Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Abstract

Treatment of Parkinson disease (PD) with L-3,4-dihydroxyphenylalanine (L-DOPA) dramatically relieves associated motor deficits, but L-DOPA-induced dyskinesias (LID) limit the therapeutic benefit over time. Previous investigations have noted changes in striatal medium spiny neurons, including abnormal activation of extracellular signal-regulated kinase1/2 (ERK). Using two PD models, the traditional 6-hydroxydopamine toxic lesion and a genetic model with nigrostriatal dopaminergic deficits, we found that acute dopamine challenge induces ERK activation in medium spiny neurons in denervated striatum. After repeated L-DOPA treatment, however, ERK activation diminishes in medium spiny neurons and increases in striatal cholinergic interneurons. ERK activation leads to enhanced basal firing rate and stronger excitatory responses to dopamine in striatal cholinergic neurons. Pharmacological blockers of ERK activation inhibit L-DOPA-induced changes in ERK phosphorylation, neuronal excitability, and the behavioral manifestation of LID. In addition, a muscarinic receptor antagonist reduces LID. These data indicate that increased dopamine sensitivity of striatal cholinergic neurons contributes to the expression of LID, which suggests novel therapeutic targets for LID.antagonist D opaminergic drugs are effective treatments for the motor symptoms of Parkinson disease (PD), but long-term therapy is limited by disabling abnormal involuntary movements, referred to as L-DOPA-induced dyskinesias (LID) (1). Thus, understanding the molecular and cellular mechanisms underlying LID will help identify more effective treatments for PD, and may also help elucidate the role of dopamine (DA) signaling in motor control.Several biochemical markers of LID have been studied in striatum using animal models. FosB/δFosB expression show a long-term temporal correlation with LID development in DA denervation PD models (2). The increased FosB expression persists over days or weeks and may contribute to the development of LID, but does not correlate with the L-DOPA-induced episodes of dyskinesia that follow each dose. To mediate expression of LID directly, cell signals should grow stronger with repeated L-DOPA treatment and show temporal correlation with acute dopaminergic stimulation. Acute administration of L-DOPA or dopamine agonists activates ERK1/2 by phosphorylation in striatal neurons of DA-denervated animals (3-7). In animals with unilateral 6-hydroxydopamine (6-OHDA) lesions, coadministration of inhibitors of ERK1/2 phosphorylation during repeated L-DOPA treatments reduce LID development (4,8). Studies on these molecular changes have focused on the predominant cell type in the striatum, medium spiny neurons (MSN). In addition, although the unilateral 6-OHDA lesion has been the standard model for the PD phenotype, and particularly for LID, the abrupt nature of the lesion and extreme depletion of dopaminergic afferents has posed limitations in behavioral and biochemical studies.In this study, we used both a unilateral 6-OHDA lesion model and a g...

Cellular and Behavioral Outcomes of Dorsal Striatonigral Neuron Ablation: New Insights into Striatal Functions

“…This antidyskinetic effect is in agreement with the one obtained after genetic inactivation of DARPP-32 in striatonigral MSNs (Bateup et al, 2010). The shift in ERK activation from MSNs to cholinergic interneurons described after long-term exposure to L-DOPA (7 weeks) suggests that the cholinergic interneurons might also be involved in LID expression (Ding et al, 2011). Here the beneficial effect of striatonigral MSNs ablation on LID was observed as early as 7 days post-L-DOPA treatment (not shown), a time where ERK activation in cholinergic interneurons is not yet turned on (Ding et al, 2011).…”

“…The shift in ERK activation from MSNs to cholinergic interneurons described after long-term exposure to L-DOPA (7 weeks) suggests that the cholinergic interneurons might also be involved in LID expression (Ding et al, 2011). Here the beneficial effect of striatonigral MSNs ablation on LID was observed as early as 7 days post-L-DOPA treatment (not shown), a time where ERK activation in cholinergic interneurons is not yet turned on (Ding et al, 2011). Thus our results support a primary role of striatonigral MSNs in the development of dyskinesia and also suggest that therapeutic strategies based on manipulation of dopamine-dependent signaling in the striatum should target the striatonigral MSNs for an efficient clinical approach to prevent LID.…”

Cholinergic activity and levodopa‐induced dyskinesia: a multitracer molecular imaging study

“…Previous findings in animal models also support direct involvement of the nicotinic cholinergic system. In particular, elevated cholinergic signaling may contribute to motor complications arising from long‐term levodopa therapy in PD 7. Increasing evidence also suggests that nicotine and agonists of the nicotinic acetylcholine receptors (nAChRs) reduce LIDs via nAChRs desensitization 8…”

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

“…Elimination of striatal cholinergic interneurons in the lesioned striatum of hemi-Parkinsonian mice attenuates the development of L-DOPA-induced dyskinesia without affecting the beneficial anti-Parkinsonian action of L-DOPA [100,115]. Cholinergic interneurons in the striatum establish intricate axonal projections that represent a widespread neurotransmission system [116][117][118].…”