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Role of dopamine D3 and serotonin 5-HT1A receptors in l-DOPA-induced dyskinesias and effects of sarizotan in the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease

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Abstract

Sarizotan, a 5-HT1A agonist with additional affinity for D3 and D4 receptors, has been demonstrated to have anti-dyskinetic effects. The mechanism by which these effects occur is not clear. Using unilateral 6-hydroxydopamine-lesioned rats that received chronic intraperitoneal (ip) administration of l-3,4-dihydroxyphenylalanine (l-DOPA) we investigated the involvement of D3 and 5-HT1A receptors in the effects of sarizotan on contraversive circling and abnormal involuntary movements (AIMs). Before sensitization by chronic l-DOPA treatment (12.5 with 3.25 mg/kg benserazide ip, twice daily for 21 days), no effect of the selective D3 agonist, PD128907 (1 or 3 mg/kg ip), or the selective D3 antagonist, GR103691 (0.5 or 1.5 mg/kg ip), was observed. Treatment with sarizotan (1 or 5 mg/kg ip) dose-dependently inhibited the l-DOPA-induced contraversive turning and AIMs. In co-treatment with the 5-HT1A antagonist, WAY100635 (1 mg/kg ip), sarizotan failed to affect this behaviour, confirming the prominent 5-HT1A receptor-mediated mechanism of action. In the presence of PD128907 (3 mg/kg ip), the effects of sarizotan on contraversive turning, locomotive dyskinesia and axial dystonia, but not on orolingual and forelimb dyskinesia, were blocked. On its own, PD128907 had no effect on the behavioural effects of l-DOPA except that it tended to reduce orolingual and forelimb dyskinesia. GR103691 had no effect on its own or in combination with sarizotan. These data identify an involvement of D3 receptors in the action of sarizotan on some, but not all l-DOPA-induced motor side effects. This selective involvement is in contrast to the more general involvement of 5-HT1A receptors in the anti-dyskinetic effects of sarizotan.

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Abbreviations

AIMs:

Abnormal involuntary movements

ip:

Intraperitoneally and introperitoneal, respectively

l-DOPA:

Levodopa, l-3,4-dihydroxyphenylalanine

LID:

l-DOPA-induced dyskinesia

PD:

Parkinson’s disease

5-HT:

Serotonin, 5-hydroxytryptamine

6-OHDA:

6-Hydroxydopamine

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Acknowledgment

This study was funded by Merck KGaA (Darmstadt, Germany) without restriction.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Laboratory for Clinical Neurobiology, University of Würzburg, Füchsleinstrasse 15, 97080, Würzburg, Germany

    Manfred Gerlach

  2. Extended Profiling, Medical Science and Innovation, Merck Serono Research and Development, Frankfurter Strasse 250, 64293, Darmstadt, Germany

    Gerd D. Bartoszyk

  3. Laboratory for Clinical Neurochemistry, Department of Psychiatry, Psychosomatics and Psychotherapy, and National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research, University of Würzburg, Füchsleinstrasse 15, 97080, Würzburg, Germany

    Peter Riederer

  4. Behavioural Neuroscience Laboratory, Mental Health Research Institute, 155 Oak Street, Parkville, VIC, 3052, Australia

    Olivia Dean & Maarten van den Buuse

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  1. Manfred Gerlach
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  2. Gerd D. Bartoszyk
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  3. Peter Riederer
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  4. Olivia Dean
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  5. Maarten van den Buuse
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Correspondence to Manfred Gerlach.

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Gerlach, M., Bartoszyk, G.D., Riederer, P. et al. Role of dopamine D3 and serotonin 5-HT1A receptors in l-DOPA-induced dyskinesias and effects of sarizotan in the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease. J Neural Transm 118, 1733–1742 (2011). https://doi.org/10.1007/s00702-010-0571-8

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  • DOI: https://doi.org/10.1007/s00702-010-0571-8

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