On the Effect of Eltoprazine in Dyskinetic Hemiparkinsonian Rats

5-HT1A/1B receptor agonists have pronunced antidyskinetic effects in animal models of Parkinson’s disease (PD). These effects have been attributed to a blunting of extracellular dopamine levels, which transiently increase after Ldopa administration. Eltoprazine is an interesting 5-HT1A/ 1B candidate drug that exerts striking antidyskinetic effects in both rat and macaque models of L-dopa-induced dyskinesia (LID) and has been recently shown to also improve human LID. An article recently published in Movement Disorders confirmed the striking antidyskinetic effect of eltoprazine in 6-hydroxydopamine (6-OHDA)-lesioned rats. The authors, however, attributed this effect to the blunting of supersensitive signaling in striatonigral neurons as well as a reduction in glutamate and gamma-aminobutyric acid (GABA) release in striatum and substantia nigra. Previous studies have attributed the antidyskinetic effect of eltoprazine to its ability to attenuate L-dopa-induced dopamine release from serotonergic terminals. Accordingly, microdialysis studies in 6-OHDA-lesioned rats have shown that 5-HT1A/ 1B agonist cotreatment markedly attenuates the extracellular dopamine peaks induced by L-dopa administration. However, Paolone et al reported that eltoprazine had no effect on Ldopa-induced dopamine efflux. When looking at their corresponding figure (Fig. 5), we noticed that (a) the L-dopa-induced dopamine increase in the denervated striatum was markedly modest when compared with that reported by other studies, and (b) despite this modest effect, there was a clear trend toward reduction of extracellular dopamine levels by eltoprazine. It is likely that a few more subjects would have turned this trend into a statistically significant effect. However, neither of these points were discussed by the authors. Furthermore, the Discussion section of the article did not mention previous studies that have shown eltoprazine to be ineffective on dyskinesia induced by apomorphine at doses allowing complete LID suppression. These results suggest that the antidyskinetic action of eltoprazine relies on a presynaptic mechanism recruited by L-dopa, but not by direct dopamine receptor agonists. A discussion of these critical points is lacking from the article, and the title instead posits a relationship of causality between the antidyskinetic effect of eltoprazine and the observed reduction in striatonigral signaling and GABA/glutamate levels. It would have been appropriate to verify the effects of the same dose of eltoprazine on dyskinesias induced by apomorphine before claiming this relationship. While congratulating the authors for their extensive work, we are concerned that an inaccurate discussion of the results may create confusion in the field. A number of recent studies support the concept that a reduction of serotonin neurondependent dopamine release is the most plausible mechanism mediating the antidyskinetic effect of 5-HT1A/1B agonists, at least at relatively low doses. Moreover, serotonin neuron silencing by toxin lesion suppresses both LID and L-dopa-induced dopamine efflux in parkinsonian rats. Recent PET imaging studies have shown this mechanism to be relevant also to human LID, which is associated with a large striatal dopamine efflux shortly after L-dopa administration. Buspirone, a partial 5-HT1A receptor agonist, was able to dampen both peak-dose LID and striatal dopamine release in dyskinetic PD patients, suggesting that the presynaptic dysfunctions observed in the rodent models of LID have translational relevance.