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

• Published in: Brain (London, England : 1878) Vol. 131; no. 12; pp. 3380 - 3394
• Main Authors: Muñoz, Ana, Li, Qin, Gardoni, Fabrizio, Marcello, Elena, Qin, Chuan, Carlsson, Thomas, Kirik, Deniz, Di Luca, Monica, Björklund, Anders, Bezard, Erwan, Carta, Manolo
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-12-2008
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 8-Hydroxy-2-(di-n-propylamino)tetralin - administration & dosage; 8-Hydroxy-2-(di-n-propylamino)tetralin - therapeutic use; Animals; Antiparkinson Agents - adverse effects; Antiparkinson Agents - therapeutic use; Clinical Medicine; Corpus Striatum - metabolism; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical - methods; Drug Therapy, Combination; Dyskinesia; Dyskinesia, Drug-Induced - etiology; Dyskinesia, Drug-Induced - prevention & control; Female; Klinisk medicin; L-DOPA; Levodopa - adverse effects; Levodopa - therapeutic use; Macaca; Macaca fascicularis; Medical and Health Sciences; Medicin och hälsovetenskap; monkeys; Motor Activity - drug effects; MPTP; MPTP monkeys; Neurologi; Neurology; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson's disease; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - drug therapy; Proto-Oncogene Proteins c-fos - metabolism; Pyridines - administration & dosage; Pyridines - therapeutic use; Receptors, N-Methyl-D-Aspartate - metabolism; Serotonin 5-HT1 Receptor Agonists; Serotonin agonists; Serotonin Receptor Agonists - administration & dosage; Serotonin Receptor Agonists - therapeutic use; Treatment Outcome; Serotonin agonists; Parkinson's disease; DOPA; MPTP monkeys; Dyskinesia
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awn235

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