The effects of GABA transporter inhibition on synaptophysin and synaptotagmin expression in diazepam tolerance
BACKGROUND: In light of the differential interactions seen between benzodiazepine, GABA transporter (GAT) inhibition and drug tolerance, the locomotor effects of a GAT1-specific inhibitor (SKF89976A) following diazepam tolerance were analysed and compared with the concomitant expression of synaptic vesicle proteins implicated in synaptic plasticity.
METHODS: Male PVG/OlaHsd rats were chronically dosed with diazepam to produce tolerance, and the expression of mRNA for synaptophysin and synaptotagmin were analysed in the hippocampus by means of in situ hybridisation. The action of the GAT inhibitor SKF89976A on the expression of these mRNAs, and on open field behaviour was subsequently observed.
RESULTS: The results show an unexpected sedative effect of GAT-inhibition in diazepam-tolerant rats. The expression data show a significant effect of diazepam treatment on synaptophysin expression, which is reversible by SKF89976A treatment.
CONCLUSIONS: The increased synaptophysin expression in the hippocampus of diazepam-tolerant rats may indicate a role for modulation of transmitter release, synaptic plasticity and learning in pharmacological tolerance. The reversibility of this effect following acute GAT inhibition suggests a complicated relationship between the benzodiazepine-binding site and other synaptic GABA-binding sites. Furthermore, the sedative behavioural effect of the GAT inhibitor in diazepam-tolerant rats is an unusual observation with implications for the treatment of drug-tolerant individuals.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2010 |
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| Erschienen: |
2010 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry - 11(2010), 2 Pt 2 vom: 16. März, Seite 439-46 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schmitt, Ulrich [VerfasserIn] |
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| Links: |
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| Themen: |
134193-27-4 |
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| Anmerkungen: |
Date Completed 14.06.2010 Date Revised 21.11.2013 published: Print Citation Status MEDLINE |
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| doi: |
10.1080/15622970902874932 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM188622845 |
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| 100 | 1 | |a Schmitt, Ulrich |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The effects of GABA transporter inhibition on synaptophysin and synaptotagmin expression in diazepam tolerance |
| 264 | 1 | |c 2010 | |
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| 500 | |a Date Completed 14.06.2010 | ||
| 500 | |a Date Revised 21.11.2013 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: In light of the differential interactions seen between benzodiazepine, GABA transporter (GAT) inhibition and drug tolerance, the locomotor effects of a GAT1-specific inhibitor (SKF89976A) following diazepam tolerance were analysed and compared with the concomitant expression of synaptic vesicle proteins implicated in synaptic plasticity | ||
| 520 | |a METHODS: Male PVG/OlaHsd rats were chronically dosed with diazepam to produce tolerance, and the expression of mRNA for synaptophysin and synaptotagmin were analysed in the hippocampus by means of in situ hybridisation. The action of the GAT inhibitor SKF89976A on the expression of these mRNAs, and on open field behaviour was subsequently observed | ||
| 520 | |a RESULTS: The results show an unexpected sedative effect of GAT-inhibition in diazepam-tolerant rats. The expression data show a significant effect of diazepam treatment on synaptophysin expression, which is reversible by SKF89976A treatment | ||
| 520 | |a CONCLUSIONS: The increased synaptophysin expression in the hippocampus of diazepam-tolerant rats may indicate a role for modulation of transmitter release, synaptic plasticity and learning in pharmacological tolerance. The reversibility of this effect following acute GAT inhibition suggests a complicated relationship between the benzodiazepine-binding site and other synaptic GABA-binding sites. Furthermore, the sedative behavioural effect of the GAT inhibitor in diazepam-tolerant rats is an unusual observation with implications for the treatment of drug-tolerant individuals | ||
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| 700 | 1 | |a Rapp, Simone |e verfasserin |4 aut | |
| 700 | 1 | |a Kissling, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Jennen-Steinmetz, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Hünnerkopf, Regina |e verfasserin |4 aut | |
| 700 | 1 | |a Coogan, Andrew N |e verfasserin |4 aut | |
| 700 | 1 | |a Thome, Johannes |e verfasserin |4 aut | |
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