ArticlePsychopharmacology2012
Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats.
Article in Psychopharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 56 citations in OpenAlex.
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- Deficits in medial prefrontal cortex parvalbumin expression and distraction-dependent memory in rats and mice in the sub-chronic phencyclidine model for schizophrenia.Frontiers in cellular neuroscience · 2025Article
- Inhibition of fatty acid amide hydrolase reverses aberrant prefrontal gamma oscillations in the sub-chronic PCP model for schizophrenia.Experimental brain research · 2024Article
- The molecular basis of drug selectivity for α5 subunit-containing GABANature structural & molecular biology · 2023Article
- Hippocampal α5-GABABiological psychiatry global open science · 2023Article
- The Case for Clinical Trials with Novel GABAergic Drugs in Diabetes Mellitus and Obesity.Life (Basel, Switzerland) · 2022Article
- Modulation of relapse-like drinking in male Sprague-Dawley rats by ligands targeting the α5GABANeuropharmacology · 2021Article
- Basmisanil, a highly selective GABAScientific reports · 2021Article
- α5GABAPsychopharmacology · 2019Article
- The α5-Containing GABAJournal of molecular neuroscience : MN · 2019Review
- Quercetin Reduces Cortical GABAergic Transmission and Alleviates MK-801-Induced Hyperactivity.EBioMedicine · 2018Article
- GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia.Acta pharmacologica Sinica · 2018Review
- GABABrain structure & function · 2018Article
- Short-Term Exposure to Enriched Environment in Adult Rats Restores MK-801-Induced Cognitive Deficits and GABAergic Interneuron Immunoreactivity Loss.Molecular neurobiology · 2018Article
- Vortioxetine Treatment Reverses Subchronic PCP Treatment-Induced Cognitive Impairments: A Potential Role for Serotonin Receptor-Mediated Regulation of GABA Neurotransmission.Frontiers in pharmacology · 2018Article
- MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs.Psychopharmacology · 2017Article
- Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABAEuropean journal of pharmacology · 2016Article
- Enhancement of postsynaptic GABAA and extrasynaptic NMDA receptor-mediated responses in the barrel cortex of Mecp2-null mice.Journal of neurophysiology · 2016Article
- Article
- The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia.Psychopharmacology · 2015Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
rationaleA growing body of evidence suggests that negative modulation of γ-aminobutyric acid (GABA) GABA(A) α5 receptors may be a promising strategy for the treatment of certain facets of cognitive impairment; however, selective modulators of GABA(A) α5 receptors have not yet been tested in "schizophrenia-relevant" cognitive assay/model systems in animals.
objectivesThe objectives of this study were to investigate the potential of RO4938581, a negative modulator of GABA(A) α5 receptors, and to attenuate cognitive impairments induced following sub-chronic (sub-PCP) and early postnatal PCP (neo-PCP) administration in the novel object recognition (NOR) and intra-extradimensional shift (ID/ED) paradigms in rats. Complementary in vitro, ex vivo and in vivo studies were performed to confirm negative modulatory activity of RO4938581 and to investigate animal model validity, concept validity and potential side effect issues, respectively.
resultsIn vitro studies confirmed the reported negative modulatory activity of RO4938581, whilst immunohistochemical analyses revealed significantly reduced parvalbumin-positive cells in the prefrontal cortex of sub-PCP- and neo-PCP-treated rats. RO4938581 (1 mg/kg) ameliorated both sub-PCP- and neo-PCP-induced cognitive deficits in NOR and ID/ED performance, respectively. In contrast, QH-II-066 (1 and 3 mg/kg), a GABA(A) α5 receptor positive modulator, impaired cognitive performance in the NOR task when administered to vehicle-treated animals. Additional studies revealed that both RO4938581 (1 mg/kg) and QH-II-066 (1 and 3 mg/kg) attenuated amphetamine-induced hyperactivity in rats.
conclusionsTaken 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.
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