Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

Abstract

The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson's disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients.

The missing, the short, and the long: Levodopa responses and dopamine actions

“…A large literature demonstrates that normal modulation of corticostriate synaptic plasticity requires dopamine receptor activation (see reviews by Calabresi and colleagues). 55,56 This is true for both long term potentiation (LTP) and long term depression (LTD), including the spike timing dependent plasticity (STDP) thought to be critical for fine modulation of synaptic strength. 57,58,59 60,61,62 .…”

Maladaptive Synaptic Plasticity in L-DOPA-Induced Dyskinesia

“…The dMSNs had abnormally persistent cortically-evoked LTD, whereas the iMSNs exhibited LTP, rather than LTD, in response to the same stimulation (Belujon et al, 2010). Such findings suggest that LID might be caused by cell type-specific altered induction of plasticity in striatal MSNs (Calabresi et al, 2015). In a dyskinetic state, the direct pathway exhibits only LTP, while the indirect pathway exhibits only LTD. By contrast, in a parkinsonian state, the indirect pathway exhibits only LTP and the direct pathway exhibits only LTD.…”

Release of chemical transmitters from cell bodies and dendrites of nerve cells

“…In Parkinson's disease, the loss of dopaminergic neurons of the substantia nigra compacta causes the development of distinctive a-synuclein (a-syn) inclusions in nigrostriatal projections, in addition to decreasing the concentration of dopamine in the striatum [41]. The a-syn inclusions can serve as a pathological measure of the severity of the disease.…”