In vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to L-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels.

Abstract

Evidence for an involvement of striatal D1 receptors in levodopa-induced dyskinesia has been presented whereas the contribution of striatal D2 receptors remains controversial. In addition, whether D1 and D2 receptors located in the substantia nigra reticulata shape the response to levodopa remains unknown. We therefore used dual probe microdialysis to unravel the impact of striatal and nigral D1 or D2 receptor blockade on abnormal involuntary movements (AIMs) and striatal output pathways in unilaterally 6-hydroxydopamine lesioned dyskinetic rats. Regional perfusion of D1/D5 (SCH23390) and D2/D3 (raclopride) receptor antagonists was combined with systemic administration of levodopa. Levodopa-induced AIMs coincided with a prolonged surge of GABA and glutamate levels in the substantia nigra reticulata. Intrastriatal SCH23390 attenuated the levodopa-induced AIM scores (~50%) and prevented the accompanying neurochemical response whereas raclopride was ineffective. When perfused in the substantia nigra, both antagonists attenuated AIM expression (~21-40%). However, only intranigral SCH23390 attenuated levodopa-induced nigral GABA efflux, whereas raclopride reduced basal GABA levels without affecting the response to levodopa. In addition, intranigral raclopride elevated amino acid release in the striatum and revealed a (mild) facilitatory effect of levodopa on striatal glutamate. We conclude that both striatal and nigral D1 receptors play an important role in dyskinesia possibly via modulation of the striato-nigral direct pathway. In addition, the stimulation of nigral D2 receptors contributes to dyskinesia while modulating glutamate and GABA efflux both locally and in the striatum.

• Authors: Flora Mela, Matteo Marti, Simone Bido, M Angela Cenci, Michele Morari
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 45 Issue 1 Pg. 573-82 (Jan 2012) ISSN: 1095-953X [Electronic] United States
• PMID: 22001605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Benzazepines
• Dopamine Antagonists
• Receptors, Dopamine D1
• Receptors, Dopamine D2
• SCH 23390
• Glutamic Acid
• Raclopride
• Levodopa
• gamma-Aminobutyric Acid

Topics

• Animals
• Benzazepines (pharmacology)
• Corpus Striatum (drug effects, metabolism)
• Dopamine Antagonists (pharmacology)
• Dyskinesia, Drug-Induced (metabolism)
• Glutamic Acid (metabolism)
• Levodopa (adverse effects)
• Male
• Microdialysis
• Raclopride (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Dopamine D1 (metabolism)
• Receptors, Dopamine D2 (metabolism)
• Substantia Nigra (drug effects, metabolism)
• gamma-Aminobutyric Acid (metabolism)