A Movement Disorder That's Hard to Forget

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Science's STKE  06 May 2003:
Vol. 2003, Issue 181, pp. tw174-TW174
DOI: 10.1126/stke.2003.181.tw174

Picconi et al. investigated the development of L-dihydroxyphenylalanine (L-DOPA)-dependent dyskinesias and obtained evidence supporting the hypothesis that these abnormal involuntary movements represent an aberrant form of motor learning. Parkinson's disease (PD), which results from degeneration of dopaminergic neurons projecting to the striatum, is most effectively treated with the dopamine precursor L-DOPA. Although L-DOPA initially alleviates many of the motor symptoms of PD, prolonged therapy leads to serious side effects, including dyskinesias. Picconi et al. used 6-hydroxydopamine to lesion dopaminergic neurons in a rat model of Parkinson's disease and evaluated the motor effects of therapeutic doses of L-DOPA. After therapy with L-DOPA, about half the rats recovered from the motor deficits produced by the lesion; the rest developed dyskinetic effects so that their motor performance actually worsened. Striatal long-term potentiation (LTP) after high-frequency stimulation of glutamatergic synapses, which depends on dopaminergic input, was not apparent in brain slices from lesioned rats, but was rescued by long-term treatment with L-DOPA in both rats with and without dyskinesia. In rats treated with L-DOPA, low-frequency stimulation reversed striatal LTP ("depotentiation") in rats without dyskinesia but not those with dyskinesia. Pharmacological analysis indicated that depotentiation depended on phosphatase activation and could be blocked by stimulation of the D1 dopamine receptor. Moreover, rats with dyskinesia showed elevated phosphorylation of striatal DARPP-32 (dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kD), which inhibits protein phosphatase 1. Thus the development of L-DOPA-dependent dyskinesias appears to reflect abnormal persistence of striatal LTP mediated through activation of D1 pathways. Abnormal movements that had been "learned" could not be unlearned. Dunnett discusses the implications of this research.

B. Picconi, D. Centonze, K. Håkansson, G. Bernardi, P. Greengard, G. Fisone, M. A. Cenci, P. Calabresi, Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat. Neurosci. 6, 501-506 (2003). [Online Journal]

S. Dunnett, L-DOPA, dyskinesia and striatal plasticity. Nat. Neurosci. 6, 437-438 (2003). [Online Journal]

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