Effects of locally administered pentylenetetrazole on nigral single unit activity and severity of dystonia in a genetic model of paroxysmal dystonia.
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.
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine Hannover, Hannover, Germany.
Maren
M
Fedrowitz
Melanie
M
Hamann
Jan H
JH
Rehders
Angelika
A
Richter
Manuela
M
Gernert
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003292:Convulsants / Q000494:pharmacology*; D006224:Cricetinae; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics / Q000503:physiopathology*; D004594:Electrophysiology; D008647:Mesocricetus; D008845:Microinjections; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010433:Pentylenetetrazole / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000502:physiology; D012720:Severity of Illness Index; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects*
D003292:Convulsants; D011963:Receptors, GABA-A; D010433:Pentylenetetrazole