Study of the antidyskinetic effect of eltoprazine in animal models of levodopa‐induced dyskinesia

Abstract

The serotonin (5-hydroxytryptamine [5HT]) system has recently emerged as an important player in the appearance of l-3,4-dihydroxyphenylalanine (levodopa [l-dopa])-induced dyskinesia in animal models of Parkinson's disease. In fact, dopamine released as a false transmitter from serotonin neurons appears to contribute to the pulsatile stimulation of dopamine receptors, leading to the appearance of the abnormal involuntary movements. Thus, drugs able to dampen the activity of serotonin neurons hold promise for the treatment of dyskinesia. The authors investigated the ability of the mixed 5-HT 1A/1B receptor agonist eltoprazine to counteract l-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned rats and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. The data demonstrated that eltoprazine is extremely effective in suppressing dyskinesia in experimental models, although this effect was accompanied by a partial worsening of the therapeutic effect of l-dopa. Interestingly, eltoprazine was found to (synergistically) potentiate the antidyskinetic effect of amantadine. The current data indicated that eltoprazine is highly effective in counteracting dyskinesia in preclinical models. However, the partial worsening of the l-dopa effect observed after eltoprazine administration represents a concern; whether this side effect is due to a limitation of the animal models or to an intrinsic property of eltoprazine needs to be addressed in ongoing clinical trials. The data also suggest that the combination of low doses of eltoprazine with amantadine may represent a valid strategy to increase the antidyskinetic effect and reduce the eltoprazine-induced worsening of l-dopa therapeutic effects.

Serotonin-to-dopamine transporter ratios in Parkinson disease

“…12 Similarly, a recent phase I/IIa clinical trial in patients with PD 29 confirmed antidyskinetic effects of the 5-HT1a/5-HT1b partial agonist eltoprazine following the promising results of the same drug in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. 12 Taken together, these studies suggest that the development of LIDs is dependent on compromised dopaminergic function and on aberrant serotonergic function in the striatum.…”

“…5 Serotonergic terminals have been found capable of converting exogenous levodopa into dopamine, store it in synaptic vesicles, and release it in an activity-dependent manner. [6][7][8][9] The above studies propose that serotonergic terminals in the degenerating striatum are responsible for mishandling exogenous levodopa and exacerbating dyskinesia in the animal model [10][11][12] and PD. 13 Accordingly, the presence of dyskinesia could be a reflection of serotonergic over dopaminergic terminals' activity.…”

“…10,12,26,27 In addition, serotonin receptor agonists have been shown to have antidyskinetic effects in both rodent and nonhuman primate models of dyskinesias. 12,28 In humans, a recent clinical and PET imaging study from our group showed that buspirone, a 5-HT1a partial agonist, when administered acutely prior to levodopa in patients with PD with LIDs, is able to normalize levodopa-derived levels of synaptic dopamine and to alleviate dyskinesias.…”

“…10,12,26,27 In addition, serotonin receptor agonists have been shown to have antidyskinetic effects in both rodent and nonhuman primate models of dyskinesias. 12,28 In humans, a recent clinical and PET imaging study from our group showed that buspirone, a 5-HT1a partial agonist, when administered acutely prior to levodopa in patients with PD with LIDs, is able to normalize levodopa-derived levels of synaptic dopamine and to alleviate dyskinesias. 12 Similarly, a recent phase I/IIa clinical trial in patients with PD 29 confirmed antidyskinetic effects of the 5-HT1a/5-HT1b partial agonist eltoprazine following the promising results of the same drug in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques.…”

“…12,28 In humans, a recent clinical and PET imaging study from our group showed that buspirone, a 5-HT1a partial agonist, when administered acutely prior to levodopa in patients with PD with LIDs, is able to normalize levodopa-derived levels of synaptic dopamine and to alleviate dyskinesias. 12 Similarly, a recent phase I/IIa clinical trial in patients with PD 29 confirmed antidyskinetic effects of the 5-HT1a/5-HT1b partial agonist eltoprazine following the promising results of the same drug in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques. 12 Taken together, these studies suggest that the development of LIDs is dependent on compromised dopaminergic function and on aberrant serotonergic function in the striatum.…”