Although large attention has been devoted to striatal synapses and genes, recent studies indicate that L-DOPA-induced plasticity may also affect mechanisms of L-DOPA or DA uptake, conversion, and metabolism in the brain (summarized in Fig. 2). Using the 6-OHDA lesion model of PD, (Meissner et al. 2006) found that the surge in striatal extracellular DA levels elicited by a peripheral dose of L-DOPA is heavily conditioned by a prior course of L-DOPA treatment. After an i.p. injection of L-DOPA, striatal DA levels were increased in both L-DOPA-primed and non-primed animals, but to a much larger level in the former compared to the latter groups. Moreover, the larger increase in extracellular DA levels in dyskinetic rats was not matched by a proportional increase in the production of the DA metabolites, 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Thus, after a challenge injection of L-DOPA, an index of DA turnover (i.e. the ratio, DA metabolites/DA) was significantly elevated in drug-naive animals but not in previously L-DOPA-treated, dyskinetic rats. Taken together, these data strongly indicate that treatment with L-DOPA alters the regulation of DA release (or uptake) and DA metabolism in the striatum. In agreement with Meissner and colleagues, 105>Ahn et al. (2004) found that an i.p. injection of L-DOPA produced a much larger increase in striatal DA levels in 6-OHDA-lesioned rats rendered dyskinetic by a prior course of L-DOPA treatment compared to non-dyskinetic animals. Interestingly, Ahn et al. (2004) could identify one key mechanism for the large DA surge occurring in dyskinetic rats, namely, a reversal of DAT function. Indeed, the L-DOPA-induced increase in extracellular DA was blocked by intrastriatal infusion of a DAT inhibitor (Ahn et al. 2004). In addition to DAT dysfunction, larger increases in extracellular DA postdrug injection may also reflect higher striatal levels of L-DOPA. In our laboratory, we have found that the concentrations of L-DOPA in the brain extracellular fluid are higher in dyskinetic rats compared to non-dyskinetic cases after a peripheral drug dose, although plasma L-DOPA levels do not differ between these two conditions (Carta et al. 2006). In our study, the temporal rise and decline of striatal L-DOPA levels in dyskinetic rats matched closely the time course of the L-DOPA-induced AIMs (Carta et al. 2006). Moreover, when L-DOPA was directly infused in the striatum, even non-dyskinetic rats exhibited AIMs in a concentration-dependent fashion. These data indicate that the amount of L-DOPA present in the striatal extracellular fluid determines the acute expression of dyskinesia and its severity, at least in this rat model. Further studies will be required to assess the generality of these findings, and to determine whether a higher central bioavailability of L-DOPA in dyskinetic animals reflects treatment-related adaptations versus individual features that are pre-existent to treatment (the latter question will have to be addressed with techniques that allow for a longitudinal monitoring of the same animal during chronic L-DOPA treatment). Nevertheless, the above studies collectively provide evidence of presynaptic plasticity in L-DOPA-induced dyskinesia. Intriguingly, these studies also raise the possibility that individual differences in the susceptibility to dyskinesia may reflect a variation in the magnitude and kinetics of central changes in L-DOPA and DA levels following peripheral drug administration. Such an hypothesis is quite compatible with recent PET studies in PD patients, which indicate that rapid fluctuations in central DA levels are at the heart of both motor fluctuations and dyskinesia (de la Fuente-Fernandez et al. 2004a; de la Fuente-Fernandez et al. 2004b). These studies are discussed in detail below.