Pharmacological modulation of glutamate transmission in a rat model of L-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signalling.

Summary, in English

L-DOPA-induced dyskinesia (LID) in Parkinson's disease has been linked to altered dopamine and glutamate transmission within the basal ganglia. In the present study, we compared compounds targeting specific subtypes of glutamate receptors or calcium channels for their ability to attenuate LID and the associated activation of striatal nuclear signalling and gene expression in the rat. Rats with 6-hydroxydopamine lesions were treated acutely or chronically with L-DOPA in combination with the following selective compounds: antagonists of group I metabotropic glutamate receptors (MTEP for mGluR5, and EMQMCM for mGluR1), agonist of group II mGluR (LY379268), NR2B-selective NMDA receptor antagonists (Ro631908 and Ro256981), and antagonist of L-type calcium channels (isradipine). Dyskinesia and rotarod performance were monitored during chronic drug treatment. The striatal expression of phospho-ERK1/2 and MSK-1, or prodynorphin mRNA were examined following acute or chronic treatment, respectively. In the acute treatment studies, only MTEP and EMQMCM significantly attenuated L-DOPA-induced phospho-ERK 1/2 and/or phospho-MSK-1 expression, MTEP being the most effective (70-80% reduction). In the chronic experiment, only MTEP significantly attenuated dyskinesia without adverse motor effects, whereas EMQMCM and LY379268 inhibited the L-DOPA-induced improvement in rotarod performance. The NR2B antagonist had positive anti-akinetic effects but did not reduce dyskinesia. Only MTEP blocked the upregulation of prodynorphin mRNA induced by L-DOPA. Among the pharmacological treatments here examined, MTEP was most effective in inhibiting LID and the associated molecular alterations. Antagonism of mGluR5 seems to be a promising strategy to reduce dyskinesia in Parkinson's disease.

• Author: Daniella Rylander; Alessandra Recchia; Flora Mela; Andrzej Dekundy; Wojciech Danysz; Angela Cenci Nilsson
• Department/s: Basal Ganglia Pathophysiology
• Publishing year: 2009
• Language: English
• Pages: 227-235
• Publication/Series: Journal of Pharmacology and Experimental Therapeutics
• Volume: 330
• Issue: 1
• Links: http://www.ncbi.nlm.nih.gov/pubmed/19357321?dopt=Abstract; http://dx.doi.org/10.1124/jpet.108.150425
• Document type: Journal article
• Publisher: American Society for Pharmacology and Experimental Therapeutics
• Topic: Neurosciences
• Status: Published
• Research group: Basal Ganglia Pathophysiology
• ISBN/ISSN/Other: ISSN: 1521-0103