title: Differential responsiveness of rat striatal nerve endings to the mitochondrial toxin 3-nitropropionic acid: implications for Huntington's disease.
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.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Marti
authors.forename: Flora
authors.initials: F
authors.lastname: Mela
authors.forename: Linda
authors.initials: L
authors.lastname: Ulazzi
authors.forename: Stefania
authors.initials: S
authors.lastname: Hanau
authors.forename: Sara
authors.initials: S
authors.lastname: Stocchi
authors.forename: Francesca
authors.initials: F
authors.lastname: Paganini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Beani
authors.forename: Clementina
authors.initials: C
authors.lastname: Bianchi
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D003292:Convulsants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D006816:Huntington Disease / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009574:Nitro Compounds; D009924:Organ Culture Techniques; D015221:Potassium Channels / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
chemical_list: D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D009574:Nitro Compounds; D015221:Potassium Channels; D011422:Propionates; D015222:Sodium Channels; D018698:Glutamic Acid; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D019782:Riluzole; D013385:Succinate Dehydrogenase; D000109:Acetylcholine; C015392:3-nitropropionic acid; D004298:Dopamine