l‐DOPA‐induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson’s disease: temporal and quantitative relationship to the expression of dyskinesia

Abstract

J. Neurochem. (2010) 112, 1465–1476. Abstract 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.

The serotonin system: a potential target for anti-dyskinetic treatments and biomarker discovery

“…Similar findings have been reported in dyskinetic rats [8]. Blunting the efflux of dopamine, by a 5-HT-specific lesion, dramatically reduces the severity of LID [6].…”

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

“…Removing striatal serotonin (5-HT) afferents, or dampening serotonergic activity with 5-HT receptor type 1A (5-HT 1A ) receptor agonists (including buspirone) or 5-HT receptor type 1B (5-HT 1B ) receptor agonists, attenuated abnormal involuntary movements without increasing parkinsonism (12)(13)(14)(15)(16)(17)(18)(19). However, this mechanism has not been investigated in vivo in PD patients.…”

PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking

“…At the molecular level, the subcellular organization of and functional interactions between glutamate and DA receptors within the striatum are crucial both in the pathogenesis of PD (9) and in the development of LID (10,11). LID has indeed been associated with plastic changes in postsynaptic neuronal targets in the striatum, including elevated extracellular levels of glutamate (12) and DA (13) and abnormal trafficking of DA D1 receptor (D1R) (14,15) and of NMDA and AMPA glutamate receptor subunits (5,10,16,17). Such exaggerated DA and glutamate receptor expression at the plasma membrane results in abnormal activation of key signaling kinases (18)(19)(20)(21)(22).…”