Differential Dopamine Receptor Occupancy Underlies L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson's Disease

Abstract

Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease.

Relationship Between L-DOPA-Induced Reduction in Motor and Exploratory Activity and Striatal Dopamine D2 Receptor Binding in the Rat

“…So far, there are four small animal imaging studies, which assessed striatal D 2 receptor binding after L-DOPA in healthy (Opacka-Juffry et al, 1998 ) or 6-hydoxydopamine(6-OHDA)-lesioned rats (Hume et al, 1995 ; Sossi et al, 2009 ; Sahin et al, 2014 ). In healthy animals, challenge with 20 or 100 mg/kg L-DOPA plus 25 mg/kg carbidopa led to a significant 40% increase of striatal [ 11 C]raclopride binding relative to untreated controls (Opacka-Juffry et al, 1998 ).…”

l-DOPA-induced dyskinesia in Parkinson's disease: Are neuroinflammation and astrocytes key elements?

“…iNOS, inducible nitric oxide synthase; nNOS, neuronal nitric oxide synthase; COX2, cyclooxygenase-2; TH, tyrosine hydroxylase that triggers inflammation. The action L-DOPA treatment enhances neuronal activity in the striatum, evidenced by the increase in the FOS-B expression due to L-DOPA stimulation on D1 receptor(Darmopil, Martín, De Diego, Ares, & Moratalla, 2009;Engeln et al, 2016;Sahin et al, 2014;Solís, Espadas, Del-Bel, & Moratalla, 2015;Solís, Garcia- Montes, Gonz alez-Granillo, Xu, & Moratalla, 2015).The excessive levels of neurotransmitters such as glutamate, which are released in the striatal extracellular fluid, following lesion induces together with dopamine decrease, a proinflammatory environment in the striatum. The chronic neuroinflammation state is also associated with L-DOPA chronic treatment, which could lead to the production of proinflammatory factors such as nitric oxide and superoxide radical, contributing to degeneration of dopaminergic neurons.…”

On the Effect of Eltoprazine in Dyskinetic Hemiparkinsonian Rats

“…When looking at their corresponding figure (Fig. 5), we noticed that (a) the L-dopa-induced dopamine increase in the denervated striatum was markedly modest when compared with that reported by other studies, 3,6,7 and (b) despite this modest effect, there was a clear trend toward reduction of extracellular dopamine levels by eltoprazine. It is likely that a few more subjects would have turned this trend into a statistically significant effect.…”