| Reversal of ketamine-induced working memory impairments by the GABAAalpha2/3 agonist TPA023. | |
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MedLine Citation:
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PMID: 20189164 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Ketamine has been used to model cognitive and behavioral symptoms of schizophrenia. Current hypotheses state that inadequate glutamatergic transmission in schizophrenia leads to a deficiency in gamma-aminobutyric acid (GABA)ergic inhibitory mechanisms and treatment with a GABA type A receptor subunits alpha2/alpha3 (GABA(Aalpha2/3)) modulator improved working memory performance in a preliminary study in patients. Here, we used ketamine to impair spatial working memory and disrupt behavior to examine the capacity for the GABA(Aalpha2/3) agonist 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) to reverse these symptoms. METHODS: Rhesus monkeys received TPA023 (.7, 2.0, and 5 mg/kg; by mouth) or vehicle 45 minutes before ketamine (1.0-1.7 mg/kg; intramuscular) or saline in a semirandomized Latin square design. Behavioral observations were acquired at approximately 5 minutes, and spatial delayed response performance was tested at 15 minutes postinjection. RESULTS: Ketamine produced a profound impairment in spatial working memory in association with the emergence of hallucinatory-like behaviors. TPA023 at all doses blocked ketamine's cognitive-impairing ability but did not influence the behavioral symptoms. CONCLUSIONS: Acute GABA(Aalpha2/3) agonist administration reverses the working memory deficits induced by ketamine in primates. This finding indicates that the consequences of N-methyl-D-aspartate deficiency on the function of prefrontal circuits involved in working memory can be completely overcome by acute enhancement of GABA signaling. |
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Authors:
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Stacy A Castner; Jeffrey L Arriza; John C Roberts; Ladislav Mrzljak; Edward P Christian; Graham V Williams |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-02-26 |
Journal Detail:
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Title: Biological psychiatry Volume: 67 ISSN: 1873-2402 ISO Abbreviation: Biol. Psychiatry Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-03 Completed Date: 2010-07-22 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0213264 Medline TA: Biol Psychiatry Country: United States |
Other Details:
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Languages: eng Pagination: 998-1001 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Behavior, Animal / drug effects Dose-Response Relationship, Drug Drug Interactions Ketamine / antagonists & inhibitors*, pharmacology Macaca mulatta Memory Disorders / chemically induced* Memory, Short-Term / drug effects* Pyridazines / pharmacology* Receptors, GABA-A / agonists* Triazoles / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 MH 65552/MH/NIMH NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo(4,3-b)pyridazine; 0/Pyridazines; 0/Receptors, GABA-A; 0/Triazoles; 6740-88-1/Ketamine |
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