Regulation of cortical and striatal 5-HT1A receptors in the MPTP-lesioned macaque.
Serotonergic 1A (5-HT(1A)) receptor agonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in Parkinson's disease (PD), though the mechanism(s) and site(s) of action remain unclear. We employed [(3)H]-WAY 100,635 autoradiographic receptor binding to measure 5-HT(1A) receptor levels in 4 groups of macaques: normal (vehicle-vehicle); 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, without exposure to L-DOPA, i.e., untreated parkinsonian (MPTP-vehicle); MPTP-lesioned, receiving a single administration of L-DOPA to alleviate parkinsonism (MPTP-L-DOPA-acute); and MPTP-lesioned, chronically treated with L-DOPA, parkinsonism alleviated but exhibiting dyskinesia (MPTP-L-DOPA-chronic). We demonstrate that 5-HT(1A) receptor binding decreases (by 10%-20%, p < 0.05) in the external layers, but increases (by 80%-100%, p < 0.05) in the middle layers, of the premotor and motor cortex of all MPTP-lesioned macaques. In the striosomes of the caudate nucleus, 5-HT(1A) receptor binding increases in MPTP-vehicle macaques (by 50%, p < 0.05), compared with normal macaques. While 5-HT(1A) receptor binding is low in the matrix of the caudate nucleus in normal macaques, it increases (by 200%, p < 0.05) in MPTP-L-DOPA-chronic macaques. These data suggest that 5-HT(1A) receptors are involved in the pathophysiology of both parkinsonism and complications of L-DOPA therapy.
Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
Philippe
P
Huot
Tom H
TH
Johnston
James B
JB
Koprich
Lieke
L
Winkelmolen
Susan H
SH
Fox
Jonathan M
JM
Brotchie
D000818:Animals; D001345:Autoradiography; D002421:Caudate Nucleus / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology; D005260:Female; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects*; D008252:Macaca fascicularis; D009044:Motor Cortex / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism* / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use
D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa