A 38-year-old patient with Parkinson's disease has been on levodopa/carbidopa for 4 years and now develops wearing-off episodes and dyskinesias. Which mechanism BEST explains levodopa-induced dyskinesias?

• A Dopaminergic neurotoxicity from levodopa metabolites
• B Loss of serotonergic neurons converting levodopa to excess dopamine
• C Pulsatile stimulation of dopamine receptors causing striatal sensitisation ✓
• D Supersensitivity of D2 receptors in the substantia nigra

Explanation

Levodopa-induced dyskinesias arise primarily due to pulsatile (non-physiological) stimulation of striatal dopamine receptors, which leads to abnormal plasticity and sensitisation of direct pathway neurons in the putamen. Continuous dopaminergic stimulation (via continuous duodopa infusion or subcutaneous apomorphine) reduces dyskinesia risk. The mechanism involves altered receptor phosphorylation and ERK signalling in striatal neurons, not direct neurotoxicity from metabolites.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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