Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia.
Long-term treatment with the dopamine precursor levodopa (L-DOPA) induces dyskinesia in Parkinson's disease (PD) patients. We divided hemiparkinsonian rats treated chronically with L-DOPA into two groups: one showed motor improvement without dyskinesia, and the other developed debilitating dyskinesias in response to the treatment. We then compared the plasticity of corticostriatal synapses between the two groups. High-frequency stimulation of cortical afferents induced long-term potentiation (LTP) of corticostriatal synapses in both groups of animals. Control and non-dyskinetic rats showed synaptic depotentiation in response to subsequent low-frequency synaptic stimulation, but dyskinetic rats did not. The depotentiation seen in both L-DOPA-treated non-dyskinetic rats and intact controls was prevented by activation of the D1 subclass of dopamine receptors or inhibition of protein phosphatases. The striata of dyskinetic rats contained abnormally high levels of phospho[Thr34]-DARPP-32, an inhibitor of protein phosphatase 1. These results indicate that abnormal information storage in corticostriatal synapses is linked with the development of L-DOPA-induced dyskinesia.
Picconi
Barbara
B
Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Centonze
Diego
D
Håkansson
Kerstin
K
Bernardi
Giorgio
G
Greengard
Paul
P
Fisone
Gilberto
G
Cenci
M Angela
MA
Calabresi
Paolo
P
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D009419:Nerve Tissue Proteins; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D007980:Levodopa