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Wei JY, Liu H, Li Y, Zhao D, Wang B, Wang HJ, Wang L, Wang KJ, Yue JL, Zhang HY, Li TY, Miao YJ, Wang KL, Tong PG, Zhang Z, Li ZY, Shi Z, Yao JY, Liu DX, Fang WG, Li B, Shang DS, Lyu Y, Sun HZ, Zhao WD, Chen YH. Melatonin Protects Against Cocaine-Induced Blood-Brain Barrier Dysfunction and Cognitive Impairment by Regulating miR-320a-Dependent GLUT1 Expression. J Pineal Res 2024; 76:e70002. [PMID: 39539049 DOI: 10.1111/jpi.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 10/10/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
Cocaine abuse has been strongly linked to blood-brain barrier (BBB) dysfunction, though the exact mechanism by which cocaine disrupts the BBB remains unclear. In this study, we found that cocaine treatment reduces the expression of glucose transporter 1 (GLUT1) in brain microvascular endothelial cells, a key factor in cocaine-induced brain glucose uptake, BBB leakage, and cognitive impairment. Mechanistically, our results show that cocaine upregulates miR-320a, which in turn suppresses GLUT1 expression via the beta 2-adrenergic receptor (ADRB2). Notably, the administration of adeno-associated viruses encoding full-length GLUT1 or miR-320a inhibitors to the brain microvascular endothelium significantly mitigated cocaine-induced BBB leakage and cognitive deficits. Additionally, we discovered that melatonin, a well-known neuroprotective hormone, alleviates cocaine-induced BBB disruption and cognitive impairment. This protective effect of melatonin was mediated through the upregulation of miR-320a-dependent GLUT1 expression in brain endothelial cells via MT1 receptor-mediated inhibition of the cAMP/PKA/CREB signaling pathway. In conclusion, our findings demonstrate that cocaine downregulates brain microvascular GLUT1, leading to BBB dysfunction, and highlight melatonin as a potential therapeutic agent for treating cocaine-related complications.
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Affiliation(s)
- Jia-Yi Wei
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Hui Liu
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Yuan Li
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Dan Zhao
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Bo Wang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hui-Jie Wang
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Li Wang
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Kang-Ji Wang
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Jin-Li Yue
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Hong-Yan Zhang
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Tian-Yue Li
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Yi-Jue Miao
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Kai-Li Wang
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Pai-Ge Tong
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Zhuo Zhang
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Ze-Ye Li
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Zheng Shi
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Jia-Yuan Yao
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Dong-Xin Liu
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Wen-Gang Fang
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Bo Li
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - De-Shu Shang
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Yuan Lyu
- Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Department of Obstetrics and Gynecology, Research Center of China Medical University Birth Cohort, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hong-Zan Sun
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wei-Dong Zhao
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
| | - Yu-Hua Chen
- Key Laboratory of Cell Biology and Key Laboratory of Medical Cell Biology, Department of Developmental Cell Biology, Ministry of Public Health and Ministry of Education, China Medical University, Shenyang, China
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Rodriguez P, Blakely RD. Sink or swim: Does a worm paralysis phenotype hold clues to neurodegenerative disease? J Cell Physiol 2024; 239:e31125. [PMID: 37795580 DOI: 10.1002/jcp.31125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 09/07/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023]
Abstract
Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease-modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming-induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip-10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease-modifying therapeutics.
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Affiliation(s)
- Peter Rodriguez
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Boca Raton, Florida, USA
| | - Randy D Blakely
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Boca Raton, Florida, USA
- Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, Florida, USA
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Zhang Y, Randesi M, Blendy JA, Kreek MJ, Butelman ER. Impact of OPRM1 (Mu-opioid Receptor Gene) A112G Polymorphism on Dual Oxycodone and Cocaine Self-administration Behavior in a Mouse Model. Neuroscience 2024; 539:76-85. [PMID: 38211933 DOI: 10.1016/j.neuroscience.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 12/28/2023] [Accepted: 01/05/2024] [Indexed: 01/13/2024]
Abstract
The use of mu-opioid receptor (MOP-r) agonists such as oxycodone together with cocaine is prevalent, and deaths attributed to using these combinations have increased. RATIONALE It is unknown if functional single nucleotide polymorphisms (SNPs), such as the OPRM1 (MOP-r gene) SNP A118G, can predispose individuals to more dual opioid and psychostimulant intake. The dual self-administration (SA) of MOP-r agonists and cocaine has not been thoroughly examined, especially with regard to neurobiological changes. OBJECTIVES We examined oxycodone SA and subsequent dual oxycodone and cocaine SA in male and female A112G (A/G and G/G, heterozygote and homozygote, respectively) mice, models of human A118G carriers, versus wild-type (A/A) mice. METHODS Adult male and female A/G, G/G and A/A mice self-administered oxycodone (0.25 mg/kg/infusion, 4hr/session, FR 1.) for 10 consecutive days (sessions 1-10). Mice then self-administered cocaine (2 hr) following oxycodone SA (4 hr, as above) in each session for a further 10 consecutive days (sessions 11-20). Message RNA transcripts of 24 reward-related genes were examined in the dorsal striatum. RESULTS Male and female A/G and G/G mice had greater oxycodone SA than A/A mice did in the initial 10 days and in the last 10 sessions. Further, A/G and G/G mice showed greater cocaine intake than A/A mice. Dorsal striatal mRNA levels of Pdyn, Fkbp5, Oprk1, and Oprm1 were altered following oxycodone and cocaine SA. CONCLUSIONS These studies demonstrated that this functional genetic variation in Oprm1 affected dual opioid and cocaine SA and altered specific gene expression in the striatum.
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Affiliation(s)
- Yong Zhang
- Laboratory of the Biology of Addictive Diseases, the Rockefeller University, New York, NY 10065, United States.
| | - Matthew Randesi
- Laboratory of the Biology of Addictive Diseases, the Rockefeller University, New York, NY 10065, United States
| | - Julie A Blendy
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Mary Jeanne Kreek
- Laboratory of the Biology of Addictive Diseases, the Rockefeller University, New York, NY 10065, United States
| | - Eduardo R Butelman
- Laboratory of the Biology of Addictive Diseases, the Rockefeller University, New York, NY 10065, United States; Neuropsychoimaging of Addictions and Related Conditions Research Program, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
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Bian X, Zhu J, Jia X, Liang W, Yu S, Li Z, Zhang W, Rao Y. Suggestion of creatine as a new neurotransmitter by approaches ranging from chemical analysis and biochemistry to electrophysiology. eLife 2023; 12:RP89317. [PMID: 38126335 PMCID: PMC10735228 DOI: 10.7554/elife.89317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023] Open
Abstract
The discovery of a new neurotransmitter, especially one in the central nervous system, is both important and difficult. We have been searching for new neurotransmitters for 12 y. We detected creatine (Cr) in synaptic vesicles (SVs) at a level lower than glutamate and gamma-aminobutyric acid but higher than acetylcholine and 5-hydroxytryptamine. SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in Slc6a8 and Agat mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP-dependent manner. Our biochemical, chemical, genetic, and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.
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Affiliation(s)
- Xiling Bian
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityBeijingChina
- Chinese Institute for Brain Research (CIBR)BeijingChina
| | - Jiemin Zhu
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityBeijingChina
- Chinese Institute for Brain Research (CIBR)BeijingChina
| | - Xiaobo Jia
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityBeijingChina
- Chinese Institute for Brain Research (CIBR)BeijingChina
| | - Wenjun Liang
- Chinese Institutes of Medical Research, Capital Medical UniversityBeijingChina
- Changping Laboratory, Yard 28, Science Park Road, Changping DistrictBeijingChina
| | - Sihan Yu
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityBeijingChina
- Changping Laboratory, Yard 28, Science Park Road, Changping DistrictBeijingChina
| | - Zhiqiang Li
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityBeijingChina
| | - Wenxia Zhang
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityBeijingChina
- Chinese Institutes of Medical Research, Capital Medical UniversityBeijingChina
- Institute of Molecular Physiology, Shenzhen Bay LaboratoryShenzhenChina
| | - Yi Rao
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking UniversityBeijingChina
- Chinese Institute for Brain Research (CIBR)BeijingChina
- Chinese Institutes of Medical Research, Capital Medical UniversityBeijingChina
- Changping Laboratory, Yard 28, Science Park Road, Changping DistrictBeijingChina
- Institute of Molecular Physiology, Shenzhen Bay LaboratoryShenzhenChina
- Research Unit of Medical Neurobiology, Chinese Academy of Medical SciencesBeijingChina
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Jia X, Zhu J, Bian X, Liu S, Yu S, Liang W, Jiang L, Mao R, Zhang W, Rao Y. Importance of glutamine in synaptic vesicles revealed by functional studies of SLC6A17 and its mutations pathogenic for intellectual disability. eLife 2023; 12:RP86972. [PMID: 37440432 PMCID: PMC10393021 DOI: 10.7554/elife.86972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/15/2023] Open
Abstract
Human mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of SLC6A17 and pathogenesis of SLC6A17-based-ID were both unclear. Here, we report learning deficits in Slc6a17 knockout and point mutant mice. Biochemistry, proteomic, and electron microscopy (EM) support SLC6A17 protein localization in synaptic vesicles (SVs). Chemical analysis of SVs by liquid chromatography coupled to mass spectrometry (LC-MS) revealed glutamine (Gln) in SVs containing SLC6A17. Virally mediated overexpression of SLC6A17 increased Gln in SVs. Either genetic or virally mediated targeting of Slc6a17 reduced Gln in SVs. One ID mutation caused SLC6A17 mislocalization while the other caused defective Gln transport. Multidisciplinary approaches with seven types of genetically modified mice have shown Gln as an endogenous substrate of SLC6A17, uncovered Gln as a new molecule in SVs, established the necessary and sufficient roles of SLC6A17 in Gln transport into SVs, and suggested SV Gln decrease as the key pathogenetic mechanism in human ID.
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Affiliation(s)
- Xiaobo Jia
- Chinese Institute for Brain ResearchBeijingChina
- Changping LaboratoryBeijingChina
- Research Unit of Medical Neurobiology, Chinese Academy of Medical SciencesBeijingChina
| | - Jiemin Zhu
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, School of Chemistry and Chemical Engineering, Peking UniversityBeijingChina
| | - Xiling Bian
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, School of Chemistry and Chemical Engineering, Peking UniversityBeijingChina
| | | | - Sihan Yu
- Chinese Institute for Brain ResearchBeijingChina
| | | | - Lifen Jiang
- Institute of Molecular Physiology, Shenzhen Bay LaboratoryShenzhenChina
| | - Renbo Mao
- Chinese Institute for Brain ResearchBeijingChina
| | - Wenxia Zhang
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, School of Chemistry and Chemical Engineering, Peking UniversityBeijingChina
| | - Yi Rao
- Chinese Institute for Brain ResearchBeijingChina
- Changping LaboratoryBeijingChina
- Research Unit of Medical Neurobiology, Chinese Academy of Medical SciencesBeijingChina
- Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, School of Chemistry and Chemical Engineering, Peking UniversityBeijingChina
- Institute of Molecular Physiology, Shenzhen Bay LaboratoryShenzhenChina
- Capital Medical UniversityBeijingChina
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Goulty M, Botton-Amiot G, Rosato E, Sprecher SG, Feuda R. The monoaminergic system is a bilaterian innovation. Nat Commun 2023; 14:3284. [PMID: 37280201 DOI: 10.1038/s41467-023-39030-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 05/25/2023] [Indexed: 06/08/2023] Open
Abstract
Monoamines like serotonin, dopamine, and adrenaline/noradrenaline (epinephrine/norepinephrine) act as neuromodulators in the nervous system. They play a role in complex behaviours, cognitive functions such as learning and memory formation, as well as fundamental homeostatic processes such as sleep and feeding. However, the evolutionary origin of the genes required for monoaminergic modulation is uncertain. Using a phylogenomic approach, in this study, we show that most of the genes involved in monoamine production, modulation, and reception originated in the bilaterian stem group. This suggests that the monoaminergic system is a bilaterian novelty and that its evolution may have contributed to the Cambrian diversification.
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Affiliation(s)
- Matthew Goulty
- Department of Genetics and Genome Biology, University of Leicester, Leicestershire, UK
| | - Gaelle Botton-Amiot
- Department of Biology, Institute of Zoology, University of Fribourg, CH-1700, Fribourg, Switzerland
| | - Ezio Rosato
- Department of Genetics and Genome Biology, University of Leicester, Leicestershire, UK
| | - Simon G Sprecher
- Department of Biology, Institute of Zoology, University of Fribourg, CH-1700, Fribourg, Switzerland
| | - Roberto Feuda
- Department of Genetics and Genome Biology, University of Leicester, Leicestershire, UK.
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Kundu D, Zhu A, Kim E, Paudel S, Jang CG, Lee YS, Kim KM. Potential Functional Role of Phenethylamine Derivatives in Inhibiting Dopamine Reuptake: Structure-Activity Relationship. Biomol Ther (Seoul) 2023; 31:108-115. [PMID: 36098044 PMCID: PMC9810443 DOI: 10.4062/biomolther.2022.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 07/25/2022] [Accepted: 08/03/2022] [Indexed: 01/13/2023] Open
Abstract
Numerous psychotropic and addictive substances possess structural features similar to those of β-phenethylamine (β-PEA). In this study, we selected 29 β-PEA derivatives and determined their structure-activity relationship (SAR) to their ability to inhibit dopamine (DA) reuptake; conducted docking simulation for two selected compounds; and identified their potential functionals. The compounds were subdivided into arylethylamines, 2-(alkyl amino)-1-arylalkan-1-one derivatives and alkyl 2-phenyl-2-(piperidin-2-yl)acetate derivatives. An aromatic group, alkyl group, and alkylamine derivative were attached to the arylethylamine and 2-(alkyl amino)-1-arylalkan-1-one derivatives. The inhibitory effect of the compounds on dopamine reuptake increased in the order of the compounds substituted with phenyl, thiophenyl, and substituted phenyl groups in the aromatic position; compounds with longer alkyl groups and smaller ring-sized compounds at the alkylamine position showed stronger inhibitory activities. Docking simulation conducted for two compounds, 9 and 28, showed that the (S)-form of compound 9 was more stable than the (R)-form, with a good fit into the binding site covered by helices 1, 3, and 6 of human dopamine transporter (hDAT). In contrast, the (R, S)-configuration of compound 28 was more stable than that of other isomers and was firmly placed in the binding pocket of DAT bound to DA. DA-induced endocytosis of dopamine D2 receptors was inhibited when they were co-expressed with DAT, which lowered extracellular DA levels, and uninhibited when they were pretreated with compound 9 or 28. In summary, this study revealed critical structural features responsible for the inhibition of DA reuptake and the functional role of DA reuptake inhibitors in regulating D2 receptor function.
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Affiliation(s)
- Dooti Kundu
- College of Pharmacy, Chonnam National University, Gwangju 61146, Republic of Korea
| | - Anlin Zhu
- College of Pharmacy, Chonnam National University, Gwangju 61146, Republic of Korea
| | - Eunae Kim
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Suresh Paudel
- College of Pharmacy, Chonnam National University, Gwangju 61146, Republic of Korea
| | - Choon-Gon Jang
- College of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Yong Sup Lee
- College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyeong-Man Kim
- College of Pharmacy, Chonnam National University, Gwangju 61146, Republic of Korea,Corresponding Author E-mail: , Tel: +82-62-530-2936, Fax: +82-62-530-2949
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8
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Catale C, Lo Iacono L, Martini A, Heil C, Guatteo E, Mercuri NB, Viscomi MT, Palacios D, Carola V. Early Life Social Stress Causes Sex- and Region-Dependent Dopaminergic Changes that Are Prevented by Minocycline. Mol Neurobiol 2022; 59:3913-3932. [PMID: 35435618 PMCID: PMC9148283 DOI: 10.1007/s12035-022-02830-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 04/02/2022] [Indexed: 02/03/2023]
Abstract
Early life stress (ELS) is known to modify trajectories of brain dopaminergic development, but the mechanisms underlying have not been determined. ELS perturbs immune system and microglia reactivity, and inflammation and microglia influence dopaminergic transmission and development. Whether microglia mediate the effects of ELS on dopamine (DA) system development is still unknown. We explored the effects of repeated early social stress on development of the dopaminergic system in male and female mice through histological, electrophysiological, and transcriptomic analyses. Furthermore, we tested whether these effects could be mediated by ELS-induced altered microglia/immune activity through a pharmacological approach. We found that social stress in early life altered DA neurons morphology, reduced dopamine transporter (DAT) and tyrosine hydroxylase expression, and lowered DAT-mediated currents in the ventral tegmental area but not substantia nigra of male mice only. Notably, stress-induced DA alterations were prevented by minocycline, an inhibitor of microglia activation. Transcriptome analysis in the developing male ventral tegmental area revealed that ELS caused downregulation of dopaminergic transmission and alteration in hormonal and peptide signaling pathways. Results from this study offer new insight into the mechanisms of stress response and altered brain dopaminergic maturation after ELS, providing evidence of neuroimmune interaction, sex differences, and regional specificity.
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Affiliation(s)
- Clarissa Catale
- Division of Experimental Neuroscience, Neurobiology of Behavior Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Luisa Lo Iacono
- Department of Dynamic and Clinical Psychology, and Health Studies, Sapienza University of Rome, Via degli Apuli 1, Rome, Italy
| | - Alessandro Martini
- Division of Experimental Neuroscience, Experimental Neurology Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Constantin Heil
- Division of Experimental Neuroscience, Epigenetics and Signal Transduction Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy
| | - Ezia Guatteo
- Division of Experimental Neuroscience, Experimental Neurology Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy
- Department of Motor Science and Wellness, University of Naples Parthenope, Naples, Italy
| | - Nicola Biagio Mercuri
- Division of Experimental Neuroscience, Experimental Neurology Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy
- Department of Systems Medicine, Università Degli Studi Di Roma Tor Vergata, Rome, Italy
| | - Maria Teresa Viscomi
- Department of Life Science and Public Health, Section of Histology and Embryology, Università Cattolica Del S. Cuore, Rome, Italy
- IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
| | - Daniela Palacios
- Division of Experimental Neuroscience, Epigenetics and Signal Transduction Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy
- IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Department of Life Science and Public Health, Section of Biology, Università Cattolica Del S. Cuore, Rome, Italy
| | - Valeria Carola
- Division of Experimental Neuroscience, Neurobiology of Behavior Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.
- Department of Dynamic and Clinical Psychology, and Health Studies, Sapienza University of Rome, Via degli Apuli 1, Rome, Italy.
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Lavrova AV, Gretskaya NM, Bezuglov VV. Role of Oxidative Stress in the Etiology of Parkinson’s Disease: Advanced Therapeutic Products. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2021. [DOI: 10.1134/s1068162021050307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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10
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Kim H, Lee D, Kim K. Combined Exposure to Metals in Drinking Water Alters the Dopamine System in Mouse Striatum. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18126558. [PMID: 34207128 PMCID: PMC8296366 DOI: 10.3390/ijerph18126558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 11/25/2022]
Abstract
Environmental exposure to arsenic (As), lead (Pb), and cadmium (Cd) frequently occurs; however, data on the specific effects of combined exposure on neurotransmission, specifically dopaminergic neurotransmission, are lacking. In this study, motor coordination and dopamine content, along with the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and dopamine receptors (DRs), were examined in the striatum of adult male mice following exposure to drinking water containing As, Pb, and/or Cd. We found that exposure to a metal mixture impaired motor coordination. After 4 weeks of treatment, a significant decrease in dopamine content and expression of TH, DAT, and VMAT2 was observed in the striatum of metal-mixture-treated mice, compared to the controls or single-metal-exposed groups. However, DRD1 and DRD2 expression did not significantly change with metal treatment. These results suggest that altered dopaminergic neurotransmission by the collective action of metals may contribute to metal-mixture-induced neurobehavioral disorders.
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Affiliation(s)
| | | | - Kisok Kim
- Correspondence: ; Tel.: +82-53-580-5932
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11
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Kappa Opioid Receptor Mediated Differential Regulation of Serotonin and Dopamine Transporters in Mood and Substance Use Disorder. Handb Exp Pharmacol 2021; 271:97-112. [PMID: 34136961 DOI: 10.1007/164_2021_499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Dynorphin (DYN) is an endogenous neurosecretory peptide which exerts its activity by binding to the family of G protein-coupled receptors, namely the kappa opioid receptor (KOR). Opioids are associated with pain, analgesia, and drug abuse, which play a central role in mood disorders with monoamine neurotransmitter interactions. Growing evidence demonstrates the cellular signaling cascades linked to KOR-mediated monoamine transporters regulation in cell models and native brain tissues. This chapter will review DYN/KOR role in mood and addiction in relevance to dopaminergic and serotonergic neurotransmissions. Also, we discuss the recent findings on KOR-mediated differential regulation of serotonin and dopamine transporters (SERT and DAT). These findings led to a better understanding of the role of DYN/KOR system in aminergic neurotransmission via its modulatory effect on both amine release and clearance. Detailed knowledge of these processes at the molecular level enables designing novel pharmacological reagents to target transporter motifs to treat mood and addiction and reduce unwanted side effects such as aversion, dysphoria, sedation, and psychomimesis.
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12
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Pidathala S, Mallela AK, Joseph D, Penmatsa A. Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters. Nat Commun 2021; 12:2199. [PMID: 33850134 PMCID: PMC8044178 DOI: 10.1038/s41467-021-22385-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 03/01/2021] [Indexed: 12/23/2022] Open
Abstract
Norepinephrine is a biogenic amine neurotransmitter that has widespread effects on alertness, arousal and pain sensation. Consequently, blockers of norepinephrine uptake have served as vital tools to treat depression and chronic pain. Here, we employ the Drosophila melanogaster dopamine transporter as a surrogate for the norepinephrine transporter and determine X-ray structures of the transporter in its substrate-free and norepinephrine-bound forms. We also report structures of the transporter in complex with inhibitors of chronic pain including duloxetine, milnacipran and a synthetic opioid, tramadol. When compared to dopamine, we observe that norepinephrine binds in a different pose, in the vicinity of subsite C within the primary binding site. Our experiments reveal that this region is the binding site for chronic pain inhibitors and a determinant for norepinephrine-specific reuptake inhibition, thereby providing a paradigm for the design of specific inhibitors for catecholamine neurotransmitter transporters.
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Affiliation(s)
| | | | - Deepthi Joseph
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India
| | - Aravind Penmatsa
- Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
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13
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Ryan RM, Ingram SL, Scimemi A. Regulation of Glutamate, GABA and Dopamine Transporter Uptake, Surface Mobility and Expression. Front Cell Neurosci 2021; 15:670346. [PMID: 33927596 PMCID: PMC8076567 DOI: 10.3389/fncel.2021.670346] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 03/15/2021] [Indexed: 01/31/2023] Open
Abstract
Neurotransmitter transporters limit spillover between synapses and maintain the extracellular neurotransmitter concentration at low yet physiologically meaningful levels. They also exert a key role in providing precursors for neurotransmitter biosynthesis. In many cases, neurons and astrocytes contain a large intracellular pool of transporters that can be redistributed and stabilized in the plasma membrane following activation of different signaling pathways. This means that the uptake capacity of the brain neuropil for different neurotransmitters can be dynamically regulated over the course of minutes, as an indirect consequence of changes in neuronal activity, blood flow, cell-to-cell interactions, etc. Here we discuss recent advances in the mechanisms that control the cell membrane trafficking and biophysical properties of transporters for the excitatory, inhibitory and modulatory neurotransmitters glutamate, GABA, and dopamine.
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Affiliation(s)
- Renae M. Ryan
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Susan L. Ingram
- Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, United States
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14
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Patthy Á, Murai J, Hanics J, Pintér A, Zahola P, Hökfelt TGM, Harkany T, Alpár A. Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer's Disease. J Clin Med 2021; 10:jcm10081555. [PMID: 33917176 PMCID: PMC8067882 DOI: 10.3390/jcm10081555] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/01/2021] [Accepted: 04/05/2021] [Indexed: 12/18/2022] Open
Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.
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Affiliation(s)
- Ágoston Patthy
- Department of Anatomy, Semmelweis University, H-1094 Budapest, Hungary; (Á.P.); (J.M.); (J.H.); (A.P.); (P.Z.)
| | - János Murai
- Department of Anatomy, Semmelweis University, H-1094 Budapest, Hungary; (Á.P.); (J.M.); (J.H.); (A.P.); (P.Z.)
| | - János Hanics
- Department of Anatomy, Semmelweis University, H-1094 Budapest, Hungary; (Á.P.); (J.M.); (J.H.); (A.P.); (P.Z.)
- SE NAP Research Group of Experimental Neuroanatomy and Developmental Biology, Hungarian Academy of Sciences, H-1094 Budapest, Hungary
| | - Anna Pintér
- Department of Anatomy, Semmelweis University, H-1094 Budapest, Hungary; (Á.P.); (J.M.); (J.H.); (A.P.); (P.Z.)
| | - Péter Zahola
- Department of Anatomy, Semmelweis University, H-1094 Budapest, Hungary; (Á.P.); (J.M.); (J.H.); (A.P.); (P.Z.)
| | - Tomas G. M. Hökfelt
- Department of Neuroscience, Biomedicum 7D, Karolinska Institutet, 17165 Stockholm, Sweden; (T.G.M.H.); (T.H.)
| | - Tibor Harkany
- Department of Neuroscience, Biomedicum 7D, Karolinska Institutet, 17165 Stockholm, Sweden; (T.G.M.H.); (T.H.)
- Center for Brain Research, Department of Molecular Neurosciences, Medical University of Vienna, 1090 Vienna, Austria
| | - Alán Alpár
- Department of Anatomy, Semmelweis University, H-1094 Budapest, Hungary; (Á.P.); (J.M.); (J.H.); (A.P.); (P.Z.)
- SE NAP Research Group of Experimental Neuroanatomy and Developmental Biology, Hungarian Academy of Sciences, H-1094 Budapest, Hungary
- Correspondence:
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15
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Fairweather SJ, Shah N, Brӧer S. Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 21:13-127. [PMID: 33052588 DOI: 10.1007/5584_2020_584] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Solute carriers form one of three major superfamilies of membrane transporters in humans, and include uniporters, exchangers and symporters. Following several decades of molecular characterisation, multiple solute carriers that form obligatory heteromers with unrelated subunits are emerging as a distinctive principle of membrane transporter assembly. Here we comprehensively review experimentally established heteromeric solute carriers: SLC3-SLC7 amino acid exchangers, SLC16 monocarboxylate/H+ symporters and basigin/embigin, SLC4A1 (AE1) and glycophorin A exchanger, SLC51 heteromer Ost α-Ost β uniporter, and SLC6 heteromeric symporters. The review covers the history of the heteromer discovery, transporter physiology, structure, disease associations and pharmacology - all with a focus on the heteromeric assembly. The cellular locations, requirements for complex formation, and the functional role of dimerization are extensively detailed, including analysis of the first complete heteromer structures, the SLC7-SLC3 family transporters LAT1-4F2hc, b0,+AT-rBAT and the SLC6 family heteromer B0AT1-ACE2. We present a systematic analysis of the structural and functional aspects of heteromeric solute carriers and conclude with common principles of their functional roles and structural architecture.
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Affiliation(s)
- Stephen J Fairweather
- Research School of Biology, Australian National University, Canberra, ACT, Australia. .,Resarch School of Chemistry, Australian National University, Canberra, ACT, Australia.
| | - Nishank Shah
- Research School of Biology, Australian National University, Canberra, ACT, Australia
| | - Stefan Brӧer
- Research School of Biology, Australian National University, Canberra, ACT, Australia.
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16
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Harraz MM, Guha P, Kang IG, Semenza ER, Malla AP, Song YJ, Reilly L, Treisman I, Cortés P, Coggiano MA, Veeravalli V, Rais R, Tanda G, Snyder SH. Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter. Mol Psychiatry 2021; 26:370-382. [PMID: 33414501 PMCID: PMC8625012 DOI: 10.1038/s41380-020-00978-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 11/18/2020] [Accepted: 12/01/2020] [Indexed: 01/29/2023]
Abstract
Cocaine exerts its stimulant effect by inhibiting dopamine reuptake leading to increased dopamine signaling. This action is thought to reflect binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share the behavioral actions of cocaine. We previously showed that toxic levels of cocaine induce autophagic neuronal cell death. Here, we show that subnanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Autophagy inhibitors reduce the locomotor stimulant effect of cocaine in mice. Cocaine-induced autophagy degrades transporters for dopamine but not serotonin in the nucleus accumbens. Autophagy inhibition impairs cocaine conditioned place preference in mice. Our findings indicate that autophagic degradation of DAT modulates behavioral actions of cocaine.
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Affiliation(s)
- Maged M Harraz
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Prasun Guha
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - In Guk Kang
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Evan R Semenza
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Adarsha P Malla
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Young Jun Song
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Luke Reilly
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Isaac Treisman
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Pedro Cortés
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Mark A Coggiano
- Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA
| | - Vijayabhaskar Veeravalli
- Department of Neurology and Johns Hopkins Drug Discovery (JHDD) Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Rana Rais
- Department of Neurology and Johns Hopkins Drug Discovery (JHDD) Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Gianluigi Tanda
- Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA
| | - Solomon H Snyder
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
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17
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Abstract
Inhibitors of Na+/Cl- dependent high affinity transporters for norepinephrine (NE), serotonin (5-HT), and/or dopamine (DA) represent frequently used drugs for treatment of psychological disorders such as depression, anxiety, obsessive-compulsive disorder, attention deficit hyperactivity disorder, and addiction. These transporters remove NE, 5-HT, and/or DA after neuronal excitation from the interstitial space close to the synapses. Thereby they terminate transmission and modulate neuronal behavioral circuits. Therapeutic failure and undesired central nervous system side effects of these drugs have been partially assigned to neurotransmitter removal by low affinity transport. Cloning and functional characterization of the polyspecific organic cation transporters OCT1 (SLC22A1), OCT2 (SLC22A2), OCT3 (SLC22A3) and the plasma membrane monoamine transporter PMAT (SLC29A4) revealed that every single transporter mediates low affinity uptake of NE, 5-HT, and DA. Whereas the organic transporters are all located in the blood brain barrier, OCT2, OCT3, and PMAT are expressed in neurons or in neurons and astrocytes within brain areas that are involved in behavioral regulation. Areas of expression include the dorsal raphe, medullary motoric nuclei, hypothalamic nuclei, and/or the nucleus accumbens. Current knowledge of the transport of monoamine neurotransmitters by the organic cation transporters, their interactions with psychotropic drugs, and their locations in the brain is reported in detail. In addition, animal experiments including behavior tests in wildtype and knockout animals are reported in which the impact of OCT2, OCT3, and/or PMAT on regulation of salt intake, depression, mood control, locomotion, and/or stress effect on addiction is suggested.
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Affiliation(s)
- Hermann Koepsell
- Institute of Anatomy and Cell Biology, University Würzburg, Würzburg, Germany.
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18
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Green AL, Eid A, Zhan L, Zarbl H, Guo GL, Richardson JR. Epigenetic Regulation of the Ontogenic Expression of the Dopamine Transporter. Front Genet 2019; 10:1099. [PMID: 31749842 PMCID: PMC6844290 DOI: 10.3389/fgene.2019.01099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 10/11/2019] [Indexed: 01/19/2023] Open
Abstract
The dopamine transporter (DAT) is a plasma membrane transport protein responsible for regulating the duration and intensity of dopaminergic signaling. Altered expression of DAT is linked to neurodevelopmental disorders, including attention deficit hyperactivity disorder and autism spectrum disorder, and is shown to contribute to the response of psychotropic drugs and neurotoxicants. Although the postnatal levels of DAT have been characterized, there are few data regarding the mechanisms that regulate postnatal DAT expression. Here, we examine the ontogeny of DAT mRNA from postnatal days 0 to 182 in the rat brain and define a role for epigenetic mechanisms regulating DAT expression. DAT mRNA and protein significantly increased between PND 0 and 6 months in rat midbrain and striatum, respectively. The epigenetic modifiers Dnmt1, Dnmt3a, Dnmt3b, and Hdac2 demonstrated age associated decreases in mRNA expression whereas Hdac5 and Hdac8 showed increased mRNA expression with age. Chromatin immunoprecipitation studies revealed increased protein enrichment of acetylated histone 3 at lysines 9 and 14 and the dopaminergic transcription factors Nurr1 and Pitx3 within the DAT promoter in an age-related manner. Together these studies provide evidence for the role of epigenetic modifications in the regulation of DAT during development. The identification of these mechanisms may contribute to potential therapeutic interventions aimed at neurodevelopmental disorders of the dopaminergic system.
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Affiliation(s)
- Ashley L. Green
- Environmental and Occupational Health Sciences Institute and Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - Aseel Eid
- Department of Environmental Health Sciences, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, FL, United States
| | - Le Zhan
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States
| | - Helmut Zarbl
- Environmental and Occupational Health Sciences Institute and Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - Grace L. Guo
- Environmental and Occupational Health Sciences Institute and Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States,Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States
| | - Jason R. Richardson
- Environmental and Occupational Health Sciences Institute and Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States,Department of Environmental Health Sciences, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, FL, United States,*Correspondence: Jason R. Richardson,
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19
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Akinyemi AJ, Miah MR, Ijomone OM, Tsatsakis A, Soares FAA, Tinkov AA, Skalny AV, Venkataramani V, Aschner M. Lead (Pb) exposure induces dopaminergic neurotoxicity in Caenorhabditis elegans: Involvement of the dopamine transporter. Toxicol Rep 2019; 6:833-840. [PMID: 31463204 PMCID: PMC6709386 DOI: 10.1016/j.toxrep.2019.08.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/29/2019] [Accepted: 08/02/2019] [Indexed: 12/12/2022] Open
Abstract
Lead (Pb) is an environmental neurotoxicant, and has been implicated in several neurological disorders of dopaminergic dysfunction; however, the molecular mechanism of its toxicity has yet to be fully understood. This study investigated the effect of Pb exposure on dopaminergic neurodegeneration and function, as well as expression level of several dopaminergic signaling genes in wild type (N2) and protein kinase C (pkc) mutant Caenorhabditis elegans. Both N2 and pkc mutant worms were exposed to Pb2+ for 1 h. Thereafter, dopaminergic (DAergic) neurodegeneration, behavior and gene expression levels were assessed. The results revealed that Pb2+ treatment affects dopaminergic cell morphology and structure in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. Also, there was a significant impairment in dopaminergic neuronal function as tested by basal slowing response (BSR) in wild-type, N2 worms, but no effect was observed in pkc mutant worms. Furthermore, Pb2+ exposure increased dat-1 gene expression level when compared with N2 worms, but no alteration was observed in the pkc mutant strains. LC–MS analysis revealed a significant decrease in dopamine content in worms treated with Pb2+ when compared with controls. In summary, our results revealed that Pb2+ exposure induced dopaminergic dysfunction in C. elegans by altering dat-1 gene levels, but pkc mutants showed significant resistance to Pb2+ toxicity. We conclude that PKC activation is directly involved in the neurotoxicity of Pb.
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Affiliation(s)
- Ayodele Jacob Akinyemi
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States
| | - Mahfuzur R Miah
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States
| | - Omamuyovwi M Ijomone
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States.,Department of Anatomy, School of Health and Health Technology, Federal University of Technology Akure (FUTA), Nigeria
| | - Aristidis Tsatsakis
- Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, Heraklion, Greece
| | - Félix Alexandre Antunes Soares
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States.,Universidade Federal de Santa Maria, Centro de Ciências Naturais e Exatas, Departamento de Bioquímica e Biologia Molecular, Santa Maria, RS, Brazil
| | | | - Anatoly V Skalny
- Peoples' Friendship University of Russia (RUDN University), Moscow, Russian Federation.,I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Vivek Venkataramani
- Department of Hematology and Medical Oncology, University Medical Center Göttingen (UMG), Göttingen, Germany.,Institute of Pathology, University Medical Center Göttingen (UMG), Göttingen, Germany
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States
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20
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Nielsen AK, Möller IR, Wang Y, Rasmussen SGF, Lindorff-Larsen K, Rand KD, Loland CJ. Substrate-induced conformational dynamics of the dopamine transporter. Nat Commun 2019; 10:2714. [PMID: 31221956 PMCID: PMC6586795 DOI: 10.1038/s41467-019-10449-w] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 05/09/2019] [Indexed: 02/02/2023] Open
Abstract
The dopamine transporter is a member of the neurotransmitter:sodium symporters (NSSs), which are responsible for termination of neurotransmission through Na+-driven reuptake of neurotransmitter from the extracellular space. Experimental evidence elucidating the coordinated conformational rearrangements related to the transport mechanism has so far been limited. Here we probe the global Na+- and dopamine-induced conformational dynamics of the wild-type Drosophila melanogaster dopamine transporter using hydrogen-deuterium exchange mass spectrometry. We identify Na+- and dopamine-induced changes in specific regions of the transporter, suggesting their involvement in protein conformational transitions. Furthermore, we detect ligand-dependent slow cooperative fluctuations of helical stretches in several domains of the transporter, which could be a molecular mechanism that assists in the transporter function. Our results provide a framework for understanding the molecular mechanism underlying the function of NSSs by revealing detailed insight into the state-dependent conformational changes associated with the alternating access model of the dopamine transporter.
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Affiliation(s)
- Anne Kathrine Nielsen
- Laboratory for Membrane Protein Dynamics, Department of Neuroscience, University of Copenhagen, 2200, Copenhagen N, Denmark
- Protein Analysis Group, Department of Pharmacy, University of Copenhagen, 2100, Copenhagen Ø, Denmark
| | - Ingvar R Möller
- Laboratory for Membrane Protein Dynamics, Department of Neuroscience, University of Copenhagen, 2200, Copenhagen N, Denmark
- Protein Analysis Group, Department of Pharmacy, University of Copenhagen, 2100, Copenhagen Ø, Denmark
| | - Yong Wang
- Structural Biology and NMR Laboratory, Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, 2200, Copenhagen N, Denmark
| | - Søren G F Rasmussen
- Department of Neuroscience, University of Copenhagen, 2200, Copenhagen N, Denmark
| | - Kresten Lindorff-Larsen
- Structural Biology and NMR Laboratory, Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, 2200, Copenhagen N, Denmark
| | - Kasper D Rand
- Protein Analysis Group, Department of Pharmacy, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
| | - Claus J Loland
- Laboratory for Membrane Protein Dynamics, Department of Neuroscience, University of Copenhagen, 2200, Copenhagen N, Denmark.
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21
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Canseco-Alba A, Schanz N, Sanabria B, Zhao J, Lin Z, Liu QR, Onaivi ES. Behavioral effects of psychostimulants in mutant mice with cell-type specific deletion of CB2 cannabinoid receptors in dopamine neurons. Behav Brain Res 2019; 360:286-297. [PMID: 30508607 PMCID: PMC6327973 DOI: 10.1016/j.bbr.2018.11.043] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 11/15/2018] [Accepted: 11/29/2018] [Indexed: 12/26/2022]
Abstract
Activation of the endocannabinoid system modulate dopaminergic pathways that are involved in the effects of psychostimulants including amphetamine, cocaine, nicotine and other drugs of abuse. Genetic deletion or pharmacological activation of CB2 cannabinoid receptor is involved in the modulation of the effects of psychostimulants and their rewarding properties. Here we report on the behavioral effects of psychostimulants in DAT-Cnr2 conditional knockout (cKO) mice with selective deletion of type 2 cannabinoid receptors in dopamine neurons. There was enhanced psychostimulant induced hyperactivity in DAT-Cnr2 cKO mice, but the psychostimulant-induced sensitization was absent in DAT-Cnr2 cKO compared to the WT mice. Intriguingly, lower doses of amphetamine reduced locomotor activity of the DAT-Cnr2 cKO mice. While cocaine, amphetamine and methamphetamine produced robust conditioned place preference (CPP) in both DAT-Cnr2 cKO and WT mice, nicotine at the dose used induced CPP only in the WT but not in the DAT-Cn2 cKO mice. However, pre-treatment with the CB2R selective agonist JWH133, blocked cocaine and nicotine induced CPP in the WT mice. The deletion of CB2Rs in dopamine neurons modified the levels of tyrosine hydroxylase, and reduced the expression of dopamine transporter gene expression in DAT-Cnr2 cKO midbrain region. Taken together, our data suggest that CB2Rs play a role in the modulation of dopamine-related effects of psychostimulants and could be exploited as therapeutic target in psychostimulant addiction and other psychiatric disorders associated with dopamine dysregulation.
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Affiliation(s)
- Ana Canseco-Alba
- Department of Biology, William Paterson University, Wayne, NJ, 07470, USA
| | - Norman Schanz
- Department of Biology, William Paterson University, Wayne, NJ, 07470, USA
| | - Branden Sanabria
- Department of Biology, William Paterson University, Wayne, NJ, 07470, USA
| | - Juan Zhao
- Department of Psychiatry, Harvard Medical School, Psychiatric Neurogenomics, Division of Alcohol and Drug Abuse, and Mailman Neuroscience Research Center, McLean Hospital, Belmont, MA, USA
| | - Zhicheng Lin
- Department of Psychiatry, Harvard Medical School, Psychiatric Neurogenomics, Division of Alcohol and Drug Abuse, and Mailman Neuroscience Research Center, McLean Hospital, Belmont, MA, USA
| | - Qing-Rong Liu
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Emmanuel S Onaivi
- Department of Biology, William Paterson University, Wayne, NJ, 07470, USA.
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22
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Blakely RD, El Mestikawy S, Robinson MB. The brain in flux: Genetic, physiologic, and therapeutic perspectives on transporters in the CNS. Neurochem Int 2018; 123:1-6. [PMID: 30571999 DOI: 10.1016/j.neuint.2018.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The brain has specific properties that make it uniquely dependent upon transporters. This is the 3rd edition of a biennial special issue that originates from a scientific meeting devoted to studies of transporters and their relationship to brain function and to neurodevelopmental, neurologic, and psychiatric disorders. The field continues to rapidly evolve with advances in studies of structure that inform mechanism, with genetic analyses in humans revealing surprising aspects of biology, and with integrated cellular to whole animal analyses of the role of transporters in their control of physiology and pathophysiology. This special issue includes a sampling of review articles that address timely questions of the field followed by several primary research articles.
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Affiliation(s)
- Randy D Blakely
- Florida Atlantic University Brain Institute, Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, 33458, United States
| | - Salah El Mestikawy
- Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, H4H 1R3, Canada; Sorbonne Universités, Université Pierre et Marie Curie UM 119 - CNRS UMR 8246 - INSERM U1130, Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005, Paris, France
| | - Michael B Robinson
- Departments of Pediatrics and Systems Pharmacology and Translational Therapeutics, Children's Hospital of Philadelphia/University of Pennsylvania, Philadelphia, PA, 19104, United States.
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23
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Kalinderi K, Papaliagkas V, Fidani L. Pharmacogenetics and levodopa induced motor complications. Int J Neurosci 2018; 129:384-392. [DOI: 10.1080/00207454.2018.1538993] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Kallirhoe Kalinderi
- Department of General Biology, Medical School Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vasileios Papaliagkas
- Laboratory of Clinical Neurophysiology, Aristotle University of Thessaloniki AHEPA University Hospital, Thessaloniki, Greece
| | - Liana Fidani
- Department of General Biology, Medical School Aristotle University of Thessaloniki, Thessaloniki, Greece
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24
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Aversa D, Martini A, Guatteo E, Pisani A, Mercuri NB, Berretta N. Reversal of dopamine-mediated firing inhibition through activation of the dopamine transporter in substantia nigra pars compacta neurons. Br J Pharmacol 2018; 175:3534-3547. [PMID: 29933497 DOI: 10.1111/bph.14422] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 06/11/2018] [Accepted: 06/14/2018] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND PURPOSE One of the hallmarks of ventral midbrain dopamine-releasing neurons is membrane hyperpolarization in response to stimulation of somato-dendritic D2 receptors. At early postnatal age, under sustained dopamine, this inhibitory response is followed by a slow recovery, resulting in dopamine inhibition reversal (DIR). In the present investigation, we aimed to get a better insight into the cellular mechanisms underlying DIR. EXPERIMENTAL APPROACH We performed single-unit extracellular recordings with a multi-electrode array device and conventional patch-clamp recordings on midbrain mouse slices. KEY RESULTS While continuous dopamine (100 μM) perfusion gave rise to firing inhibition that recovered in 10 to 15 min, the same effect was not obtained with the D2 receptor agonist quinpirole (100 nM). Moreover, firing inhibition caused by the GABAB receptor agonist baclofen (300 nM) was reversed by dopamine (100 μM), albeit D2 receptors had been blocked by sulpiride (10 μM). Conversely, the block of the dopamine transporter (DAT) with cocaine (30 μM) prevented firing recovery by dopamine under GABAB receptor stimulation. Accordingly, in whole-cell recordings from single cells, the baclofen-induced outward current was counteracted by dopamine (100 μM) in the presence of sulpiride (10 μM), and this effect was prevented by the DAT antagonists cocaine (30 μM) and GBR12909 (2 μM). CONCLUSIONS AND IMPLICATIONS Our results indicate that the DAT plays a major role in DIR, mediating it under conditions of sustained dopamine exposure, and point to DAT as an important target for pharmacological therapies leading to prolonged enhancement of the dopaminergic signal.
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Affiliation(s)
- Daniela Aversa
- Fondazione Santa Lucia IRCCS, Rome, Italy.,Dipartimento di Medicina dei Sistemi, Università di Roma Tor Vergata, Rome, Italy
| | - Alessandro Martini
- Fondazione Santa Lucia IRCCS, Rome, Italy.,Dipartimento di Medicina dei Sistemi, Università di Roma Tor Vergata, Rome, Italy
| | - Ezia Guatteo
- Fondazione Santa Lucia IRCCS, Rome, Italy.,Dipartimento di Scienze Motorie e del Benessere, Università 'Parthenope', Naples, Italy
| | - Antonio Pisani
- Fondazione Santa Lucia IRCCS, Rome, Italy.,Dipartimento di Medicina dei Sistemi, Università di Roma Tor Vergata, Rome, Italy
| | - Nicola Biagio Mercuri
- Fondazione Santa Lucia IRCCS, Rome, Italy.,Dipartimento di Medicina dei Sistemi, Università di Roma Tor Vergata, Rome, Italy
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25
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Mackie P, Lebowitz J, Saadatpour L, Nickoloff E, Gaskill P, Khoshbouei H. The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson's Disease. Brain Behav Immun 2018; 70:21-35. [PMID: 29551693 PMCID: PMC5953824 DOI: 10.1016/j.bbi.2018.03.020] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 03/13/2018] [Accepted: 03/14/2018] [Indexed: 02/06/2023] Open
Abstract
The second-most common neurodegenerative disease, Parkinson's Disease (PD) has three hallmarks: dysfunctional dopamine transmission due, at least in part, to dopamine neuron degeneration; intracellular inclusions of α-synuclein aggregates; and neuroinflammation. The origin and interplay of these features remains a puzzle, as does the underlying mechanism of PD pathogenesis and progression. When viewed in the context of neuroimmunology, dopamine also plays a role in regulating peripheral immune cells. Intriguingly, plasma dopamine levels are altered in PD, suggesting collateral dysregulation of peripheral dopamine transmission. The dopamine transporter (DAT), the main regulator of dopaminergic tone in the CNS, is known to exist in lymphocytes and monocytes/macrophages, but little is known about peripheral DAT biology or how DAT regulates the dopaminergic tone, much less how peripheral DAT alters immune function. Our review is guided by the hypothesis that dysfunctional peripheral dopamine signaling might be linked to the dysfunctional immune responses in PD and thereby suggests a potential bidirectional communication between central and peripheral dopamine systems. This review seeks to foster new perspectives concerning PD pathogenesis and progression.
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Affiliation(s)
- Phillip Mackie
- University of Florida College of Medicine, Department of Neuroscience, Gainesville, FL 32611, United States
| | - Joe Lebowitz
- University of Florida College of Medicine, Department of Neuroscience, Gainesville, FL 32611, United States
| | - Leila Saadatpour
- University of Florida College of Medicine, Department of Neuroscience, Gainesville, FL 32611, United States
| | - Emily Nickoloff
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, United States
| | - Peter Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, United States
| | - Habibeh Khoshbouei
- University of Florida College of Medicine, Department of Neuroscience, Gainesville, FL 32611, United States.
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Abstract
Synthetic cathinones are derivatives of the naturally occurring compound cathinone, the main psychoactive ingredient in the khat plant Catha edulis. Cathinone is the β-keto analog of amphetamine, and all synthetic cathinones display a β-keto moiety in their structure. Several synthetic cathinones are widely prescribed medications (e.g., bupropion, Wellbutrin®), while others are problematic drugs of abuse (e.g., 4-methylmethcathinone, mephedrone). Similar to amphetamines, synthetic cathinones are psychomotor stimulants that exert their effects by impairing the normal function of plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT). Ring-substituted cathinones like mephedrone are transporter substrates that evoke neurotransmitter release by reversing the normal direction of transporter flux (i.e., releasers), whereas pyrrolidine-containing cathinones like 3,4-methylenedioxypyrovalerone (MDPV) are potent transporter inhibitors that block neurotransmitter uptake (i.e., blockers). Regardless of molecular mechanism, all synthetic cathinones increase extracellular monoamine concentrations in the brain, thereby enhancing cell-to-cell monoamine signaling. Here, we briefly review the mechanisms of action, structure-activity relationships, and in vivo pharmacology of synthetic cathinones. Overall, the findings show that certain synthetic cathinones are powerful drugs of abuse that could pose significant risk to users.
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Abstract
The dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters, which are collectively referred to as monoamine transporters (MATs), play significant roles in regulating the neuronal response to these neurotransmitters. MATs terminate the action of these neurotransmitters by translocating them from the synaptic space into the presynaptic neurons. These three transmitters are responsible for controlling a number of physiological, emotional, and behavioral functions, with their transporters being the site of action of drugs employed for the treatment of a variety of conditions, including depression, anxiety, ADHD, schizophrenia, and psychostimulant abuse. Provided in this unit is information on the localization and regulation of MATs and the structural components of these proteins most responsible for the translocation process. Also included is a brief description of the evolution of ligands that interact with these transporters, as well as current theories concerning the pharmacological effects of substances that interact with these sites, including the molecular mechanisms of action of uptake inhibitors and allosteric modulators. Data relating to the presence, structure, and functions of allosteric modulators are included as well. The aim of this review is to provide background information on MATs to those who are new to this field, with a focus on the therapeutic potential of compounds that interact with these substrate transport sites. © 2017 by John Wiley & Sons, Inc.
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Affiliation(s)
- Shaili Aggarwal
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Pennsylvania
| | - Ole V Mortensen
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Pennsylvania
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28
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Karam CS, Javitch JA. Phosphorylation of the Amino Terminus of the Dopamine Transporter: Regulatory Mechanisms and Implications for Amphetamine Action. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2017; 82:205-234. [PMID: 29413521 DOI: 10.1016/bs.apha.2017.09.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Amphetamines (AMPHs) are potent psychostimulants that are widely used and abused, with profound medical and societal impact. Their actions at dopaminergic neurons are thought to mediate their therapeutic efficacy as well as their liability for abuse and dependence. AMPHs target the dopamine transporter (DAT), the plasmalemmal membrane protein that mediates the inactivation of released dopamine (DA) through its reuptake. AMPHs act as substrates for DAT and are known to cause mobilization of dopamine (DA) to the cell exterior via DAT-mediated reverse transport (efflux). It has become increasingly evident that the mechanisms that regulate AMPH-induced DA efflux are distinct from those that regulate DA uptake. Central to these mechanisms is the phosphorylation of the DAT amino (N)-terminus, which has been repeatedly demonstrated to facilitate DAT-mediated DA efflux, without impacting other aspects of DAT physiology. This review aims to summarize the current status of knowledge regarding DAT N-terminal phosphorylation and its regulation by protein modulators and the membrane microenvironment. A better understanding of these mechanisms may lead to the identification of novel therapeutic approaches that interfere selectively with the pharmacological effects of AMPHs without altering the physiological function of DAT.
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Affiliation(s)
- Caline S Karam
- College of Physicians & Surgeons, Columbia University, New York, NY, United States; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, United States
| | - Jonathan A Javitch
- College of Physicians & Surgeons, Columbia University, New York, NY, United States; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, United States.
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29
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Arreola R, Alvarez-Herrera S, Pérez-Sánchez G, Becerril-Villanueva E, Cruz-Fuentes C, Flores-Gutierrez EO, Garcés-Alvarez ME, de la Cruz-Aguilera DL, Medina-Rivero E, Hurtado-Alvarado G, Quintero-Fabián S, Pavón L. Immunomodulatory Effects Mediated by Dopamine. J Immunol Res 2016; 2016:3160486. [PMID: 27795960 PMCID: PMC5067323 DOI: 10.1155/2016/3160486] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 07/29/2016] [Accepted: 08/08/2016] [Indexed: 01/11/2023] Open
Abstract
Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.
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Affiliation(s)
- Rodrigo Arreola
- Psychiatric Genetics Department, National Institute of Psychiatry “Ramón de la Fuente”, Clinical Research Branch, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Samantha Alvarez-Herrera
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Gilberto Pérez-Sánchez
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Enrique Becerril-Villanueva
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Carlos Cruz-Fuentes
- Psychiatric Genetics Department, National Institute of Psychiatry “Ramón de la Fuente”, Clinical Research Branch, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Enrique Octavio Flores-Gutierrez
- National Institute of Psychiatry “Ramón de la Fuente”, Clinical Research Branch, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - María Eugenia Garcés-Alvarez
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Dora Luz de la Cruz-Aguilera
- Laboratory of Neuroimmunoendocrinology, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Avenida Insurgentes Sur 3877, La Fama, Tlalpan, 14269 Mexico City, Mexico
| | - Emilio Medina-Rivero
- Unidad de Investigación y Desarrollo, Probiomed S.A. de C.V. Cruce de Carreteras Acatzingo-Zumpahuacán S/N, 52400 Tenancingo, MEX, Mexico
| | - Gabriela Hurtado-Alvarado
- Area of Neurosciences, Department of Biology of Reproduction, CBS, Universidad Autonoma Metropolitana, Unidad Iztapalapa, Avenida San Rafael Atlixco No. 186, Colonia Vicentina, Iztapalapa, 09340 Mexico City, Mexico
| | - Saray Quintero-Fabián
- Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Instituto Nacional de Pediatría, Av. del Iman No. 1, Cuarto Piso, 04530 Mexico City, Mexico
| | - Lenin Pavón
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
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30
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Abstract
Biogenic amine transporters mediate two important steps in the reuptake and recycling of monoamines released by neurons in the central nervous system. First, high-affinity transporters found in the plasma membrane of neurons and glial cells mediate the removal of neurotransmitter from the extracellular space, thus terminating the action of the monoamines serotonin, norepinephrine, and dopamine. Within the cell, vesicular transporters repackage monoamines into vesicles for additional cycles of release. Two gene families are involved in the transport of the biogenic amines—the Na+/Cl--dependent plasma membrane carriers and the H+-dependent vesicular amine carriers. These transporters are known to regulate neurotransmitter con centrations in monoaminergic pathways and are the primary targets for a wide variety of clinically important antidepressants, antihypertensives, stimulants, and stimulant drugs of abuse. The Neuroscientist 1:259-267, 1995
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Affiliation(s)
- Susan G. Amara
- The Vollum Institute and Howard Hughes Medical Institute
Oregon Health Sciences University Portland, Oregon
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31
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Stehouwer JS, Goodman MM. Fluorine-18 Radiolabeled PET Tracers for Imaging Monoamine Transporters: Dopamine, Serotonin, and Norepinephrine. PET Clin 2016; 4:101-28. [PMID: 20216936 DOI: 10.1016/j.cpet.2009.05.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
This review focuses on the development of fluorine-18 radiolabeled PET tracers for imaging the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). All successful DAT PET tracers reported to date are members of the 3β-phenyl tropane class and are synthesized from cocaine. Currently available carbon-11 SERT PET tracers come from both the diphenylsulfide and 3β-phenyl nortropane class, but so far only the nortropanes have found success with fluorine-18 derivatives. NET imaging has so far employed carbon-11 and fluorine-18 derivatives of reboxetine but due to defluorination of the fluorine-18 derivatives further research is still necessary.
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32
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Janowsky A, Tosh DK, Eshleman AJ, Jacobson KA. Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine. J Pharmacol Exp Ther 2016; 357:24-35. [PMID: 26813929 PMCID: PMC4809312 DOI: 10.1124/jpet.115.229666] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 01/22/2016] [Indexed: 12/19/2022] Open
Abstract
Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [(125)I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [(3)H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N(6)-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [(125)I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4'-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter uptake.
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Affiliation(s)
- Aaron Janowsky
- VA Portland Health Care System, Research Service (R&D-22), and Departments of Psychiatry and Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon (A.J., A.J.E.); and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.K.T., K.A.J.)
| | - Dilip K Tosh
- VA Portland Health Care System, Research Service (R&D-22), and Departments of Psychiatry and Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon (A.J., A.J.E.); and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.K.T., K.A.J.)
| | - Amy J Eshleman
- VA Portland Health Care System, Research Service (R&D-22), and Departments of Psychiatry and Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon (A.J., A.J.E.); and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.K.T., K.A.J.)
| | - Kenneth A Jacobson
- VA Portland Health Care System, Research Service (R&D-22), and Departments of Psychiatry and Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon (A.J., A.J.E.); and Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.K.T., K.A.J.)
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Rincón DA, Cordeiro MNDS, Mosquera RA. On the effects of the basis set superposition error on the change of QTAIM charges in adduct formation. Application to complexes between morphine and cocaine and their main metabolites. RSC Adv 2016. [DOI: 10.1039/c6ra22736h] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
QTAIM atomic properties variation upon interaction is analyzed by: (i) deformation; (ii) BSSE estimated by counterpoise method; and (iii) binding.
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Affiliation(s)
- David A. Rincón
- Departamento de Química Física
- Universidade de Vigo
- 36310 Vigo
- Spain
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Sharma H, Santra S, Dutta A. Triple reuptake inhibitors as potential next-generation antidepressants: a new hope? Future Med Chem 2015; 7:2385-406. [PMID: 26619226 PMCID: PMC4976848 DOI: 10.4155/fmc.15.134] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The current therapy for depression is less than ideal with remission rates of only 25-35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.
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Affiliation(s)
- Horrick Sharma
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA
| | - Soumava Santra
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA
| | - Aloke Dutta
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA
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Kobayashi Y, Kulikova SP, Shibato J, Rakwal R, Satoh H, Pinault D, Masuo Y. DNA microarray unravels rapid changes in transcriptome of MK-801 treated rat brain. World J Biol Chem 2015; 6:389-408. [PMID: 26629322 PMCID: PMC4657125 DOI: 10.4331/wjbc.v6.i4.389] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 01/20/2015] [Accepted: 08/31/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the impact of MK-801 on gene expression patterns genome wide in rat brain regions.
METHODS: Rats were treated with an intraperitoneal injection of MK-801 [0.08 (low-dose) and 0.16 (high-dose) mg/kg] or NaCl (vehicle control). In a first series of experiment, the frontoparietal electrocorticogram was recorded 15 min before and 60 min after injection. In a second series of experiments, the whole brain of each animal was rapidly removed at 40 min post-injection, and different regions were separated: amygdala, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum on ice followed by DNA microarray (4 × 44 K whole rat genome chip) analysis.
RESULTS: Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline gamma frequency (30-80 Hz) oscillations in the frontoparietal electroencephalogram. DNA microarray analysis showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose (0.08 mg/kg) of MK-801. Under high-dose (0.16 mg/kg), ventral striatum (811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region.
CONCLUSION: Acute MK-801 treatment increases synchrony of baseline gamma oscillations, and causes very early changes in gene expressions in six individual rat brain regions, a first report.
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36
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German CL, Baladi MG, McFadden LM, Hanson GR, Fleckenstein AE. Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease. Pharmacol Rev 2015; 67:1005-24. [PMID: 26408528 PMCID: PMC4630566 DOI: 10.1124/pr.114.010397] [Citation(s) in RCA: 129] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders.
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Affiliation(s)
- Christopher L German
- School of Dentistry (C.L.G., M.G.B., G.R.H., A.E.F.) and Department of Pharmacology and Toxicology (L.M.M., G.R.H.), University of Utah, Salt Lake City, Utah
| | - Michelle G Baladi
- School of Dentistry (C.L.G., M.G.B., G.R.H., A.E.F.) and Department of Pharmacology and Toxicology (L.M.M., G.R.H.), University of Utah, Salt Lake City, Utah
| | - Lisa M McFadden
- School of Dentistry (C.L.G., M.G.B., G.R.H., A.E.F.) and Department of Pharmacology and Toxicology (L.M.M., G.R.H.), University of Utah, Salt Lake City, Utah
| | - Glen R Hanson
- School of Dentistry (C.L.G., M.G.B., G.R.H., A.E.F.) and Department of Pharmacology and Toxicology (L.M.M., G.R.H.), University of Utah, Salt Lake City, Utah
| | - Annette E Fleckenstein
- School of Dentistry (C.L.G., M.G.B., G.R.H., A.E.F.) and Department of Pharmacology and Toxicology (L.M.M., G.R.H.), University of Utah, Salt Lake City, Utah
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Epigenetic Regulation of Dopamine Transporter mRNA Expression in Human Neuroblastoma Cells. Neurochem Res 2015; 40:1372-8. [PMID: 25963949 DOI: 10.1007/s11064-015-1601-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 04/29/2015] [Accepted: 05/04/2015] [Indexed: 12/16/2022]
Abstract
The dopamine transporter (DAT) is a key regulator of dopaminergic neurotransmission. As such, proper regulation of DAT expression is important to maintain homeostasis, and disruption of DAT expression can lead to neurobehavioral dysfunction. Based on genomic features within the promoter of the DAT gene, there is potential for DAT expression to be regulated through epigenetic mechanisms, including DNA methylation and histone acetylation. However, the relative contribution of these mechanisms to DAT expression has not been empirically determined. Using pharmacologic and genetic approaches, we demonstrate that inhibition of DNA methyltransferase (DNMT) activity increased DAT mRNA approximately 1.5-2 fold. This effect was confirmed by siRNA knockdown of DNMT1. Likewise, the histone deacetylase (HDAC) inhibitors valproate and butyrate also increased DAT mRNA expression, but the response was much more robust with expression increasing over tenfold. Genetic knockdown of HDAC1 by siRNA also increased DAT expression, but not to the extent seen with pharmacological inhibition, suggesting additional isoforms of HDAC or other targets may contribute to the observed effect. Together, these data identify the relative contribution of DNMTs and HDACs in regulating expression. These finding may aid in understanding the mechanistic basis for changes in DAT expression in normal and pathophysiological states.
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Wang KH, Penmatsa A, Gouaux E. Neurotransmitter and psychostimulant recognition by the dopamine transporter. Nature 2015; 521:322-7. [PMID: 25970245 DOI: 10.1038/nature14431] [Citation(s) in RCA: 332] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 03/23/2015] [Indexed: 12/17/2022]
Abstract
Na(+)/Cl(-)-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants d-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.
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Affiliation(s)
- Kevin H Wang
- Vollum Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
| | - Aravind Penmatsa
- Vollum Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
| | - Eric Gouaux
- 1] Vollum Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA [2] Howard Hughes Medical Institute, Oregon Health &Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
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Huot P, Fox SH, Brotchie JM. Monoamine reuptake inhibitors in Parkinson's disease. PARKINSON'S DISEASE 2015; 2015:609428. [PMID: 25810948 PMCID: PMC4355567 DOI: 10.1155/2015/609428] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 12/26/2014] [Indexed: 12/13/2022]
Abstract
The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia.
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Affiliation(s)
- Philippe Huot
- Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8
- Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8
- Department of Pharmacology and Division of Neurology, Faculty of Medicine, Université de Montréal and Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada
| | - Susan H. Fox
- Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8
- Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8
| | - Jonathan M. Brotchie
- Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8
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Extracellular dopamine and alterations on dopamine transporter are related to reserpine toxicity in Caenorhabditis elegans. Arch Toxicol 2015; 90:633-45. [PMID: 25579234 DOI: 10.1007/s00204-015-1451-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 01/06/2015] [Indexed: 10/24/2022]
Abstract
Reserpine is used as an animal model of parkinsonism. We hypothesized that the involuntary movements induced by reserpine in rodents are induced by dopaminergic toxicity caused by extracellular dopamine accumulation. The present study tested the effects of reserpine on the dopaminergic system in Caenorhabditis elegans. Reserpine was toxic to worms (decreased the survival, food intake, development and changed egg laying and defecation cycles). In addition, reserpine increased the worms' locomotor rate on food and decreased dopamine levels. Morphological evaluations of dopaminergic CEP neurons confirmed neurodegeneration characterized by decreased fluorescence intensity and the number of worms with intact CEP neurons, and increased number of shrunken somas per worm. These effects were unrelated to reserpine's effect on decreased expression of the dopamine transporter, dat-1. Interestingly, the locomotor rate on food and the neurodegenerative parameters fully recovered to basal conditions upon reserpine withdrawal. Furthermore, reserpine decreased survival in vesicular monoamine transporter and dat-1 loss-of-function mutant worms. In addition, worms pre-exposed to dopamine followed by exposure to reserpine had decreased survival. Reserpine activated gst-4, which controls a phase II detoxification enzymes downstream of nuclear factor (erythroid-derived-2)-like 2. Our findings establish that the dopamine transporter, dat-1, plays an important role in reserpine toxicity, likely by increasing extracellular dopamine concentrations.
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Quick M, Shi L. The sodium/multivitamin transporter: a multipotent system with therapeutic implications. VITAMINS AND HORMONES 2015; 98:63-100. [PMID: 25817866 PMCID: PMC5530880 DOI: 10.1016/bs.vh.2014.12.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
The Na(+)/multivitamin transporter (SMVT) is a member of the solute:sodium symporter family that catalyzes the Na(+)-dependent uptake of the structurally diverse water-soluble vitamins pantothenic acid (vitamin B5) and biotin (vitamin H), α-lipoic acid-a vitamin-like substance with strong antioxidant properties-and iodide. The organic substrates of SMVT play central roles in the cellular metabolism and are, therefore, essential for normal human health and development. For example, biotin deficiency leads to growth retardation, dermatological disorders, and neurological disorders. Animal studies have shown that biotin deficiency during pregnancy is directly correlated to embryonic growth retardation, congenital malformation, and death of the embryo. This chapter focuses on the structural and functional features of the human isoform of SMVT (hSMVT); the discovery of which was greatly facilitated by the cloning and expression of hSMVT in tractable expression systems. Special emphasis will be given to mechanistic implications of the transport process of hSMVT that will inform our understanding of the molecular determinants of hSMVT-mediated transport in dynamic context to alleviate the development and optimization of hSMVT as a multipotent platform for drug delivery.
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Affiliation(s)
- Matthias Quick
- Department of Psychiatry, Division of Molecular Therapeutics, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, USA.
| | - Lei Shi
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, USA
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Roncancio D, Yu H, Xu X, Wu S, Liu R, Debord J, Lou X, Xiao Y. A label-free aptamer-fluorophore assembly for rapid and specific detection of cocaine in biofluids. Anal Chem 2014; 86:11100-6. [PMID: 25342426 DOI: 10.1021/ac503360n] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
We report a rapid and specific aptamer-based method for one-step cocaine detection with minimal reagent requirements. The feasibility of aptamer-based detection has been demonstrated with sensors that operate via target-induced conformational change mechanisms, but these have generally exhibited limited target sensitivity. We have discovered that the cocaine-binding aptamer MNS-4.1 can also bind the fluorescent molecule 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND) and thereby quench its fluorescence. We subsequently introduced sequence changes into MNS-4.1 to engineer a new cocaine-binding aptamer (38-GC) that exhibits higher affinity to both ligands, with reduced background signal and increased signal gain. Using this aptamer, we have developed a new sensor platform that relies on the cocaine-mediated displacement of ATMND from 38-GC as a result of competitive binding. We demonstrate that our sensor can detect cocaine within seconds at concentrations as low as 200 nM, which is 50-fold lower than existing assays based on target-induced conformational change. More importantly, our assay achieves successful cocaine detection in body fluids, with a limit of detection of 10.4, 18.4, and 36 μM in undiluted saliva, urine, and serum samples, respectively.
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Affiliation(s)
- Daniel Roncancio
- Department of Chemistry and Biochemistry, Florida International University , 11200 SW Eighth Street, Miami, Florida 33199, United States
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Heal DJ, Gosden J, Smith SL. Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine. Neuropharmacology 2014; 87:19-40. [PMID: 24953830 DOI: 10.1016/j.neuropharm.2014.06.012] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 05/07/2014] [Accepted: 06/09/2014] [Indexed: 12/20/2022]
Abstract
The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. However, drugs with rapid brain penetration like sibutramine, bupropion, mazindol and tesofensine, which are equal to or more potent than cocaine as dopamine reuptake inhibitors, produce no discernable subjective effects such as drug "highs" or euphoria in drug-experienced human volunteers. Moreover they are dysphoric and aversive when given at high doses. In vivo experiments in animals demonstrate that cocaine's monoaminergic pharmacology is profoundly different from that of other prescribed monoamine reuptake inhibitors, with the exception of methylphenidate. These findings led us to conclude that the highly unusual stimulant profile of cocaine and related compounds, eg methylphenidate, is not mediated by monoamine reuptake inhibition alone. We describe the experimental findings which suggest cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport. This results in a firing-dependent, retro-transport of dopamine into the synaptic cleft. The proposed mechanism of cocaine is, therefore, different from other small molecule negative allostereric modulators of the monoamine reuptake transporters, eg SoRI-6238, which merely reduce the rate of inward transport. Because the physiological role of DAT is to remove dopamine from the synapse and the action of cocaine is the opposite of this, we have postulated that cocaine's effect is analogous to an inverse agonist. If this hypothesis is validated then cocaine is the prototypical compound that exemplifies a new class of monoaminergic drugs; DAT "inverse agonists". This article is part of the Special Issue entitled 'CNS Stimulants'.
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Affiliation(s)
- David J Heal
- RenaSci Limited, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
| | - Jane Gosden
- RenaSci Limited, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK
| | - Sharon L Smith
- RenaSci Limited, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
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Genetic Addiction Risk Score (GARS): molecular neurogenetic evidence for predisposition to Reward Deficiency Syndrome (RDS). Mol Neurobiol 2014; 50:765-96. [PMID: 24878765 PMCID: PMC4225054 DOI: 10.1007/s12035-014-8726-5] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 04/29/2014] [Indexed: 12/21/2022]
Abstract
We have published extensively on the neurogenetics of brain reward systems with reference to the genes related to dopaminergic function in particular. In 1996, we coined “Reward Deficiency Syndrome” (RDS), to portray behaviors found to have gene-based association with hypodopaminergic function. RDS as a useful concept has been embraced in many subsequent studies, to increase our understanding of Substance Use Disorder (SUD), addictions, and other obsessive, compulsive, and impulsive behaviors. Interestingly, albeit others, in one published study, we were able to describe lifetime RDS behaviors in a recovering addict (17 years sober) blindly by assessing resultant Genetic Addiction Risk Score (GARS™) data only. We hypothesize that genetic testing at an early age may be an effective preventive strategy to reduce or eliminate pathological substance and behavioral seeking activity. Here, we consider a select number of genes, their polymorphisms, and associated risks for RDS whereby, utilizing GWAS, there is evidence for convergence to reward candidate genes. The evidence presented serves as a plausible brain-print providing relevant genetic information that will reinforce targeted therapies, to improve recovery and prevent relapse on an individualized basis. The primary driver of RDS is a hypodopaminergic trait (genes) as well as epigenetic states (methylation and deacetylation on chromatin structure). We now have entered a new era in addiction medicine that embraces the neuroscience of addiction and RDS as a pathological condition in brain reward circuitry that calls for appropriate evidence-based therapy and early genetic diagnosis and that requires further intensive investigation.
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45
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Loland CJ. The use of LeuT as a model in elucidating binding sites for substrates and inhibitors in neurotransmitter transporters. Biochim Biophys Acta Gen Subj 2014; 1850:500-10. [PMID: 24769398 DOI: 10.1016/j.bbagen.2014.04.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Revised: 04/09/2014] [Accepted: 04/11/2014] [Indexed: 01/24/2023]
Abstract
BACKGROUND The mammalian neurotransmitter transporters are complex proteins playing a central role in synaptic transmission between neurons by rapid reuptake of neurotransmitters. The proteins which transport dopamine, noradrenaline and serotonin belong to the Neurotransmitter:Sodium Symporters (NSS). Due to their important role, dysfunctions are associated with several psychiatric and neurological diseases and they also serve as targets for a wide range of therapeutic and illicit drugs. Despite the central physiological and pharmacological importance, direct evidence on structure-function relationships on mammalian NSS proteins has so far been unsuccessful. The crystal structure of the bacterial NSS protein, LeuT, has been a turning point in structural investigations. SCOPE OF REVIEW To provide an update on what is known about the binding sites for substrates and inhibitors in the LeuT. The different binding modes and binding sites will be discussed with special emphasis on the possible existence of a second substrate binding site. It is the goal to give an insight into how investigations on ligand binding in LeuT have provided basic knowledge about transporter conformations and translocation mechanism which can pave the road for a deeper understanding of drug binding and function of the mammalian transporters. MAJOR CONCLUSIONS The LeuT is a suitable model for the structural investigation of NSS proteins including the possible location of drug binding sites. It is still debated whether the LeuT is a suitable model for the molecular mechanisms behind substrate translocation. GENERAL SIGNIFICANCE Structure and functional aspects of NSS proteins are central for understanding synaptic transmission. With the purification and crystallization of LeuT as well as the dopamine transporter from Drosophila melanogaster, the application of biophysical methods such as fluorescence spectroscopy, neutron- or x-ray scattering and NMR for understanding its function becomes increasingly available. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.
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Affiliation(s)
- Claus J Loland
- Molecular Neuropharmacology Laboratory, Department of Neuroscience and Pharmacology, The Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
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46
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Bornhorst J, Chakraborty S, Meyer S, Lohren H, Brinkhaus SG, Knight AL, Caldwell KA, Caldwell GA, Karst U, Schwerdtle T, Bowman A, Aschner M. The effects of pdr1, djr1.1 and pink1 loss in manganese-induced toxicity and the role of α-synuclein in C. elegans. Metallomics 2014; 6:476-90. [PMID: 24452053 DOI: 10.1039/c3mt00325f] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Parkinson's disease (PD) is a neurodegenerative brain disorder characterized by selective dopaminergic (DAergic) cell loss that results in overt motor and cognitive deficits. Current treatment options exist to combat PD symptomatology, but are unable to directly target its pathogenesis due to a lack of knowledge concerning its etiology. Several genes have been linked to PD, including three genes associated with an early-onset familial form: parkin, pink1 and dj1. All three genes are implicated in regulating oxidative stress pathways. Another hallmark of PD pathophysiology is Lewy body deposition, associated with the gain-of-function genetic risk factor α-synuclein. The function of α-synuclein is poorly understood, as it shows both neurotoxic and neuroprotective activities in PD. Using the genetically tractable invertebrate Caenorhabditis elegans (C. elegans) model system, the neurotoxic or neuroprotective role of α-synuclein upon acute Mn exposure in the background of mutated pdr1, pink1 or djr1.1 was examined. The pdr1 and djr1.1 mutants showed enhanced Mn accumulation and oxidative stress that was reduced by α-synuclein. Moreover, DAergic neurodegeneration, while unchanged with Mn exposure, returned to wild-type (WT) levels for pdr1, but not djr1.1 mutants expressing α-synuclein. Taken together, this study uncovers a novel, neuroprotective role for WT human α-synuclein in attenuating Mn-induced toxicity in the background of PD-associated genes, and further supports the role of extracellular dopamine in exacerbating Mn neurotoxicity.
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Affiliation(s)
- Julia Bornhorst
- Institute of Food Chemistry, University of Münster, Münster, Germany
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Gowrishankar R, Hahn MK, Blakely RD. Good riddance to dopamine: roles for the dopamine transporter in synaptic function and dopamine-associated brain disorders. Neurochem Int 2013; 73:42-8. [PMID: 24231471 DOI: 10.1016/j.neuint.2013.10.016] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 10/29/2013] [Accepted: 10/31/2013] [Indexed: 11/25/2022]
Abstract
The neurotransmitter dopamine (DA) plays a critical role in CNS circuits that provide for attention, executive function, reward responses, motivation and movement. DA is inactivated by the cocaine- and amphetamine-sensitive DA transporter (DAT), a protein that also provides a pathway for non-vesicular DA release. After a brief review of DAT function and psychostimulant actions, we consider the importance DAT in relation to the distinct firing patterns of DA neurons that permit awareness of novelty and reward. Finally, we review recent efforts to gather direct support for DAT-linked disorders, with a specific focus on DAT mutations recently identified in subjects with ADHD.
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Affiliation(s)
- Raajaram Gowrishankar
- Vanderbilt International Scholars Program, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States
| | - Maureen K Hahn
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States; Department of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States
| | - Randy D Blakely
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States; Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
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Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area. J Neurosci 2013; 33:12329-36. [PMID: 23884939 DOI: 10.1523/jneurosci.0809-13.2013] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Potentiation of glutamate responses is a critical synaptic response to cocaine exposure in ventral tegmental area (VTA) neurons. However, the mechanism by which cocaine exposure promotes potentiation of NMDA receptors (NMDARs) and subsequently AMPA receptors (AMPARs) is not fully understood. In this study we demonstrate that repeated cocaine treatment causes loss of D2 dopamine receptor functional responses via interaction with lysosome-targeting G-protein-associated sorting protein1 (GASP1). We also show that the absence of D2 downregulation in GASP1-KO mice prevents cocaine-induced potentiation of NMDAR currents, elevation of the AMPA/NMDA ratio, and redistribution of NMDAR and AMPAR subunits to the membrane. As a pharmacological parallel, coadministration of the high-affinity D2 agonist, aripiprazole, reduces not only functional downregulation of D2s in response to cocaine but also potentiation of NMDAR and AMPAR responses in wild-type mice. Together these data suggest that functional loss of D2 receptors is a critical mechanism mediating cocaine-induced glutamate plasticity in VTA neurons.
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Hall FS, Itokawa K, Schmitt A, Moessner R, Sora I, Lesch KP, Uhl GR. Decreased vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) function in knockout mice affects aging of dopaminergic systems. Neuropharmacology 2013; 76 Pt A:146-55. [PMID: 23978383 DOI: 10.1016/j.neuropharm.2013.07.031] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 07/22/2013] [Accepted: 07/30/2013] [Indexed: 01/15/2023]
Abstract
Dopamine (DA) is accumulated and compartmentalized by the dopamine transporter (DAT; SLC3A6) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2). These transporters work at the plasma and vesicular membranes of dopaminergic neurons, respectively, and thus regulate levels of DA in neuronal compartments that include the extravesicular cytoplasmic compartment. DA in this compartment has been hypothesized to contribute to oxidative damage that can reduce the function of dopaminergic neurons in aging brains and may contribute to reductions in dopaminergic neurochemical markers, locomotor behavior and responses to dopaminergic drugs that are found in aged animals. The studies reported here examined aged mice with heterozygous deletions of VMAT2 or of DAT, which each reduce transporter expression to about 50% of levels found in wild-type (WT) mice. Aged mice displayed reduced locomotor responses under a variety of circumstances, including in response to locomotor stimulants, as well as changes in monoamine levels and metabolites in a regionally dependent manner. Several effects of aging were more pronounced in heterozygous VMAT2 knockout (KO) mice, including aging induced reductions in locomotion and reduced locomotor responses to cocaine. By contrast, some effects of aging were reduced or not observed in heterozygous DAT KO mice. These findings support the idea that altered DAT and VMAT2 expression affect age-related changes in dopaminergic function. These effects are most likely mediated by alterations in DA compartmentalization, and might be hypothesized to be exacerbated by other factors that affect the metabolism of cytosolic DA. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
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Affiliation(s)
- F S Hall
- Molecular Neurobiology Branch, Intramural Research Program, NIDA, NIH/DHHS, Baltimore, MD 21224, USA.
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Blum K, Oscar-Berman M, Barh D, Giordano J, Gold MS. Dopamine Genetics and Function in Food and Substance Abuse. JOURNAL OF GENETIC SYNDROMES & GENE THERAPY 2013; 4:1000121. [PMID: 23543775 PMCID: PMC3609029 DOI: 10.4172/2157-7412.1000121] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Having entered the genomics era with confidence in the future of medicine, including psychiatry, identifying the role of DNA and polymorphic associations with brain reward circuitry has led to a new understanding of all addictive behaviors. It is noteworthy that this strategy may provide treatment for the millions who are the victims of "Reward Deficiency Syndrome" (RDS) a genetic disorder of brain reward circuitry. This article will focus on drugs and food being mutuality addictive, and the role of dopamine genetics and function in addictions, including the interaction of the dopamine transporter, and sodium food. We will briefly review our concept that concerns the genetic antecedents of multiple-addictions (RDS). Studies have also shown that evaluating a panel of established reward genes and polymorphisms enables the stratification of genetic risk to RDS. The panel is called the "Genetic Addiction Risk Score (GARS)", and is a tool for the diagnosis of a genetic predisposition for RDS. The use of this test, as pointed out by others, would benefit the medical community by identifying at risk individuals at a very early age. We encourage, in depth work in both animal and human models of addiction. We encourage further exploration of the neurogenetic correlates of the commonalities between food and drug addiction and endorse forward thinking hypotheses like "The Salted Food Addiction Hypothesis".
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Affiliation(s)
- K Blum
- Department of Psychiatry & McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA
- Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West Bengal, India
- Department of Nutrigenomics, LifeGen, Inc., Austin, Texas, USA
| | - M Oscar-Berman
- Department of Anatomy & Neurobiology, Boston University School of Medicine, 72 East Concord Street, Boston, MA, USA
| | - D Barh
- Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West Bengal, India
| | - J Giordano
- Department of Holistic Medicine, G & G Health Care Services LLC, North Miami Beach, FL, USA
| | - MS Gold
- Department of Psychiatry & McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA
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