Levodopa-induced dyskinesias in patients with Parkinson's disease: filling the bench-to-bedside gap

Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates

“…Thus the concomitant reversal of pausing changes in those neurons could be interpreted as pausing participating in the mechanisms of dyskinesias. The release of involuntary movements has been attributed to imbalance of the striatal outputs, as occurring between the direct and indirect pathways (Calabresi et al 2010;Jenner 2008; or among single MSN discharges (Boldry et al 1995;Liang et al 2008). Pauses increased with levodopa influx in the on state, suggesting that pausing may be a constitutive MSN activity pattern in normal motor behavior, but its reversal to the reduced pausing rate of the off state in some MSNs (precisely the same neurons that do not maintain the DA-induced frequency changes) could create an imbalance of discharges and contribute to the expression of dyskinesias.…”

GαolfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

“…Hypersensitivity of the D 1 R/G␣ olf /cAMP pathway is not responsible for dyskinetic behavior but has a permissive role A variety of dysregulations take place in DA-denervated striatum and are likely to concur to the occurrence of LID (Cenci, 2007;Jenner, 2008;Santini et al, 2008;Calabresi et al, 2010;Feyder et al, 2011;Gerfen and Surmeier, 2011;Murer and Moratalla, 2011). From a therapeutic standpoint, it is important to dissect the mechanisms of induction and expression of LID, which can be targets for potential preventive or symptomatic treatments.…”

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

“…L-DOPA-induced dyskinesia (LID) is a debilitating and treatment-limiting condition, affecting up to 80% of PD patients within 10 years (15). A better understanding of the neural mechanisms that form the basis of LID is essential for designing effective therapeutic strategies (16,17).…”