Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia.
Brain. 2008-10-24; 131(12): 3380-3394
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1. Brain. 2008 Dec;131(Pt 12):3380-94. doi: 10.1093/brain/awn235. Epub 2008 Oct 24.
Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced
Muñoz A(1), Li Q, Gardoni F, Marcello E, Qin C, Carlsson T, Kirik D, Di Luca M,
Björklund A, Bezard E, Carta M.
(1)Department of Experimental Medical Science, Neurobiology Unit, Wallenberg
Neuroscience Center, University of Lund, Lund, Sweden.
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-HT(1A) and 5-HT(1B) agonists could reduce l-DOPA-induced
dyskinesia. In the present study, we have investigated the efficacy of 5-HT(1A)
and 5-HT(1B) 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-HT(1A) and 5-HT(1B) 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-HT(1) 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-HT(1A) and 5-HT(1B)
agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson’s
PMID: 18952677 [Indexed for MEDLINE]