J. Neurochem. (2010) 112, 1465–1476.

l‐DOPA‐induced dyskinesia in Parkinson’s disease is associated with large increases in brain dopamine (DA) levels following drug dosing, but the precise significance of this phenomenon is not understood. Here we compare DA efflux and metabolism in the striatum and the substantia nigra in dyskinetic and non‐dyskinetic animals following a standard dose of l‐DOPA. Rats with 6‐hydroxydopamine lesions were treated chronically with l‐DOPA, monitored on the abnormal involuntary movements scale, and then subjected to intracerebral microdialysis under freely‐moving conditions. Following s.c. l‐DOPA injection, peak extracellular DA levels in both striatum and substantia nigra were about twice as large in dyskinetic animals compared to non‐dyskinetic rats. This effect was not attributable to differences in DOPA levels or DA metabolism. The larger DA efflux in dyskinetic animals was blunted by 5‐HT1A/5‐HT1B receptor agonists and tetrodotoxin infusion, reflecting release from serotonin neurons. Striatal levels of serotonin and its main metabolite, 5‐hydroxyindolacetic acid were indeed elevated in dyskinetic animals compared to non‐dyskinetic rats, indicating a larger serotonergic innervation density in the former group. High DA release was, however, not sufficient to explain dyskinesia. The ‘abnormal involuntary movements output’ per unit concentration of striatal extracellular DA was indeed much larger in dyskinetic animals compared to non‐dyskinetic cases at most time points examined. The present results indicate that both a high DA release post‐l‐DOPA administration and an increased responsiveness to DA must coexist for a full expression of dyskinesia.