24-07-08(18:04:38)
Authors:
*M. CARTA1, A. MUÑOZ1, Q. LI2, F. GARDONI3, E. MARCELLO3, T. CARLSSON1, C. QIN2, D. KIRIK1, M. DI LUCA3, A. BJÖRKLUND1, E. BEZARD4
Institutions:
1Wallenberg Neuroscience Center, Lund, Sweden; 2China Academy of Medical Science, Beijing, China; 3University of Milano, Milano, Italy; 4University Victor Segalen Bordeaux, Bordeaux, France
Title of abstract : Serotonin autoreceptor agonists for the treatment of L-DOPA-induced dyskinesia: towards clinical investigation
Abstract text:
An increasing body of evidence points to the serotonin system as a key element in the emergence of L-DOPA-induced dyskinesia. Indeed, it is well known that the serotonin neurons can convert L-DOPA to dopamine, as well as store and release dopamine in an activity-dependent manner. In support of this hypothesis, we have recently demonstrated that toxic lesion or pharmacological blockade of the serotonin neurons activity abolishes L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. In the present study, we have investigated the efficacy of 5-HT1A and 5-HT1B agonists to counteract L-DOPA-induced dyskinesia in 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 altering the antiparkinsonian efficacy of L-DOPA. Moreover, combination of low doses of the agonists was able to prevent development of dyskinesia, and reduced the upregulation of FosB after chronic treatment with L-DOPA in parkinsonian rats. These findings and the demonstration of a synergistic effect between 5-HT1A and 5-HT1B receptor agonists in primates may have interesting clinical implication for the treatment of L-DOPA-induced dyskinesia in PD patients, where targeting of the 5-HT1A alone has not produced the expected results.
