Effects of acute and repeated zolpidem treatment on pentylenetetrazole-induced seizure threshold and on locomotor activity: Comparison with diazepam

Vlainić, Josipa; Peričić, Danka

doi:10.1016/j.neuropharm.2009.03.010

Cited by 28 publications

(32 citation statements)

References 33 publications

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“…Both empirical and theoretical systems do suggest that seizures are threshold events and that even small changes in GABA A R availability can transition an organism into a seizure-prone state. For example, even though the GABA A R antagonists, bicuculline and pentylenetetrazole, inhibit GABA-evoked currents with typical sigmoidal concentration-response curves (46,47), they produce seizures in experimental animals at specific doses with very small variances (48,49). These findings suggest that a specific threshold of functional GABA A Rs is required to prevent an organism from experiencing a seizure.…”

Section: ␣1(ad) Subunit Reduced ␣3 Subunit Expression To a Greater Exmentioning

confidence: 99%

GABAA Receptor α1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors

Ding

Feng

Macdonald

et al. 2010

Journal of Biological Chemistry

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A GABA A receptor (GABA A R) ␣1 subunit mutation, A322D (AD), causes an autosomal dominant form of juvenile myoclonic epilepsy (ADJME). Previous studies demonstrated that the mutation caused ␣1(AD) subunit misfolding and rapid degradation, reducing its total and surface expression substantially. Here, we determined the effects of the residual ␣1(AD) subunit expression on wild type GABA A R expression to determine whether the AD mutation conferred a dominant negative effect. We found that although the ␣1(AD) subunit did not substitute for wild type ␣1 subunits on the cell surface, it reduced the surface expression of ␣1␤2␥2 and ␣3␤2␥2 receptors by associating with the wild type subunits within the endoplasmic reticulum and preventing them from trafficking to the cell surface. The ␣1(AD) subunit reduced surface expression of ␣3␤2␥2 receptors by a greater amount than ␣1␤2␥2 receptors, thus altering cell surface GABA A R composition. When transfected into cultured cortical neurons, the ␣1(AD) subunit altered the time course of miniature inhibitory postsynaptic current kinetics and reduced miniature inhibitory postsynaptic current amplitudes. These findings demonstrated that, in addition to causing a heterozygous loss of function of ␣1(AD) subunits, this epilepsy mutation also elicited a modest dominant negative effect that likely shapes the epilepsy phenotype. GABA A Rs2 are ligand-gated ion channels that provide the major source of inhibitory control to the mammalian central nervous system. Each GABA A R is a pentamer whose five subunits arise from seven subunit families that contain multiple subtype isoforms. Neurons preferentially express GABA A Rs composed of distinct combinations of subunit isoforms in different brain regions at well defined times in development (1-3).At maturity, the most prevalent GABA A R throughout the brain consists of two ␣1 subunits, two ␤2 subunits, and one ␥2 subunit in a ␤2-␣1-␤2-␣1-␥2 assembly (4 -6). To date, 13 autosomal dominant mutations in GABA A R subunit genes have been associated with different epilepsy syndromes (7).The missense AD mutation in the GABA A R ␣1 subunit gene (GABRA1) causes ADJME (8), a monogenic form of a common epilepsy syndrome that begins at a distinct developmental time point (adolescence) and confers myoclonic, generalized tonicclonic, and absence seizures as well as neuropsychiatric comorbidities (9). We demonstrated previously that the AD mutation, which substitutes a negatively charged aspartate for a neutral alanine within the M3 transmembrane domain, causes the ␣1(AD) subunit to misfold with altered topology (10). Cells rapidly degrade the misfolded ␣1(AD) subunit through both proteasome-and lysosome-mediated processes (10, 11). Therefore, the ␣1(AD) subunit is expressed at substantially lower levels than the wild type ␣1 subunit. GABA A Rs that do incorporate the residual, nondegraded ␣1(AD) subunits exhibit substantially altered electrophysiological properties (8,12,13). Therefore, a major consequence of heterozygous expression of the AD mutation i...

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Section: ␣1(ad) Subunit Reduced ␣3 Subunit Expression To a Greater Exmentioning

confidence: 99%

GABAA Receptor α1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors

Ding

Feng

Macdonald

et al. 2010

Journal of Biological Chemistry

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“…Previous studies on mice [10] and rats [11] suggested that, upon repeated treatment, zolpidem produced tolerance to its anticonvulsive and sedative effects. Therefore, zolpidem has a higher abuse potential than previously suggested [12] .…”

Section: Wwwchinapharcom Vlainić J Et Almentioning

confidence: 97%

“…Although chemically different than benzodiazepines, zolpidem elicited many side effects simi-www.nature.com/aps Vlainić J et al Acta Pharmacologica Sinica npg lar to that of benzodiazepines. Vlainić and Peričić (2009) [10] demonstrated development of anticonvulsant and sedative tolerance after repeated (10 days) zolpidem treatment in mice. Similar results were obtained in rats [11] .…”

Section: Introductionmentioning

confidence: 99%

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

et al. 2012

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Aim: Zolpidem is a non-benzodiazepine agonist at benzodiazepine binding site in GABA A receptors, which is increasingly prescribed. Recent studies suggest that prolonged zolpidem treatment induces tolerance. The aim of this study was to explore the adaptive changes in GABA A receptors following short and long-term exposure to zolpidem in vitro. Methods: Human embryonic kidney (HEK) 293 cells stably expressing recombinant α1β2γ2s GABA A receptors were exposed to zolpidem (1 and 10 μmol/L) for short-term (2 h daily for 1, 2, or 3 consecutive days) or long-term (continuously for 48 h). Radioligand binding studies were used to determine the parameters of Conclusion:The results suggest that continuous, but not intermittent and short-term, zolpidem-exposure is able to induce adaptive changes in GABA A receptors that could be related to the development of tolerance and dependence.

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“…Drugs known to prevent or reduce sleep in humans such as sibutramine, modafinil, and ephedrine trigger a strong signal in the locomotor activity or wheel-running assays (Meng et al 1999;Kim et al 2005). Likewise, drugs that promote sleep or cause sedation in humans such as diazepam, zolpidem, and diphenhydramine will readily cause a decrease in locomotor activity in rats and mice (Kalivas 1982;Vlainic and Pericic 2009). …”

Section: Behavioral Approaches To Assessing Sleep Disruptionmentioning

confidence: 99%

CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology

Fonck

Easter

Pietras

et al. 2015

Principles of Safety Pharmacology

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This chapter describes various approaches for the preclinical assessment of drug-induced central nervous system (CNS) adverse effects. Traditionally, methods to evaluate CNS effects have consisted of observing and scoring behavioral responses of animals after drug is administered. Among several behavioral testing paradigms, the Irwin and the functional observational battery (FOB) are the most commonly used assays for the assessment of CNS effects. The Irwin and FOB are considered good first-tier assays to satisfy the ICH S7A guidance for the preclinical evaluation of new chemical entities (NCE) intended for humans. However, experts have expressed concern about the subjectivity and lack of quantitation that is derived from behavioral testing. More importantly, it is difficult to gain insight into potential mechanisms of toxicity by assessing behavioral outcomes. As a complement to behavioral testing, we propose using electrophysiology-based assays, both in vivo and in vitro, such as electroencephalograms and brain slice field-potential recordings. To better illustrate these approaches, we discuss the implementation of electrophysiology-based techniques in drug-induced assessment of seizure risk, sleep disruption, and cognitive impairment.

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Effects of acute and repeated zolpidem treatment on pentylenetetrazole-induced seizure threshold and on locomotor activity: Comparison with diazepam

Cited by 28 publications

References 33 publications

GABAA Receptor α1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors

GABAA Receptor α1 Subunit Mutation A322D Associated with Autosomal Dominant Juvenile Myoclonic Epilepsy Reduces the Expression and Alters the Composition of Wild Type GABAA Receptors

Differential effects of short- and long-term zolpidem treatment on recombinant α1β2γ2s subtype of GABAA receptors in vitro

CNS Adverse Effects: From Functional Observation Battery/Irwin Tests to Electrophysiology

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