Regulation of dopamine neurotransmission from serotonergic neurons by ectopic expression of the dopamine D2 autoreceptor blocks levodopa-induced dyskinesia

Document Type

Article

Abstract

Levodopa-induced dyskinesias (LID) are a prevalent side effect of chronic treatment with levodopa (L-DOPA) for the motor symptoms of Parkinson's disease (PD). It has long been hypothesized that serotonergic neurons of the dorsal raphe nucleus (DRN) are capable of L-DOPA uptake and dysregulated release of dopamine (DA), and that this "false neurotransmission" phenomenon is a main contributor to LID development. Indeed, many preclinical studies have demonstrated LID management with serotonin receptor agonist treatment, but unfortunately, promising preclinical data has not been translated in large-scale clinical trials. Importantly, while there is an abundance of convincing clinical and preclinical evidence supporting a role of maladaptive serotonergic neurotransmission in LID expression, there is no direct evidence that dysregulated DA release from serotonergic neurons impacts LID formation. In this study, we ectopically expressed the DA autoreceptor D2R (or GFP) in the DRN of 6-hydroxydopamine (6-OHDA) lesioned rats. No negative impact on the therapeutic efficacy of L-DOPA was seen with rAAV-D2R therapy. However, D2R treated animals, when subjected to a LID-inducing dose regimen of L-DOPA, remained completely resistant to LID, even at high doses. Moreover, the same subjects remained resistant to LID formation when treated with direct DA receptor agonists, suggesting D2R activity in the DRN blocked dyskinesogenic L-DOPA priming of striatal neurons. In vivo microdialysis confirmed that DA efflux in the striatum was reduced with rAAV-D2R treatment, providing explicit evidence that abnormal DA release from DRN neurons can affect LID. This is the first direct evidence of dopaminergic neurotransmission in DRN neurons and its modulation with rAAV-D2R gene therapy confirms the serotonin hypothesis in LID, demonstrating that regulation of serotonergic neurons achieved with a gene therapy approach offers a novel and potent antidyskinetic therapy.

Keywords

5-HT, AAV, DA, Dopamine, Dorsal raphe, Dyskinesia, Gene therapy, L-DOPA, Serotonin

Medical Subject Headings

Animals; Autoreceptors (genetics, metabolism); Dopamine (metabolism); Dorsal Raphe Nucleus (metabolism); Dyskinesia, Drug-Induced (metabolism, prevention & control); Ectopic Gene Expression; HEK293 Cells; Humans; Levodopa (administration & dosage); Male; Rats, Inbred F344; Receptors, Dopamine D2 (genetics, metabolism); Serotonergic Neurons (metabolism); Synaptic Transmission

Publication Date

1-15-2019

Publication Title

Acta neuropathologica communications

E-ISSN

2051-5960

Volume

7

Issue

1

First Page

8

PubMed ID

30646956

Digital Object Identifier (DOI)

10.1186/s40478-018-0653-7

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