing effects of the non-selective conventional benzodiazepine, triazolam. Methods Rhesus monkeys (n = 4) were trained under a progressive-ratio schedule of intravenous midazolam delivery and dose–response functions were determined for triazolam, in the absence and presence of flumazenil (non-selective antagonist), βCCT and 3-PBC (α1GABAA-preferring antagonists), and XLi-093 (α5GABAA-selective antagonist). Results Flumazenil, βCCT and 3-PBC shifted the dose–response functions for triazolam to the right in a surmountable fashion, whereas XLi-093 was ineffective. Schild analyses revealed rank orders of potencies of flumazenil = βCCT > 3-PBC. Comparison of potencies between self-administration and previous binding studies with human cloned GABAA receptor subtypes suggested that the potencies for βCCT and 3-PBC were most consistent with binding at α2GABAA and α3GABAA receptors, but not α1GABAA or α5GABAA receptor subtypes. Conclusions Our findings were not entirely consistent with blockade of α1GABAA receptors and are consistent with the possibility of α2GABAA and/or α3GABAA subtype involvement in antagonism of the reinforcing effects of triazolam. The α5GABAA receptor subtype likely does not play a substantial role in self-administration under these conditions.

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Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys

Cited by 22 publications

References 35 publications

Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABA A receptor ligand MP-III-024

Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABA A receptor ligand MP-III-024

Midazolam Inhibits the Apoptosis of Astrocytes Induced by Oxygen Glucose Deprivation via Targeting JAK2-STAT3 Signaling Pathway

Antagonism of triazolam self-administration in rhesus monkeys responding under a progressive-ratio schedule: In vivo apparent pA2 analysis

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