Eltoprazine prevents levodopa-induced dyskinesias by reducing striatal glutamate and direct pathway activity

Background. Preclinical and clinical evidence that the serotonergic system plays a major role in levodopa-induced dyskinesias has been provided. Selective serotonin (5-hydroxytryptamine, 5-HT) 5-HT1A or 5-HT1B receptor agonists, and, very recently, the mixed 5-HT1A/5-HT1B receptor agonist eltoprazine, proved effective in inhibiting levodopa-induced dyskinesias in experimental animals and parkinsonian patients. Here we investigate the mechanisms underlying this effect. Methods. Microdialysis was employed in 6-hydroxydopamine hemilesioned rats chronically treated with levodopa alone or in combination with eltoprazine. Gamma-aminobutyric acid (GABA) and glutamate levels were monitored ON levodopa in the dopamine-depleted striatum and ipsilateral substantia nigra reticulata. Motor activity on the rotarod was assessed, both OFF and ON levodopa. Western blot was used to quantify ex-vivo striatal levels of phosphorylated extracellular signal regulated kinase 1 and 2. Striatal and nigral amino acid levels, as well as striatal dopamine levels were also monitored in levodopa-primed dyskinetic rats acutely challenged with levodopa and eltoprazine. Results. Eltoprazine attenuated the development and expression of dyskinesias, preserving motor coordination on the rotarod. Eltoprazine prevented the rise of nigral amino acids and striatal glutamate levels, as well as the increase in striatal phosphorylated extracellular signal regulated kinase 1 and 2, associated with dyskinesias. However, eltoprazine did not affect the levodopa-induced increase in striatal dopamine. Conclusions. Eltoprazine inhibits the sensitization of striato-nigral medium-sized gamma-aminobutyric acid spiny neurons (the direct pathway) to levodopa and their overactivation associated with dyskinesias appearance. Activation of 5-HT1A and 5-HT1B receptors regulating striatal glutamate transmission but not striatal ectopic dopamine release might underlie the symptomatic effect of eltoprazine.