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-HT2A)-mediated neurotransmission. Moreover, 5-HT2A receptor antagonists can reduce L-DOPA-induced dyskinesia (LID). We hypothesized that enhanced 5-HT2A-mediated neurotransmission may be involved in the genesis of L-DOPA-induced dyskinesia. Radioligand binding autoradiography, using [3H]-ketanserin, was performed to define 5-HT2A 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-HT2A 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-HT2A 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-HT2A antagonists against dyskinesia.