Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats

Redrobe, John P.; Elster, Lisbeth; Frederiksen, Kristen; Bundgaard, Christoffer; Jong, Inge E.M. de; Smith, Garrick; Bruun, Anne Techau; Larsen, Peter H.; Didriksen, Michael

doi:10.1007/s00213-011-2593-9

Cited by 56 publications

(56 citation statements)

References 97 publications

(129 reference statements)

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“…6). The free fraction of methaqualone was determined in vitro using standard equilibrium dialysis methods with freshly isolated mouse brain homogenate or plasma (Redrobe et al, 2012). Equilibrium dialysis was performed by incubating at 37°C for 5 hours in triplicate.…”

Section: Animal Studiesmentioning

confidence: 99%

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Hammer¹,

Bader²,

Ehnert³

et al. 2015

Mol Pharmacol

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In the present study, we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone, Quaalude), an infamous sedative-hypnotic and recreational drug from the 1960s-1970s. Methaqualone was demonstrated to be a positive allosteric modulator at human a 1,2,3,5 b 2,3 g 2S GABA A receptors (GABA A Rs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the a 4,6 b 1,2,3 d GABA A R subtypes, ranging from inactivity (Methaqualone did not interact with the benzodiazepine, barbiturate, or neurosteroid binding sites in the GABA A R. Instead, the compound is proposed to act through the transmembrane b(1) /a (-) subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative central nervous system (CNS) targets suggest that it is a selective GABA A R modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1-100 mM concentrations were quite similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in the mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator at the recombinant GABA A Rs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABA A Rs give rise to its effects as a therapeutic and recreational drug.

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Section: Animal Studiesmentioning

confidence: 99%

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Hammer¹,

Bader²,

Ehnert³

et al. 2015

Mol Pharmacol

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“…Previous evidence from animal studies has shown that the α5-containing GABA-A receptors were signifi cantly involved in cognition [11][12][13][14]. Moreover, it has been shown that a negative modulation of α5 GABA-A receptors may represent an attractive treatment option for cognitive impairments, and potentially positive symptoms, associated with schizophrenia [15]. The goal of the present study was to examine the infl uence of the inverse agonist 11,12,13,13a-tetrahydro-7-methoxy-9 oxo-9H-imidazo [1,5-a] [11], acting on α5-subunit-containing GABA-A receptor and compare its dose-response effects on locomotor activity and depression-like behavior in the forced swim test.…”

Section: Research Articlementioning

confidence: 99%

Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test

Samardžić¹,

Puškaš²,

Obradović³

et al. 2014

Acta Veterinaria

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It has been shown in electrophysiological studies that the ligand L-655,708 possesses a binding selectivity and a moderate inverse agonist functional selectivity for α5-containing GABA-A receptors. The present study is aimed to investigate the antidepressant effects of the ligand L-655,708 in the forced swim test (FST) and its impact on locomotor activity in rats. The behavior of the animals was recorded with a digital camera, and the data were analyzed by one-way ANOVA, followed by Dunnett’s test. In FST, L-655,708 significantly decreased immobility time at a dose of 3 mg/kg after a single and repeated administration (p<0.05), exerting acute and chronic antidepressant effects. However, it did not induce significant differences in the time of struggling behavior during FST. Furthermore, L-655,708 did not show a significant effect on locomotor activity (p>0.05). These data suggest that negative modulation at GABA-A receptors containing the α5 subunit may produce antidepressant effects in rats. These effects were not confounded by locomotor influences.

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“…To date, the mechanism of action of anti-psychotic drugs in schizophrenia have been linked to DA and its interaction with other neurochemicals including glutamate, GABA, 5-HT and acetylcholine (Redrobe et al, 2012). GABA and glutamate regulate the activity of DA.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Quetiapine Fumarate and its Solid Lipid Nanoparticles as antipsychotic drug in rat model of schizophrenia

Said

Elmenoufy

2017

Biomed. Res. Ther.

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Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats

Abstract: Taken together, these novel findings suggest that negative modulation of GABA(A) α5 receptors may represent an attractive treatment option for the cognitive impairments, and potentially positive symptoms, associated with schizophrenia.

Cited by 56 publications

References 97 publications

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test

Evaluation of Quetiapine Fumarate and its Solid Lipid Nanoparticles as antipsychotic drug in rat model of schizophrenia

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Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats

Abstract: Taken together, these novel findings suggest that negative modulation of GABA(A) α5 receptors may represent an attractive treatment option for the cognitive impairments, and potentially positive symptoms, associated with schizophrenia.

Cited by 56 publications

References 97 publications

A Multifaceted GABAAReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

A Multifaceted GABAAReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test

Evaluation of Quetiapine Fumarate and its Solid Lipid Nanoparticles as antipsychotic drug in rat model of schizophrenia

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Product

Resources

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A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)

A Multifaceted GABA_AReceptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)