Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications

Abstract

The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson's disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

Keywords: basal ganglia; dystonia; monoamines; movement disorders; neuropharmacology; neuroplasticity; neuropsychiatry; neurovascular unit.

Figure 1

The pattern of motor response to l-DOPA changes during the progression of PD. This drawing illustrates how the therapeutic window of l-DOPA narrows during the progression of PD [based on (172, 173)]. While oral l-DOPA therapy achieves a stable symptomatic control during the first years, it causes motor fluctuations and dyskinesias in more advanced disease stages. Dyskinesias are most commonly associated with high plasma levels of l-DOPA (peak-dose LID), as shown here. The blue sinuous line represents peaks-and-troughs in plasma l-DOPA levels concomitant with oral l-DOPA therapy. The empty area at the centre represents the range of l-DOPA concentrations that induce relief of PD motor features without causing dyskinesia.

Figure 2

l-DOPA-induced dyskinesia depends on both pre- and postsynaptic disturbances of DA transmission that are modulated by non-dopaminergic transmitter systems. The term “presynaptic” refers to all factors that contribute to generating fluctuating levels of l-DOPA and DA in the brain (blue boxes). The term post-synaptic refers to mechanisms that occur at the level of dopaminoceptive cells (yellow boxes). Non-dopaminergic modulatory systems are shown in white boxes. It is not well understood how these systems modulate different levels of the pathophysiological cascade (hence the question marks). DAR, dopamine receptors. Studies supporting this pathophysiological cascade have been reviewed in Ref. (3, 27, 174, 175). An updated review on the presynaptic factors is presented in this article.

Figure 3

The two sides of a dopaminergic synapse. The drawing illustrates components of the nigrostriatal dopaminergic synapse that are discussed in this article. The presynaptic nigrostriatal terminal releases DA (blue circles), and regulates extracellular DA levels through several mechanisms: DA reuptake from the extracellular fluid (via the DAT), DA transport into synaptic vesicles (via VMAT-2), DA synthesis (which is subjected to autoregulatory control via presynaptic D2 receptors), and DA metabolism (via MAO-B and COMT). The post-synaptic neuron responds to DA via two main types of receptors. The D1 receptor is coupled to G_olf and activates c-AMP-dependent intracellular signaling pathways. The D2 receptor is coupled to G_i and inhibits the same pathways. AADC, aromatic L-amino acid decarboxylase; AC, adenylate cyclase; COMT, catechol-O-methyl-transferase; DAT, dopamine transporter; MAO-B, monoamine oxidase B; TH, tyrosine hydroxylase; VMAT-2, vesicular monoamine transporter 2.

Figure 4

A large nigrostriatal DA lesion is necessary but not sufficient for therapeutic l-DOPA doses to induce dyskinesia. Rats sustained unilateral nigrostriatal DA lesions of varying severity, and were then treated with l-DOPA (6 mg/kg/day) for 4 weeks. Diagrams plot the animals cumulative Abnormal Involuntary Movement (AIM) scores (y axis) on presynaptic markers of DA neuron integrity, that is, tyrosine hydroxylase- positive cells in the substantia nigra (SN) or striatal innervation density, estimated with DAT radioligand binding using [³H]-BTCP. Data collected on the side ipsilateral to the lesion are expressed as a percentage of the values on the contralateral (ctrl) intact side. With either measure, AIM scores were found to occur only in animals that had lost more than 80% of presynaptic dopaminergic markers, and maximally severe AIMs occurred only when this loss exceeded 90%. Note however that some of the completely DA-denervated animals did not develop any dyskinesia. The dataset is derived from Ref. (36).

Figure 5

Brain endothelial cells and pericytes produce dopamine following systemic administration of l-DOPA. In the 60s, a group of Swedish pharmacologists led by E. Rosengren discovered that brain endothelial cells and pericytes are a significant site of dopamine production following treatment with l-DOPA. This photomicrograph represents a section of rat cerebellum processed for the Falck–Hillarp catecholamine histofluorescence method to visualize DA-containing cells. The rat had received an injection of l-DOPA (50 mg/kg, combined with the monoamine-B inhibitor nialamide) shortly before being killed. The authors commented, “It was evident that the fluorescent material occurred throughout the capillary walls giving almost a three-dimensional appearance of the capillary tubes. Fluorescence of high intensity (was found) in cytoplasm and nucleus of both endothelial cells and pericytes” [Reproduced with permission from Ref. (51)].