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

A. Munoz, Q. Li, F. Gardoni, E. Marcello, C. Qin, T. Carlsson, D. Kirik, M. Di Luca, A. Bjorklund, E. Bezard, M. Carta
Brain. 2008-10-24; 131(12): 3380-3394
DOI: 10.1093/brain/awn235

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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.

Author information:
(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
disease patients.

DOI: 10.1093/brain/awn235
PMID: 18952677 [Indexed for MEDLINE]

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