Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia

• DOI: 10.1093/brain/awn235
• Publication Date: 2008-10-25T00:26:09Z
• Authors: A. Munoz; Q. Li; F. Gardoni; E. Marcello; C. Qin; T. Carlsson; D. Kirik; M. Di Luca; A. Bjorklund; E. Bezard; M. Carta
• Keywords: 0301 basic medicine; 8-Hydroxy-2-(di-n-propylamino)tetralin; Dyskinesia, Drug-Induced; Pyridines; Drug Evaluation, Preclinical; Parkinson Disease; Motor Activity; Serotonin 5-HT1 Receptor Agonists; Receptors, N-Methyl-D-Aspartate; Corpus Striatum; Drug Administration Schedule; 3. Good health; Antiparkinson Agents; Levodopa; Disease Models, Animal; Macaca fascicularis; 03 medical and health sciences; Parkinsonian Disorders; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Drug Therapy, Combination; Female; Proto-Oncogene Proteins c-fos

Appearance of dyskinesia is a common problem long-term l-DOPA treatment in Parkinson's disease patients and represents major limitation for the pharmacological management motor symptoms advanced stages. We have recently demonstrated that dopamine released from serotonin neurons responsible l-DOPA-induced 6-hydroxydopamine (6-OHDA)-lesioned rats, raising possibility blockade neuron activity by combination 5-HT1A 5-HT1B agonists could reduce dyskinesia. In present study, we investigated efficacy to counteract 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, gold standard model disease. addition, studied ability this prevent development 6-OHDA-lesioned rats. The results demonstrate existence potent synergistic effect between their dampen MPTP-treated macaques. Sub-threshold doses drugs, which individually produced no effect, were able abnormal involuntary movements up 80% when administered combination, without affecting anti-parkinsonian properties l-DOPA. Furthermore, chronic administration low 5-HT1 was dyskinesia, up-regulation FosB after daily with rat 6-OHDA model. Our support importance clinical investigation agonists, particularly dyskinetic l-DOPA-treated patients.