Eltoprazine attenuates L-DOPA induced dyskinesia along with GABA and Glutamate release in rat substantia nigra

Background. Preclinical and clinical evidence that the serotonergic system plays a major role in levodopa-induced dyskinesias has been provided. 5-HT1A and 5-HT1B receptor agonists proved effective in inhibiting dyskinesia in rodents and nonhuman primates, and, more recently, the mixed 5-HT1A and 5-HT1B receptor agonist eltoprazine was proposed as a novel antidyskinetic drug. Here we investigate the mechanisms through which eltoprazine inhibits levodopa-induced dyskinesia. Methods. 6-hydroxydopamine hemilesioned rats chronically treated with levodopa alone or in combination with eltoprazine were implanted with one microdialysis probe in the dopamine-depleted striatum and another in ipsilateral substantia nigra pars reticulata. GABA and glutamate levels were monitored ON levodopa, simultaneously with dyskinesia scoring. Western blot was used to quantify striatal levels of phosphorylated extracellular signal regulated kinase 1 and 2 (pERK 1/2) ex-vivo. Striatal and nigral glutamate and GABA as well as striatal dopamine were also monitored in dyskinetic rats acutely challenged with levodopa and eltoprazine. Results. Eltoprazine attenuated the occurrence of dyskinesia in rats either chronically or acutely treated with levodopa, preserving motor coordination on the rotarod. Eltoprazine also prevented the rise of nigral and striatal amino acid levels, and striatal pERK 1/2 which are fingerprints of dyskinesias. However, eltoprazine did not affect the levodopa-induced increase in striatal dopamine. Conclusions. Eltoprazine attenuates the priming to levodopa which underlies the development of dyskinesia, likely through the inhibition of the striato-nigral medium-sized spiny neurons (the so-called direct pathway). Since eltoprazine did not inhibit striatal ectopic dopamine release which accompanies dyskinesia appearance, its action is likely mediated via 5-HT1A and 5-HT1B heteroreceptors.