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

Milić, Marija; Divljaković, Jovana; Rallapalli, Sundari; Linn, Michael L. Van; Timić, Tamara; Cook, James M.; Savić, Miroslav M.

doi:10.1097/fbp.0b013e3283512c85

Cited by 35 publications

(24 citation statements)

References 32 publications

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“…Although not measured in this study, it is possible that the decreased distance traveled during the SRM task and decreased velocity during the SWM task are due to motor deficits produced by ZOL. This hypothesis is supported by previous studies that found prominent motor effects following ZOL administration (Depoortere et al, 1986;Steiner et al, 2011;Milic et al, 2012).…”

Section: Discussionsupporting

confidence: 79%

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

Kilduff¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)September 2014 (From -To) REPORT TYPE Annual DATES COVERED P ERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SRI InternationalMenlo Park, CA 94025-3493 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENT SUPPLEMENTARY NOTES ABSTRACTDuring Year 5, we continued tests of the hypothesis that disfacilitation of wake-promoting systems by the hypocretin (Hcrt) receptor antagonist almorexant (ALM) results in less functional impairment than the inhibition of neural activity produced by the benzodiazepine receptor agonist zolpidem (ZOL). One paper was published (Morairty et al. 2014), another has been accepted for publication (Dittrich et al., in press) and a third is in resubmission (Vazquez-DeRose et al., submitted). Data collection for Aims 2c and 3b.2 have been completed and data analysis ongoing; manuscripts will be written and submitted during Year 6. Data collection and analysis of Aim 3a is nearing completion; an abstract summarizing this work has been submitted for presentation at the 2014 Society for Neuroscience meeting. Data collection for Aims 3b.3, 4c and 6a have been initiated. The overall results obtained to date are consistent with the hypothesis that the hypocretin/orexin antagonist ALM produces less functional impairment than the benzodiazepine receptor agonist zolpidem (ZOL) because ZOL causes a general inhibition of neural activity whereas ALM specifically disfacilitates wake-promoting systems. SUBJECT TERMSSleep, performance, drug, neurotransmitter, hypocretin, orexin, benzodiazepine, zolpidem, neurochemistry, microdialysis INTRODUCTIONAlmorexant (ALM) is a hypocretin/orexin (Hcrt) receptor antagonist with a novel mechanism of action that has shown promise as an effective hypnotic. Preclinical data demonstrate that animals treated with ALM are easily aroused from sleep and are free of ataxia and other behavioral impairments. If this observation is confirmed in humans, it would have enormous implications for the management of disturbed sleep in both military a...

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Section: Discussionsupporting

confidence: 79%

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

Kilduff¹

2014

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“…Specific ligands binding to GABRA5 mediate muscle relaxation (Milic et al . 2012). Some of the identified transcriptional regulators have roles in myofibre type specification ( PRDM1 ) and fatty acid and glucose metabolism ( PRDM1 , MLXIPL , LIN28A ) (Wang et al .…”

Section: Resultsmentioning

confidence: 99%

Genomic architecture of histone 3 lysine 27 trimethylation during late ovine skeletal muscle development

et al. 2014

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SummaryThe ruminant developmental transition from late foetus to lamb is associated with marked changes in skeletal muscle structure and function that reflect programming for new physiological demands following birth. To determine whether epigenetic changes are involved in this transition, we investigated the genomic architecture of the chromatin modification, histone 3 lysine 27 trimethylation (H3K27me3), which typically regulates early life developmental processes; however, its role in later life processes is unclear. Chromatin immunoprecipitation coupled with next‐generation sequencing was used to map H3K27me3 nucleosomes in ovine longissimus lumborum skeletal muscle at 100 days of gestation and 12 weeks post‐partum. In both states, H3K27me3 modification was associated with genes, transcription start sites and CpG islands and with transcriptional silencing. The H3K27me3 peaks consisted of two major categories, promoter specific and regional, with the latter the dominant feature. Genes encoding homeobox transcription factors regulating early life development and genes involved in neural functions, particularly gated ion channels, were strongly modified by H3K27me3. Gene promoters differentially modified by H3K27me3 in the foetus and lamb were enriched for gated ion channels, which may reflect changes in neuromuscular function. However, most modified genes showed no changes, indicating that H3K27me3 does not have a large role in late muscle maturation. Notably, promyogenic transcription factors were strongly modified with H3K27me3 but showed no differences between the late gestation foetus and lamb, likely reflecting their lack of involvement in the myofibre fusion process occurring in this transition. H3K27me3 is a major architectural feature of the epigenetic landscape of ruminant skeletal muscle, and it comments on gene transcription and gene function in the context of late skeletal muscle development.

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“…Studies assessing the behavioral activity of diazepam in knock-in mice, which harbor single point-mutated receptors, have attributed the muscle relaxant actions of benzodiazepines to the α2/α3/α5-subtypes (Rudolph and Möhler, 2014). We have previously demonstrated that the α5-selective antagonist XLi-093 can significantly diminish the myorelaxant actions of diazepam in rats (Milić et al, 2012). Consistently, the first muscle relaxant effect of MP-III-022 was observed at a dose (10 mg/kg) postulated to elicit a selective strong potentiation of α5-GABA A receptors.…”

Section: Discussionmentioning

confidence: 99%

Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABAA receptors containing the α5 subunit

Stamenić

Rehman

Santrač

et al. 2016

European Journal of Pharmacology

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We have synthesized and characterized MP-III-022 ((R)-8-ethynyl-6-(2-fluorophenyl)-N,4-dimethyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy-selective positive allosteric modulator of GABAA receptors containing the α5 subunit (α5GABAARs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 1-10 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of α5βγ2 GABAA receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2′F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-α5 GABAARs as well as the desired α5GABAARs at the highest dose. At the dose of 10 mg/kg, which elicits a strong positive modulation of α5GABAARs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of α5GABAARs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.

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

Cited by 35 publications

References 32 publications

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

Genomic architecture of histone 3 lysine 27 trimethylation during late ovine skeletal muscle development

Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABAA receptors containing the α5 subunit

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