Dysregulation of striatal dopamine release in a mouse model of dystonia.
Dystonia is a neurological disorder characterized by involuntary movements. We examined striatal dopamine (DA) function in hyperactive transgenic (Tg) mice generated as a model of dystonia. Evoked extracellular DA concentration was monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry in striatal slices from non-Tg mice, Tg mice with a positive motor phenotype, and phenotype-negative Tg littermates. Peak single-pulse evoked extracellular DA concentration was significantly lower in phenotype-positive mice than in non-Tg or phenotype-negative mice, but indistinguishable between non-Tg and phenotype-negative mice. Phenotype-positive mice also had higher functional D2 DA autoreceptor sensitivity than non-Tg mice, which would be consistent with lower extracellular DA concentration in vivo. Multiple-pulse (phasic) stimulation (five pulses, 10-100 Hz) revealed an enhanced frequency dependence of evoked DA release in phenotype-positive versus non-Tg or phenotype-negative mice, which was exacerbated when extracellular Ca(2+) concentration was lowered. Enhanced sensitivity to phasic stimulation in phenotype-positive mice was reminiscent of the pattern seen with antagonism of nicotinic acetylcholine receptors. Consistent with a role for altered cholinergic regulation, the difference in phasic responsiveness among groups was lost when nicotinic receptors were blocked by mecamylamine. Together, these data implicate compromised DA release regulation, possibly from cholinergic dysfunction, in the motor symptoms of this dystonia model.
Bao
Li
L
Department of Physiology and Neuroscience, NYU School of Medicine, New York, NY 10016, USA.
Patel
Jyoti C
JC
Walker
Ruth H
RH
Shashidharan
Pullanipally
P
Rice
Margaret E
ME
D000818:Animals; D017660:Autoreceptors / Q000819:agonists / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004421:Dystonia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004558:Electric Stimulation; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology
D017660:Autoreceptors; D018733:Nicotinic Antagonists; D017448:Receptors, Dopamine D2; D004298:Dopamine