title: Brain 5-HT(2A) receptors in MPTP monkeys and levodopa-induced dyskinesias.
abstract: Levodopa-induced dyskinesias (LIDs) are abnormal involuntary movements induced by the chronic use of levodopa (l-Dopa) limiting the quality of life of Parkinson's disease (PD) patients. We evaluated changes of the serotonin 5-HT(2A) receptors in control monkeys, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in l-Dopa-treated MPTP monkeys, without or with adjunct treatments to inhibit the expression of LID: CI-1041, a selective NR1A/2B subunit antagonist of glutamate N-methyl-d-aspartic acid (NMDA) receptor, or Cabergoline, a long-acting dopamine D(2) receptor agonist. All treatments were administered for 1 month and animals were killed 24 h after the last dose of l-Dopa. Striatal concentrations of serotonin were decreased in all MPTP monkeys investigated, as measured by high-performance liquid chromatography. [(3) H]Ketanserin-specific binding to 5-HT(2A) receptors was measured by autoradiography. l-Dopa treatment that induced dyskinesias increased 5-HT(2A) receptor-specific binding in the caudate nucleus and the anterior cingulate gyrus (AcgG) compared with control monkeys. Moreover, [(3) H]Ketanserin-specific binding was increased in the dorsomedial caudate nucleus in l-Dopa-treated MPTP monkeys compared with saline-treated MPTP monkeys. Nondyskinetic monkeys treated with CI-1041 or Cabergoline showed low 5-HT(2A) -specific binding in the posterior dorsomedial caudate nucleus and the anterior AcgG compared with dyskinetic monkeys. No significant difference in 5-HT(2A) receptor binding was observed in any brain regions examined in saline-treated MPTP monkeys compared with control monkeys. These results confirm the involvement of serotonergic pathways and the glutamate/serotonin interactions in LID. They also support targeting 5-HT(2A) receptors as a potential treatment for LID.
authors.affiliation: Faculty of Pharmacy, Laval University, Quebec City, Canada.
authors.forename: Golnasim
authors.initials: G
authors.lastname: Riahi
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.forename: Martin
authors.initials: M
authors.lastname: Parent
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000077465:Cabergoline; D015259:Dopamine Agents / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D006801:Humans; D007650:Ketanserin / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008251:Macaca; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D001679:Biogenic Amines; D015259:Dopamine Agents; D004873:Ergolines; D044402:Receptor, Serotonin, 5-HT2A; D007980:Levodopa; D007650:Ketanserin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000077465:Cabergoline