SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease
In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopami...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-08-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2018.00693/full |
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| author | Brian D. Robertson Abdullah S. Al Jaja Abdullah S. Al Jaja Alex A. MacDonald Nole M. Hiebert Nole M. Hiebert Ruzbeh Tamjeedi Ken N. Seergobin Ute I. Schwarz Ute I. Schwarz Richard B. Kim Richard B. Kim Penny A. MacDonald Penny A. MacDonald Penny A. MacDonald Penny A. MacDonald |
| author_facet | Brian D. Robertson Abdullah S. Al Jaja Abdullah S. Al Jaja Alex A. MacDonald Nole M. Hiebert Nole M. Hiebert Ruzbeh Tamjeedi Ken N. Seergobin Ute I. Schwarz Ute I. Schwarz Richard B. Kim Richard B. Kim Penny A. MacDonald Penny A. MacDonald Penny A. MacDonald Penny A. MacDonald |
| author_sort | Brian D. Robertson |
| collection | DOAJ |
| description | In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number 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. Our findings suggest that 9R-carrier PD patients are more 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. |
| first_indexed | 2024-12-11T06:46:02Z |
| format | Article |
| id | doaj.art-314c8fd4b0544ebca4add52439955025 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-11T06:46:02Z |
| publishDate | 2018-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-314c8fd4b0544ebca4add524399550252022-12-22T01:17:04ZengFrontiers Media S.A.Frontiers in Neurology1664-22952018-08-01910.3389/fneur.2018.00693392932SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's DiseaseBrian D. Robertson0Abdullah S. Al Jaja1Abdullah S. Al Jaja2Alex A. MacDonald3Nole M. Hiebert4Nole M. Hiebert5Ruzbeh Tamjeedi6Ken N. Seergobin7Ute I. Schwarz8Ute I. Schwarz9Richard B. Kim10Richard B. Kim11Penny A. MacDonald12Penny A. MacDonald13Penny A. MacDonald14Penny A. MacDonald15Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, CanadaBrain and Mind Institute, University of Western Ontario, London, ON, CanadaDepartment of Neuroscience, University of Western Ontario, London, ON, CanadaDepartment of Medicine, Undergraduate Faculty of Medicine, University of Toronto, Toronto, ON, CanadaBrain and Mind Institute, University of Western Ontario, London, ON, CanadaDepartment of Physiology and Pharmacology, University of Western Ontario, London, ON, CanadaFaculty of Law, University of Ottawa, Ottawa, ON, CanadaBrain and Mind Institute, University of Western Ontario, London, ON, CanadaDepartment of Physiology and Pharmacology, University of Western Ontario, London, ON, CanadaDivision of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, CanadaDepartment of Physiology and Pharmacology, University of Western Ontario, London, ON, CanadaDivision of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, CanadaBrain and Mind Institute, University of Western Ontario, London, ON, CanadaDepartment of Neuroscience, University of Western Ontario, London, ON, CanadaDepartment of Physiology and Pharmacology, University of Western Ontario, London, ON, CanadaDepartment of Clinical Neurological Sciences, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, CanadaIn Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number 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. Our findings suggest that 9R-carrier PD patients are more 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.https://www.frontiersin.org/article/10.3389/fneur.2018.00693/fullParkinson's diseasepolymorphismSLC6A3overdosedopamineencoding |
| spellingShingle | Brian D. Robertson Abdullah S. Al Jaja Abdullah S. Al Jaja Alex A. MacDonald Nole M. Hiebert Nole M. Hiebert Ruzbeh Tamjeedi Ken N. Seergobin Ute I. Schwarz Ute I. Schwarz Richard B. Kim Richard B. Kim Penny A. MacDonald Penny A. MacDonald Penny A. MacDonald Penny A. MacDonald SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease Frontiers in Neurology Parkinson's disease polymorphism SLC6A3 overdose dopamine encoding |
| title | SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease |
| title_full | SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease |
| title_fullStr | SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease |
| title_full_unstemmed | SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease |
| title_short | SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease |
| title_sort | slc6a3 polymorphism predisposes to dopamine overdose in parkinson s disease |
| topic | Parkinson's disease polymorphism SLC6A3 overdose dopamine encoding |
| url | https://www.frontiersin.org/article/10.3389/fneur.2018.00693/full |
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