Levodopa-induced dyskinesia: a pathological form of striatal synaptic plasticity?
The pathogenesis of the alterations in motor response that complicate levodopa therapy of Parkinson's disease remains obscure. Several experimental and clinical observations strongly suggest that changes in striatal activity may be crucial for this physiopathological condition. Accordingly, it has been postulated that dyskinesia might be due to abnormal activity of the corticostriatal 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-methyl-D-aspartate (NMDA) glutamate receptors in the control of the short- and long-term efficacy of corticostriatal transmission. Indeed, repetitive cortical activation can generate either long-term depression or long-term potentiation (LTP) at corticostriatal synapses depending on the subtype of glutamate receptor activated during the induction phase of these forms of synaptic plasticity. Dopamine plays an important function in the regulation of both forms of synaptic plasticity. Dopamine denervation abolishes the physiological corticostriatal plasticity by producing biochemical and morphological changes within the striatum. We have recently observed a 'pathological' form of LTP at the corticostriatal synapse during energy deprivation. We speculate that this 'pathological' LTP, depending on the activation of NMDA glutamate receptors located on spiny striatal neurons, might play a role in the generation of levodopa-induced dyskinesia.
Calabresi
P
P
Clinica Neurologica, Dipartamento Neuroscienze, Università di Roma Tor Vergata, Rome, Italy.
Giacomini
P
P
Centonze
D
D
Bernardi
G
G
D015259:Dopamine Agents / Q000009:adverse effects*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D009473:Neuronal Plasticity / Q000187:drug effects*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology
D015259:Dopamine Agents; D007980:Levodopa