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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.

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Early gene induction by L-DOPA in the striatum of dopamine denervated rats represents a useful way to study long-term modifications produced by this drug. The effects of acute and subchronic L-DOPA administration on zif-268 mRNA expression were compared in 6-hydroxydopamine-lesioned rats. Rats received a subchronic intermittent L-DOPA (6 mg/kg) treatment, which produces behavioural sensitization, a correlate of dyskinetic movements. Three days after interruption of subchronic treatment, zif-268 mRNA was evaluated after an L-DOPA challenge. Zif-268 mRNA levels increased in the lesioned dorsolateral striatum after either acute or subchronic L-DOPA administration. Double labelling of striatal cells with zif-268 and enkephalin or dynorphin mRNA probes was performed to assess neuronal activation in the indirect and direct output pathway. Single acute L-DOPA significantly increased zif-268 in all striatal neurons reflecting a hyperresponsiveness of dopamine-depleted striatum. After subchronic L-DOPA, zif-268 mRNA labelling was still increased in the striatonigral pathway, limited to dynorphin(+) neurons, whereas in all other neurons it was similar to the control value. Results suggest that striatal neurons responding to acute L-DOPA differ from those responding to subchronic L-DOPA. L-DOPA-induced behavioural sensitization was associated to a down-regulation in the responsiveness of striatopallidal and striatonigral dynorphin(-) neurons, whereas in striatonigral neurons containing dynorphin a hyperresponsiveness to L-DOPA was observed. High levels of zif-268, together with a persistent hyperresponsiveness of striatonigral dymorphinergic neurons and hyporesponsiveness of striatopallidal neurons, by creating an unbalanced state of striatal efferent neurons, may be implicated in dyskinetic movements observed in Parkinson's disease (PD).

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