Pre-synaptic Mechanisms in L-dopa-induced Dyski- Nesias: Role of Dopamine/serotonin Interaction

Dyskinesia is a severe side effect of chronic L-DOP administration in Parkinson's disease (PD) patients, which limits the therapeutic benefits of the drug in advanced stage of disease. It has been reported that within 5 years from initiation of the treatment about 50% of the patients develop these motor complications (Obeso et al., 2000). This percentage raises to about 90% after the first decade (Ahlskog and Muenter, 2001). Therefore, dyskinesias affect the quality of life of almost all advanced PD patients. The reason behind the appearance of dyskinesias, after an initial period of optimal therapeutic esponse to L-DOPA (honeymoon period), is still subject of debate. Indeed, it is unclear whether long-term exposure to the drug plays an important role, or whether the delayed appearance of the side effect is only the result of the progression of dopamine (DA) neurodegeneration. We have recently proposed that ad an early stage of disease L-DOPA acts by being taken up into the spared dopaminergic neurons and terminals, where it is converted to DA, stored into synaptic vesicles and released in a physiological-regulated manner (Carta et al., 2007). In this situation, a fine regulation of the level of neurotransmitter in the synaptic cleft is assured by the presence of the D2 autoreceptor and DA transporter. Transmitter re-uptake through the DA transporter provides an effective mechanism for eliminating excess DA from the synaptic cleft, and the D2 autoreceptor is capable of fi-netuning release from DA terminals in response to changes in edtracellular DA levels. The auto-regolatory feedback mechanism of DA release from the spared DA terminals represents, therefore, an important element in providing the terapeutic efficacy of L-DOPA medication at early stages of the disease. To investigate the mechanisms underlying the appearance of dyskinesias, we took advantage the rat model of L-DOPA-induced dyskinesias, where abnormal involuntary movements are produced in hemiparkinsonian rats upon chronic treatment with low L-DOP doses (6 to 12 mg/kg per day), resembling peak-dose dyskinesias seen in PD patients (Cenci et al., 1998). Both pre-and post-synaptic mechanisms have been described to play a role in the side effect of L-DOPA using this model.