| Anticonvulsant and biochemical effects of inhibitors of GABA aminotransferase and valproic acid during subchronic treatment in mice. | |
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MedLine Citation:
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PMID: 6805473 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mice were treated with different doses of the GABA aminotransferase (GABA-T) inhibitors aminooxyacetic acid, gamma-acetylenic acid, gamma-vinyl GABA and ethanolamine-O-sulphate via the drinking water for periods of 1-12. All drugs caused marked elevations of whole brain GABA concentrations within 4 days of treatment which were associated with increases in the electroconvulsive threshold. However, the effect on seizure threshold could not be enhanced by an increase in the daily dosage of the GABA-T inhibitors and, especially with higher doses, tolerance to the anticonvulsant effect developed. At least in part, this finding may be attributed to a decrease in the activity of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis. On the other hand, with valproic acid (VPA) no tendency towards a reduced anticonvulsant effectiveness during medication was observed. VPA caused only non-significant increases in cerebral GABA levels but elevated brain GAD activity significantly. No behavioral changes were seen following subchronic administration of GABA-T inhibitors and VPA except in cases where the daily fluid intake was markedly reduced. Our data suggest that the anticonvulsant efficacy of long term treatment with GABA-T inhibitors is limited by the development of compensatory mechanisms, such as reduction of GAD activity, which in turn reduce the amount of GABA available for synaptic transmission, though overall GABA concentrations in the brain are highly elevated. Drug such as VPA which cause only moderate effects on GABA metabolism seem superior in this respect. |
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Authors:
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W Löscher |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Biochemical pharmacology Volume: 31 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 1982 Mar |
Date Detail:
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Created Date: 1982-07-19 Completed Date: 1982-07-19 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 837-42 Citation Subset: IM |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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4-Aminobutyrate Transaminase
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antagonists & inhibitors* Animals Anticonvulsants / pharmacology* Brain Chemistry / drug effects Glutamate Decarboxylase / analysis Male Mice Mice, Inbred Strains Transaminases / antagonists & inhibitors* Valproic Acid / pharmacology* gamma-Aminobutyric Acid / analysis |
| Chemical | |
Reg. No./Substance:
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0/Anticonvulsants; 56-12-2/gamma-Aminobutyric Acid; 99-66-1/Valproic Acid; EC 2.6.1.-/Transaminases; EC 2.6.1.19/4-Aminobutyrate Transaminase; EC 4.1.1.15/Glutamate Decarboxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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