Decreased striatal dopamine D2 receptor binding in amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA): D2 receptor down-regulation versus striatal cell degeneration.
Recently, decreased striatal dopamine D2-receptor binding was demonstrated in vivo in amyotrophic lateral sclerosis (ALS). To further elucidate the pathogenetic mechanism underlying this D2-receptor deficit, a multi-level comparison was made between 30 sporadic ALS subjects and 24 patients with multiple system atrophy (MSA), a disorder clinically characterized by bradykinesia, neuroradiologically by severe D2-receptor loss, and neuropathologically by degenerating striatal cells. The extent of D2-deficit in ALS and MSA were within the same range, but extrapyramidal signs and symptoms were virtually absent in our ALS patients. Striatal cell loss in general or competitive D2-receptor occupancy could be considered unlikely in ALS. The striatum receives massive glutamatergic input and the pathogenesis of ALS may be related to increased glutamatergic excitotoxicity. As other mechanisms (cell loss, receptor occupancy) could be ruled out, and as animal studies suggest that (excess of) glutamate decreases striatal D2-receptor synthesis, the striatal D2-receptor deficit in ALS is most likely to be caused by a receptor down-regulation.
Vogels
O J
OJ
Department of Neurology, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. o.vogels@czzoneu.azn.nl
Veltman
J
J
Oyen
W J
WJ
Horstink
M W
MW
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001549:Benzamides / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D018492:Dopamine Antagonists / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D018476:Hypokinesia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D007457:Iodine Radioisotopes; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018908:Muscle Weakness / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011759:Pyrrolidines / Q000494:pharmacology; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*
D001549:Benzamides; D018492:Dopamine Antagonists; D007457:Iodine Radioisotopes; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; C055743:3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide