Regional decreases in NK-3, but not NK-1 tachykinin receptor binding in dystonic hamster (dt(sz)) brains.
Although the pathophysiology of primary dystonias is currently unknown, it is thought to involve changes in the basal ganglia-thalamus-cortex circuit, particularly activity imbalances between direct and indirect striatal pathways. Substance P, a member of the tachykinin family of neuropeptides, is a major component in the direct pathway from striatum to basal ganglia output nuclei. In the present study quantitative autoradiography was used to examine changes in neurokinin-1 (NK-1) and neurokinin-3 (NK-3) receptors in mutant dystonic hamsters (dt(sz)), a well characterized model of paroxysmal dystonia. NK-1 receptors were labeled in 10 dystonic brains and 10 age-matched controls with 3 nM [(3)H]-[Sar(9), Met(O(2))(11)]-SP. NK-3 binding sites were labeled in adjacent sections with 2.5 nM [(3)H]senktide. NK-1 binding was found to be unaltered in 27 brain areas examined. In contrast, NK-3 binding was significantly reduced in layers 4 and 5 of the prefrontal (-46%), anterior cingulate (-42%) and parietal (-45%) cortices, ventromedial thalamus (-42%) and substantia nigra pars compacta (-36%) in dystonic brains compared to controls. The latter effects may be particularly relevant in view of evidence that activation of NK-3 receptors on dopaminergic neurons in the substantia nigra pars compacta can increase nigrostriatal dopaminergic activity. Since previous studies indicated that a reduced basal ganglia output in mutant hamsters is based on an overactivity of the direct pathway which also innervates substantia nigra pars compacta neurons, the decreased NK-3 binding could be related to a receptor down-regulation. The present finding of decreased NK-3 receptor density in the substantia nigra pars compacta, thalamic and cortical areas substantiates the hypothesis that disturbances of the basal ganglia-thalamus-cortex circuit play a critical role in the pathogenesis of paroxysmal dystonia.
Friedman
Y
Y
Neuroimaging Research Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Richter
A
A
Raymond
R
R
Löscher
W
W
Nobrega
J N
JN
D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D004421:Dystonia / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D018042:Receptors, Neurokinin-3 / Q000378:metabolism*; D012016:Reference Values; D013788:Thalamus / Q000378:metabolism
D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3