5-HT2A receptor levels increase in MPTP-lesioned macaques treated chronically with L-DOPA.
Long-term L-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease (PD) is associated with motor complications such as dyskinesia. There are clear functional interactions between dopaminergic and serotonergic type 2A receptors (5-HT(2A))-mediated neurotransmission. Moreover, 5-HT(2A) receptor antagonists can reduce L-DOPA-induced dyskinesia (LID). We hypothesized that enhanced 5-HT(2A)-mediated neurotransmission may be involved in the genesis of L-DOPA-induced dyskinesia. Radioligand binding autoradiography, using [(3)H]-ketanserin, was performed to define 5-HT(2A) receptor levels in brain tissue from macaques: 6 normal; 5 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, parkinsonian macaques, without exposure to L-DOPA; 6 MPTP-lesioned, parkinsonian macaques, receiving a single administration of L-DOPA, and exhibiting no dyskinesia; and 6 MPTP-lesioned, parkinsonian, macaques chronically treated with L-DOPA, and exhibiting dyskinesia. 5-HT(2A) receptor binding was increased in the caudate, putamen, and middle layers of the motor cortex in chronically L-DOPA-treated animals, by 50%, 50%, and 45% respectively, compared with normal macaques. 5-HT(2A) binding was not significantly altered in parkinsonian, untreated, or parkinsonian, single treatment, nondyskinetic macaques, compared with normal. These data provide an anatomical basis for mechanisms to explain the efficacy of 5-HT(2A) antagonists against dyskinesia.
Huot
Philippe
P
Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
Johnston
Tom H
TH
Winkelmolen
Lieke
L
Fox
Susan H
SH
Brotchie
Jonathan M
JM
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology; D005260:Female; D007980:Levodopa / Q000008:administration & dosage* / Q000009:adverse effects* / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism*; D008252:Macaca fascicularis; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism* / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000627:therapeutic use; D009435:Synaptic Transmission
D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D007980:Levodopa