Parkinson's disease, which results from degeneration of dopaminergic neurons projecting to the striatum, is treated with the dopamine precursor L-dihydroxyphenylalanine (L-DOPA). Although this treatment initially alleviates many of the motor symptoms, 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 administered therapeutic doses of L-DOPA. About half the rats recovered from the motor deficits produced by the lesion; the rest developed dyskinetic effects, meaning their motor performance actually worsened. Striatal long-term potentiation (LTP) was not seen in lesioned rats, but was rescued by chronic L-DOPA administration in both dyskinetic and nondyskinetic rats. Low-frequency stimulation reversed striatal LTP (“depotentiation”) in nondyskinetic rats but not in dyskinetic rats. Pharmacological analysis indicated that depotentiation could be blocked by stimulation of the D1 dopamine receptor. Thus, the development of L-DOPA-dependent dyskinesias appears to reflect an abnormal persistence of striatal LTP.—EA
Nature Neurosci. 6, 501 (2003).