Levodopa-Induced Dyskinesia: An Updated Review of Pathophysiology and Therapeutic Approaches

Many people using chronic levodopa may have levodopa-induced dyskinesia (LID), which is a challenging complication to manage in the long run for Parkinson's disease (PD). Despite its continued efficacy as a symptomatic treatment for PD, intermittent dopaminergic stimulation with levodopa leads to maladaptive alterations in circuitry in the basal ganglia, which is not normal. Recent research has pointed to aberrant plasticity of corticostriatal synapses as the root cause of LID. This plasticity is defined by an excess of dopamine D1 receptors, aberrations in intracellular signaling pathways like ERK and mTOR, and a collapse of typical bidirectional synaptic modulation (Calabresi et al., 2010; Santini et al., 2007). In addition to dopaminergic mechanisms, non-dopaminergic systems, such as serotonergic and glutamatergic neurotransmission, play a crucial role in the amplification and stabilization of dyskinetic motor patterns (Carta et al., 2008; Chase & Oh, 2000). Pharmacological treatment options for LID include amantadine, while surgical treatment options include deep brain stimulation of the subthalamic nucleus or globus pallidus interna (Pahwa et al., 2017; Follett et al.,) and optimization of levodopa doses to minimize plasma fluctuations (FOLG). New therapies aim to either directly impact dysfunctional signaling pathways or provide continuous dopaminergic stimulation; nonetheless, there is a lack of robust long-term clinical evidence. More research into the molecular and network processes of LID is essential for the development of more effective and preventative treatment methods.