The effects of repeated zolpidem treatment on tolerance, withdrawal-like symptoms, and GABAA receptor mRNAs profile expression in mice: Comparison with diazepam

Wright, Brittany T.; Gluszek, Catherine F.; Heldt, Scott A.

doi:10.1007/s00213-014-3473-x

Cited by 33 publications

(10 citation statements)

References 102 publications

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“…From a therapeutic standpoint, these overlapping, yet distinct mechanisms have important implications regarding tolerance and dependence. GABA A receptor modulators have been shown in both animal models and human subjects to exhibit tolerance to repetitive dosing, becoming less efficacious over time [ 43 – 45 ], while ORAs, including suvorexant (Belsomra®), have shown no tolerance or evidence of withdrawal even after a year of treatment in patients [ 17 ] and no diminution of efficacy in animal models (reviewed in [ 46 ]). While the role of orexin in reward and withdrawal suggest that ORAs may have the capacity to diminish the dependence on rewarding influences (reviewed in [ 47 ]), the effectiveness of ORAs in animal models and human subjects following treatment with the current standard of care, GABA A receptor modulators, remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Differential sleep-promoting effects of dual orexin receptor antagonists and GABAAreceptor modulators

et al. 2014

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BackgroundThe current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABAA) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep architecture and quantitative electroencephalography (qEEG) spectral profiles across preclinical species.ResultsActive-phase dosing of DORA-22 induced consistent effects on sleep architecture in mice, rats, dogs, and rhesus monkeys; attenuation of active wake was accompanied by increases in both non─rapid eye movement (NREM) and rapid eye movement (REM) sleep. Eszopiclone, a representative GABAA receptor modulator, promoted sleep in rats and rhesus monkeys that was marked by REM sleep suppression, but had inconsistent effects in mice and paradoxically promoted wakefulness in dogs. Active-phase treatment of rats with DORA-12 similarly promoted NREM and REM sleep to magnitudes nearly identical to those seen during normal resting-phase sleep following vehicle treatment, whereas eszopiclone suppressed REM even to levels below those seen during the active phase. The qEEG changes induced by DORA-12 in rats also resembled normal resting-phase patterns, whereas eszopiclone induced changes distinct from normal active- or inactive-phase spectra. Co-dosing experiments, as well as studies in transgenic rats lacking orexin neurons, indicated partial overlap in the mechanism of sleep promotion by orexin and GABA modulation with the exception of the REM suppression exclusive to GABAA receptor modulation. Following REM deprivation in mice, eszopiclone further suppressed REM sleep while DORA-22 facilitated recovery including increased REM sleep.ConclusionDORAs promote NREM and importantly REM sleep that is similar in proportion and magnitude to that seen during the normal resting phase across mammalian animal models. While limited overlap exists between therapeutic mechanisms, orexin signaling does not appear involved in the REM suppression exhibited by GABAA receptor modulators. The ability of DORAs to promote proportional NREM and REM sleep following sleep deprivation suggests that this mechanism may be effective in alleviating recovery from sleep disturbance.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2202-15-109) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Differential sleep-promoting effects of dual orexin receptor antagonists and GABAAreceptor modulators

et al. 2014

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“…or Intralipid (Vlainic and Pericic, ; Wright et al. ). For the experiment of iron chelation, DFO (100 mg/kg i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…; Gutierrez et al., ; Wright et al. ). For example, repeated DZP (a medication in the BZD family) administration increased α 1, α 4, β 1, and γ 3 subunit mRNA levels and decreased β 2 subunit mRNA levels (Holt et al., ).…”

Section: Introductionmentioning

confidence: 99%

Chronic diazepam administration increases the expression of Lcn2 in the CNS

Furukawa

Shimoyama

Miki

et al. 2017

Pharmacol Res Perspect

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Benzodiazepines (BZDs), which bind with high affinity to gamma‐aminobutyric acid type A receptors (GABAA‐Rs) and potentiate the effects of GABA, are widely prescribed for anxiety, insomnia, epileptic discharge, and as anticonvulsants. The long‐term use of BZDs is limited due to adverse effects such as tolerance, dependence, withdrawal effects, and impairments in cognition and learning. Additionally, clinical reports have shown that chronic BZD treatment increases the risk of Alzheimer's disease. Unusual GABAA‐R subunit expression and GABAA‐R phosphorylation are induced by chronic BZD use. However, the gene expression and signaling pathways related to these effects are not completely understood. In this study, we performed a microarray analysis to investigate the mechanisms underlying the effect of chronic BZD administration on gene expression. Diazepam (DZP, a BZD) was chronically administered, and whole transcripts in the brain were analyzed. We found that the mRNA expression levels were significantly affected by chronic DZP administration and that lipocalin 2 (Lcn2) mRNA was the most upregulated gene in the cerebral cortex, hippocampus, and amygdala. Lcn2 is known as an iron homeostasis‐associated protein. Immunostained signals of Lcn2 were detected in neuron, astrocyte, microglia, and Lcn2 protein expression levels were consistently upregulated. This upregulation was observed without proinflammatory genes upregulation, and was attenuated by chronic treatment of deferoxamine mesylate (DFO), iron chelator. Our results suggest that chronic DZP administration regulates transcription and upregulates Lcn2 expression levels without an inflammatory response in the mouse brain. Furthermore, the DZP‐induced upregulation of Lcn2 expression was influenced by ambient iron.

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“…In case 2, BIS exceeded 60 even at the maximum dose rate of 2 mg/kg/h of remimazolam. Several studies have identified neuroadaptive mechanisms underlying benzodiazepine tolerance including alterations in GABA-A receptor subunit mRNA expression [ 3 , 4 ]. However, the details of these mechanisms have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Three cases of difficulty in achieving definitive loss of consciousness with remimazolam

et al. 2022

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Background Remimazolam is a novel, ultra-short-acting benzodiazepine used for general anesthesia. Because remimazolam is an emerging drug, the tolerance to remimazolam in benzodiazepine-taking patients has been unclear. Also, the efficacy of remimazolam in different races is not fully elucidated so far. Case presentation Here we experienced three cases in which high dose of remimazolam was needed for attempting to achieve appropriate anesthetic depth. Two of the three cases were of preoperatively benzodiazepine-taking patients. The other was a case of a Chinese patient. In all three cases, conversion to general anesthesia with propofol was necessitated. Conclusions When signs of inadequate sedative effect of remimazolam are observed in patients of benzodiazepine users or of different races, conversion to another sedative agent such as propofol should be considered.

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The effects of repeated zolpidem treatment on tolerance, withdrawal-like symptoms, and GABAA receptor mRNAs profile expression in mice: Comparison with diazepam

Abstract: In mice, subchronic treatment of zolpidem and diazepam can produce deficits in the locomotor-impairing effects of zolpidem, anxiety-like withdrawal symptoms, and subunit-specific mRNA changes.

Cited by 33 publications

References 102 publications

Differential sleep-promoting effects of dual orexin receptor antagonists and GABAAreceptor modulators

Differential sleep-promoting effects of dual orexin receptor antagonists and GABAAreceptor modulators

Chronic diazepam administration increases the expression of Lcn2 in the CNS

Three cases of difficulty in achieving definitive loss of consciousness with remimazolam

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