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Differential responsiveness of rat striatal nerve endings to the mitochondrial toxin 3-nitropropionic acid: implications for Huntington's disease.
- Source :
-
The European journal of neuroscience [Eur J Neurosci] 2003 Aug; Vol. 18 (4), pp. 759-67. - Publication Year :
- 2003
-
Abstract
- Rat striatal synaptosomes and slices were used to investigate the responsiveness of different populations of nerve terminals to 3-nitropropionic acid (3-NP), a suicide inhibitor of the mitochondrial enzyme succinate dehydrogenase, and to elucidate the ionic mechanisms involved. 3-NP (0.3-3 mm) stimulated spontaneous gamma-aminobutyric acid (GABA), glutamate and [3H]-dopamine efflux but left unchanged acetylcholine efflux from synaptosomes. This effect was associated with a >70% inhibition of succinate dehydrogenase, as measured in the whole synaptosomal population. The facilitation was not dependent on extracellular Ca2+ but relied on voltage-dependent Na+ channel opening, because it was prevented by tetrodotoxin and riluzole. 3-NP also elevated spontaneous glutamate efflux from slices but in a tetrodotoxin-insensitive way. To investigate whether energy depletion could change the responsiveness of nerve endings to a depolarizing stimulus, synaptosomes were pretreated with 3-NP and challenged with pulses of KCl evoking 'quasi-physiological' neurotransmitter release. 3-NP potentiated the K+-evoked GABA, glutamate and [3H]-dopamine release but inhibited the K+-evoked acetylcholine release. The 3-NP induced potentiation of GABA release was Ca2+-dependent and prevented by tetrodotoxin and riluzole whereas the 3-NP-induced inhibition of acetylcholine release was tetrodotoxin- and riluzole-insensitive but reversed by glipizide, an ATP-dependent K+ channel inhibitor. We conclude that the responsiveness of striatal nerve endings to 3-NP relies on activation of different ionic conductances, and suggest that the selective survival of striatal cholinergic interneurons following chronic 3-NP treatment (as in models of Huntington's disease) may rely on the opening of ATP-dependent K+ channels, which counteracts the fall in membrane potential as a result of mitochondrial impairment.
- Subjects :
- Acetylcholine metabolism
Animals
Corpus Striatum metabolism
Dopamine metabolism
Excitatory Amino Acid Antagonists pharmacology
Glutamic Acid drug effects
Glutamic Acid metabolism
Huntington Disease physiopathology
Male
Mitochondria metabolism
Nitro Compounds
Organ Culture Techniques
Potassium Channels metabolism
Rats
Rats, Sprague-Dawley
Riluzole pharmacology
Sodium Channels metabolism
Succinate Dehydrogenase metabolism
Synaptosomes metabolism
Tetrodotoxin pharmacology
gamma-Aminobutyric Acid drug effects
gamma-Aminobutyric Acid metabolism
Convulsants pharmacology
Corpus Striatum drug effects
Propionates pharmacology
Synaptosomes drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0953-816X
- Volume :
- 18
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The European journal of neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 12925002
- Full Text :
- https://doi.org/10.1046/j.1460-9568.2003.02806.x