Brain Advance Access published online on October 24, 2008
Brain, doi:10.1093/brain/awn235
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia
1Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, 2Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, 3Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, 4Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and 5University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France
Correspondence to:
Manolo Carta, Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, 22184 Lund, Sweden and Erwan Bezard, University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France E-mail: Manolo.Carta{at}med.lu.se and erwan.bezard{at}u-bordeaux2.fr
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.
Key Words: L-DOPA; Dyskinesia; Parkinson's disease; Serotonin agonists; MPTP monkeys
Abbreviations: AIMs, abnormal involuntary movements; AUC, area under the curve; DA, dopamine; MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine; 6-OHDA, 6-hydroxydopamine; PSD, post-synaptic density; s.c., subcutaneous; TIF = Triton X-100-insoluble fraction
.
Received May 16, 2008. Revised August 22, 2008. Accepted August 29, 2008.
*These authors contributed equally to this work.