SEROTONERGIC NERVE FIBERS IN L-DOPA-DERIVED DOPAMINE RELEASE AND DYSKINESIA

The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl- L-alanine (L-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate L-DOPA into dopamine. Nevertheless, knowledge of L-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in L-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) L-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal L-DOPA-derived dopamine release (similar to 30%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily L-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HTlesion. Moreover, chronic L-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT1A receptors. Taken together, the results indicate a central role for the 5-HT system in L-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential L-DOPA-induced deterioration of 5-HT function might reduce L-DOPA efficacy as well as promote the upcoming of motor side effects. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.