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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurol. | doi: 10.3389/fneur.2018.00693

SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson`s Disease

 Brian D. Robertson1,  Abdullah Al Jaja2, 3, 4, Alex MacDonald5,  Nole M. Hiebert2, 4, 6*, Ruzbeh Tamjeedi7, Ken N. Seergobin2, 4, Ute Schwarz1 and  Penny A. MacDonald2, 3, 4, 6
  • 1Schulich School of Medicine & Dentistry, Canada
  • 2University of Western Ontario, Canada
  • 3Department of Neuroscience, University of Western Ontario, Canada
  • 4Clinical Neurological Sciences, University of Western Ontario, Canada
  • 5Faculty of Medicine, University of Toronto, Canada
  • 6Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, Canada
  • 7University of Ottawa Faculty of Law, Canada

In Parkinson’s disease (PD), cognitive functions mediated by brain regions innervated by the substantia nigra pars compacta (SNc) improve with dopamine replacement therapy, whereas, functions mediated by regions innervated by the ventral tegmental area (VTA) worsen. We investigated whether these effects are modulated by the presence of a common polymorphism (9R) in SLC6A3, the gene that encodes dopamine transporter (DAT). 9R carriers have higher DAT concentrations and subsequently lower baseline dopamine concentrations than wildtype individuals.
We investigated the effect of SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients both on and off medication. Encoding depends upon brain regions innervated by the VTA, whereas recall depends upon brain regions innervated by the SNc.
We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype.
We found that 9R-carrier PD patients are predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients.

Keywords: Parkinson’s disease, polymorphism, Slc6a3, Overdose, Dopamine, encoding

Received: 02 May 2018; Accepted: 31 Jul 2018.

Edited by:

Antonio Pisani, Università degli Studi di Roma Tor Vergata, Italy

Reviewed by:

Erwan Bezard, UMR5293 Institut des Maladies Neurodégénératives (IMN), France
Salvatore Galati, Neurocenter of Southern Switzerland (NSI), Switzerland  

Copyright: © 2018 Robertson, Al Jaja, MacDonald, Hiebert, Tamjeedi, Seergobin, Schwarz and MacDonald. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mr. Nole M. Hiebert, University of Western Ontario, Clinical Neurological Sciences, London, Canada, nole.hiebert@gmail.com