Fachbereich Veterinärmedizin



    Effects of locally administered pentylenetetrazole on nigral single unit activity and severity of dystonia in a genetic model of paroxysmal dystonia (2002)

    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Fedrowitz, Maren
    Hamann, Melanie
    Rehders, Jan H
    Richter, Angelika
    Gernert, Manuela
    Journal of Neuroscience Research; 68(5) — S. 595–603
    ISSN: 0360-4012
    Pubmed: 12111849
    Institut für Pharmakologie und Toxikologie

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    Abstract / Zusammenfassung

    The dt(sz) hamster is a well-established animal model of idiopathic paroxysmal dystonia. Previous investigations of this mutant have indicated dysfunctions of the gamma-aminobutyric acid (GABA)-ergic system within the basal ganglia. Systemic administration of the central stimulant pentylenetetrazole (PTZ) aggravated dystonia at subconvulsant doses, whereas GABA-mimetic drugs have beneficial effects in dt(sz) hamsters. GABA mimetics also provide clinical benefit in humans with idiopathic paroxysmal dystonia. The spontaneous discharge rates of substantia nigra pars reticulata (SNr) neurons was unaltered in anesthetized dt(sz) hamsters, but systemic application of subconvulsant doses of PTZ caused significantly greater increases of discharge rates in dystonic hamsters compared with nondystonic controls. The present study tested the hypothesis that SNr neurons are more sensitive to local application of PTZ in dt(sz) hamsters than in nondystonic hamsters. PTZ applied locally by pressure injection at 2, 3, and 5 mM to the SNr during in vivo single unit recordings revealed a dose-dependent increase of SNr discharge rates in mutants and controls relative to predrug rates, with a significantly greater increase in mutants at 3 mM PTZ. To examine the functional relevance of the increased susceptibility of SNr neurons to PTZ in mutants, the effects of PTZ on severity of dystonia were investigated after microinjections into the SNr of freely moving dt(sz) hamsters. Bilateral nigral microinjection of 40 ng PTZ did not aggravate dystonia but exerted moderate antidystonic effects. Therefore, the previous findings of prodystonic effects of systemic administration of PTZ in dt(sz) hamsters are related to extranigral effects rather than to the elevation of nigral discharge rates in response to systemic, or locally applied, PTZ. The greater susceptibility of neurons within the SNr to PTZ suggests dysfunctions of the GABA(A) receptor in dt(sz) mutants.