Levodopa-induced dyskinesia: A pathological form of striatal synaptic plasticity?

The pathogenesis of the alterations in motor response that complicate levod opa therapy of Parkinson's disease remains obscure. Several experimental an d clinical observations strongly suggest that changes in striatal activity may be crucial for this physiopathological condition. Accordingly, it has b een postulated that dyskinesia might be due to abnormal activity of the cor ticostriatal pathway. Here, we review the physiological and pharmacological mechanisms underlying glutamatergic regulation of striatal neurons by the corticostriatal projection. In particular, we discuss the role of both (RS) -alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-meth yl-D-aspartate (NMDA) glutamate receptors in the control of the short- and long-term efficacy of corticostriatal transmission. Indeed, repetitive cort ical activation can generate either long-term depression or long-term poten tiation (LTP) at corticostriatal synapses depending on the subtype of gluta mate receptor activated during the induction phase of these forms of synapt ic plasticity. Dopamine plays an important function in the regulation of bo th forms of synaptic plasticity. Dopamine denervation abolishes the physiol ogical corticostriatal plasticity by producing biochemical and morphologica l changes within the striatum. We have recently observed a 'pathological' f orm of LTP at the corticostriatal synapse during energy deprivation. We spe culate that this 'pathological' LTP, depending on the activation of NMDA gl utamate receptors located on spiny striatal neurons, might play a role in t he generation of levodopa-induced dyskinesia.