What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?

Abstract

Levodopa is the most effective medication for motor symptoms in Parkinson's disease. However, various motor and non-motor complications are associated with levodopa treatment, resulting from altered levodopa-dopamine metabolism with disease progression and long-term use of the drug. The present review emphasizes the role of monoamine transporters other than the dopamine transporter in uptake of extracellular dopamine in the dopamine-denervated striatum. When dopaminergic neurons are lost and dopamine transporters decreased, serotonin and norepinephrine transporters compensate by increasing uptake of excessive extracellular dopamine in the striatum. Organic cation transporter-3 and plasma membrane monoamine transporter, low affinity, and high capacity transporters, also potentially uptake dopamine when high-affinity transporters do not work normally. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are often administered to patients with Parkinson's disease presenting with depression, pain or other non-motor symptoms. Thus, it is important to address the potential of these drugs to modify dopamine metabolism and uptake through blockade of the compensatory function of these transporters, which could lead to changes in motor symptoms of Parkinson's disease.

Keywords: Parkinson's disease; dopamine; levodopa; norepinephrine; serotonin; striatum; transporter.

Figure 1

Schematic diagram showing metabolism and uptake of levodopa-derived dopamine. Levodopa therapy is usually combined with a dopa-decarboxylase inhibitor (carbidopa or benserazide) in order to minimize peripheral conversion of levodopa. 3-MT, 3-methoxytyramine; 3-OMD, 3-O-methyldopa; AADC, aromatic amino acid decarboxylase; ALD.DH, aldehyde dehydrogenase; BBB, blood–brain barrier; COMT, catechol-O-methyltransferase; DAT, dopamine transporter; DCI, dopa-decarboxylase inhibitor; DOPAC, dihydroxyphenylacetic acid; HVA, homovanillic acid; MAO, monoamine oxidase; NET, norepinephrine transporter, noradrenaline transporter; OCT-3, organic cation transporter-3; PMAT, plasma membrane monoamine transporter; SERT, serotonin transporter.

Figure 2

Model illustrating the processes of levodopa-dopamine metabolism and uptake. (A) Normal striatum (B) Dopamine-denervated striatum. Note that MAO-A localization is unclear. A study suggests MAO-A is mainly expressed in medium spiny neurons, rather than in axon terminals in the striatum. Serotonergic neurons express MAO-B in their cell bodies, however, it is still unclear whether the neurons express MAO in axon terminals. OCT-3 also exists in neurons, however the specific subtype is unknown. PMAT is illustrated at the astrocyte membrane according to one recent study (see text), although its localization is not certain yet. 3-MT, 3-methoxytyramine; 3-OMD, 3-O-methyldopa; AADC, aromatic amino acid decarboxylase; ALD.DH, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; D2R, dopamine D2 receptor; DA, dopamine; DAT, dopamine transporter; DCI, dopa-decarboxylase inhibitor; DOPAC, dihydroxyphenylacetic acid; DOPALD, dihydroxyphenylacetaldehyde; DR, dopamine receptor; HVA, homovanillic acid; MAO, monoamine oxidase; NET, norepinephrine transporter, noradrenaline transporter; OCT, organic cation transporter; PMAT, plasma membrane monoamine transporter; SERT, serotonin transporter; VMAT-2, vesicular monoamine transporter-2.