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Local administration of sarizotan into the subthalamic nucleus attenuates levodopa-induced dyskinesias in 6-OHDA-lesioned rats

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Abstract

Rationale

Dyskinesia affects the majority of levodopa-treated parkinsonian patients within 5–10 years of treatment with levodopa. Clinical and preclinical observations suggest that an increase in serotoninergic transmission can contribute to the appearance of dyskinesias. It is thus conceivable that a modulation of synaptic dopamine (DA) levels induced by the inhibition of serotonin (5-HT) release, as a consequence of 5-HT1A agonists administration, might alleviate dyskinesias.

Objective

Since 5-HT1A receptors are expressed in the subthalamic nucleus (STN), the aim of the present study was to assess the effect of the intrasubthalamic administration of sarizotan, a compound with full 5-HT1A agonist properties, on levodopa-induced dyskinesias in the 6-hydroxydopamine (6-OHDA) model of parkinsonism.

Materials and methods

Male Sprague–Dawley rats received a unilateral 6-OHDA administration in the nigrostriatal pathway. A test of apomorphine was performed to evaluate dopamine depletion. One week later, a cannula was implanted in the STN. Animals were treated with levodopa (6 mg/kg, i.p., twice at day) for 22 consecutive days. On day 23, several doses (1 ng, 10 ng, or 1 μg) of sarizotan were administered through the cannula to the STN. The higher doses of sarizotan effectively attenuated all levodopa-induced dyskinesias including axial, limb, and orolingual subtypes.

Conclusions

These results suggest that the STN is a target structure for the antidyskinetic action of sarizotan and indicate that drug-mediated modulation of STN activity may be an alternative option for the treatment of levodopa-induced dyskinesias in Parkinson’s disease.

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Acknowledgments

This research was supported by an unrestricted grant from Merck KGaA (Darmstadt, Germany). Esther Aguilar is partially financed by the program: Ayudas para Contratos de Apoyo a la Investigación en el Sistema Nacional de Salud from the Ministerio de Sanidad y Consumo of the Spanish Government.

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Authors and Affiliations

  1. Laboratori de Neurologia Experimental, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    C. Marin & E. Aguilar

  2. Department of Neurology and Neurosurgery, Neuroscience Center, Clínica Universitaria and Medical School, University of Navarra and CIMA, Pamplona, Spain

    M. C. Rodríguez-Oroz & J. A. Obeso

  3. Centro de Investigación en Redes sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    C. Marin, M. C. Rodríguez-Oroz & J. A. Obeso

  4. Preclinical Research, Merck Serono, Darmstadt, Germany

    G. D. Bartoszyk

  5. Laboratori de Neurologia, Servei de Neurologia, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain

    C. Marin

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  1. C. Marin
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  2. E. Aguilar
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Correspondence to C. Marin.

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Marin, C., Aguilar, E., Rodríguez-Oroz, M.C. et al. Local administration of sarizotan into the subthalamic nucleus attenuates levodopa-induced dyskinesias in 6-OHDA-lesioned rats. Psychopharmacology 204, 241–250 (2009). https://doi.org/10.1007/s00213-008-1452-9

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