Citation

Marti M, Mela F, Ulazzi L, Hanau S, Stocchi S, Paganini F, Beani L, Bianchi C, Morari M. Eur. J. Neurosci. 2003; 18(4): 759-767.

Copyright

(Copyright © 2003, Federation of European Neuroscience Societies, Publisher John Wiley and Sons)

DOI

10.1046/j.1460-9568.2003.02806.x

PMID

12925002

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.

Language: en

Keywords

Acetylcholine; Animals; Convulsants; Corpus Striatum; Dopamine; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Huntington Disease; Male; Mitochondria; Nitro Compounds; Organ Culture Techniques; Potassium Channels; Propionates; Rats; Rats, Sprague-Dawley; Riluzole; Sodium Channels; Succinate Dehydrogenase; Synaptosomes; Tetrodotoxin