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American Journal of Medical Genetics.... Mar 2018The dopamine transporter (DAT) is one of the most relevant and investigated neurotransmitter transporters. DAT is a plasma membrane protein which plays a homeostatic... (Review)
Review
The dopamine transporter (DAT) is one of the most relevant and investigated neurotransmitter transporters. DAT is a plasma membrane protein which plays a homeostatic role, controlling both extracellular and intracellular concentrations of dopamine (DA). Since unbalanced DA levels are known to be involved in numerous mental disorders, a wealth of investigations has provided valuable insights concerning DAT role into normal brain functioning and pathological processes. Briefly, this extensive but non-systematic review discusses what is recently known about the role of SLC6A3 gene which encodes the dopamine transporter in psychiatric phenotypes. DAT protein, SLC6A3 gene, animal models, neuropsychology, and neuroimaging investigations are also concisely discussed. To conclude, current challenges are reviewed in order to provide perspectives for future studies.
Topics: Animals; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Mental Disorders; Phenotype
PubMed: 28766921
DOI: 10.1002/ajmg.b.32578 -
Vitamins and Hormones 2015In this chapter, we explore the basic science of the dopamine transporter (DAT), an integral component of a system that regulates dopamine homeostasis. Dopamine is a key... (Review)
Review
In this chapter, we explore the basic science of the dopamine transporter (DAT), an integral component of a system that regulates dopamine homeostasis. Dopamine is a key neurotransmitter for several brain functions including locomotor control and reward systems. The transporter structure, function, mechanism of action, localization, and distribution, in addition to gene regulation, are discussed. Over many years, a wealth of information concerning the DAT has been accrued and has led to increased interest in the role of the DAT in a plethora of central nervous system diseases. These DAT characteristics are explored in relation to a range of neurological and neuropsychiatric diseases, with a particular focus on the genetics of the DAT. In addition, we discuss the pharmacology of the DAT and how this relates to disease and addiction.
Topics: Animals; Central Nervous System Diseases; Dopamine; Dopamine Plasma Membrane Transport Proteins; Homeostasis; Humans; Time Factors
PubMed: 25817874
DOI: 10.1016/bs.vh.2014.12.009 -
European Journal of Pharmacology Oct 2015The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however,... (Review)
Review
The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs.
Topics: Action Potentials; Adrenergic Neurons; Amphetamine; Animals; Brain; Central Nervous System Stimulants; Cocaine; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Humans; Kinetics; Neuronal Plasticity; Norepinephrine; Nucleus Accumbens; Prefrontal Cortex
PubMed: 26209364
DOI: 10.1016/j.ejphar.2015.07.044 -
Movement Disorders : Official Journal... Nov 2023Preliminary studies suggested seasonality of dopaminergic functioning, but it is unknown whether dopamine transporter (DAT) expression in humans is also dependent on the...
BACKGROUND
Preliminary studies suggested seasonality of dopaminergic functioning, but it is unknown whether dopamine transporter (DAT) expression in humans is also dependent on the seasons. We, therefore, investigated seasonal and sunlight-dependent effects on DAT availability in early Parkinson's disease (PD) patients and healthy controls.
METHODS
DAT single-photon emission computed tomography scans (n = 730) were gathered from the Parkinson's Progression Marker Initiative (PPMI) database. We used global horizontal irradiance (GHI) as proxy for sun exposure/month and assessed associations between striatal DAT availability and season (autumn/winter versus spring/summer), GHI and latitude of the PPMI site.
RESULTS
In PD patients, DAT availability in the left caudate nucleus was higher in spring/summer (B [standard error (SE)] = 0.05 [0.02], P = 0.03) and positively associated with higher sun exposure (B [SE] = 0.59 [0.22] × 10 , P = 0.007). Latitude (in degrees north) of the PPMI site was negatively associated with DAT availability in both PD and healthy controls.
CONCLUSION
Striatal DAT availability may be influenced by daylight exposure. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Parkinson Disease; Sunlight; Tomography, Emission-Computed, Single-Photon
PubMed: 37670567
DOI: 10.1002/mds.29597 -
Journal of Neurogenetics Mar 2016The dopamine transporter (DAT) plays an important homeostatic role in the control of both the extracellular and intraneuronal concentrations of dopamine, thereby... (Review)
Review
The dopamine transporter (DAT) plays an important homeostatic role in the control of both the extracellular and intraneuronal concentrations of dopamine, thereby providing effective control over activity of dopaminergic transmission. Since brain dopamine is known to be involved in numerous neuropsychiatric disorders, investigations using mice with genetically altered DAT function and thus intensity of dopamine-mediated signaling have provided numerous insights into the pathology of these disorders and novel pathological mechanisms that could be targeted to provide new therapeutic approaches for these disorders. In this brief overview, we discuss recent investigations involving animals with genetically altered DAT function, particularly focusing on translational studies providing new insights into pathology and pharmacology of dopamine-related disorders. Perspective applications of these and newly developed models of DAT dysfunction are also discussed.
Topics: Animals; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Mice; Translational Research, Biomedical
PubMed: 27276191
DOI: 10.3109/01677063.2016.1144751 -
Clinical and Translational Science Jun 2023Dopamine transporter (DAT) imaging is an in vivo tool to assess presynaptic dopaminergic function in the clinical practices of Parkinson's disease (PD). Current clinical...
Dopamine transporter (DAT) imaging is an in vivo tool to assess presynaptic dopaminergic function in the clinical practices of Parkinson's disease (PD). Current clinical practices focused on qualitatively visual interpretation of DAT imaging, whereas quantitative analyses are potentially more helpful when monitoring the progression of PD. Previous cross-sectional studies indicated certain motor and non-motor features were associated with striatal DAT binding, whereas limited data were reported in terms of the longitudinal correlation between clinical features of PD with striatal DAT binding. The purpose of our study is to clarify current and longitudinal correlations between striatal DAT binding and clinical measures. A total of 352 untreated PD individuals and 167 healthy controls with complete baseline clinical measures and neuroimaging data were identified from the Parkinson's Progression and Markers Initiative (PPMI) database. Patients with PD underwent DAT imaging at the screening visit and following months 12, 24, and 48. Multiple linear regression models and linear mixed-effect models were respectively conducted to investigate the cross-sectional and longitudinal correlation between clinical characteristics and DAT binding. Associations between changes in clinical characteristics and changes in DAT binding were further evaluated and the Spearman rank correlation coefficients were reported. In the cross-sectional analysis, baseline striatal DAT binding was significantly associated with the Hoehn and Yahr scale, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) scores, the rigidity scores, and the axial scores in PD individuals (false discovery rate [FDR]-adjusted p = 0.0017 for all above). Patients who developed freezing of gait had lower striatal DAT binding (FDR-adjusted p = 0.0161). Healthy controls who had higher tremor scores and suffered more severe olfactory dysfunction had lower striatal DAT binding (FDR-adjusted p = 0.0257 for all above). Longitudinal analysis indicated that baseline severity of rapid-eye-movement sleep behavior disorder was significantly associated with longitudinal striatal DAT binding in patients with PD (FDR-adjusted p = 0.0120). Furthermore, changes in MDS-UPDRS scores and the State-Trait Anxiety Inventory (STAI) scores demonstrated significant correlations with changes in striatal DAT binding over 4 years (p = 0.005 and p = 0.032, respectively). Our findings clarified quantitative associations between certain motor and non-motor features with current and future striatal dopamine binding, suggesting the feasibility of using DAT images as a progression predictive marker for PD. Further studies are needed to investigate correlations between different regional dopamine binding with specific clinical features.
Topics: Humans; Parkinson Disease; Dopamine Plasma Membrane Transport Proteins; Dopamine; Cross-Sectional Studies; Gait Disorders, Neurologic
PubMed: 36915231
DOI: 10.1111/cts.13508 -
Nature Communications May 2022The dopamine transporter facilitates dopamine reuptake from the extracellular space to terminate neurotransmission. The transporter belongs to the...
The dopamine transporter facilitates dopamine reuptake from the extracellular space to terminate neurotransmission. The transporter belongs to the neurotransmitter:sodium symporter family, which includes transporters for serotonin, norepinephrine, and GABA that utilize the Na gradient to drive the uptake of substrate. Decades ago, it was shown that the serotonin transporter also antiports K, but investigations of K-coupled transport in other neurotransmitter:sodium symporters have been inconclusive. Here, we show that ligand binding to the Drosophila- and human dopamine transporters are inhibited by K, and the conformational dynamics of the Drosophila dopamine transporter in K are divergent from the apo- and Na-states. Furthermore, we find that K increases dopamine uptake by the Drosophila dopamine transporter in liposomes, and visualize Na and K fluxes in single proteoliposomes using fluorescent ion indicators. Our results expand on the fundamentals of dopamine transport and prompt a reevaluation of the impact of K on other transporters in this pharmacologically important family.
Topics: Animals; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drosophila; Ion Transport; Ions; Neurotransmitter Agents; Potassium; Serotonin Plasma Membrane Transport Proteins; Sodium; Symporters
PubMed: 35508541
DOI: 10.1038/s41467-022-30154-5 -
Handbook of Experimental Pharmacology 2018The human genome encodes 19 genes of the solute carrier 6 (SLC6) family; non-synonymous changes in the coding sequence give rise to mutated transporters, which are... (Review)
Review
The human genome encodes 19 genes of the solute carrier 6 (SLC6) family; non-synonymous changes in the coding sequence give rise to mutated transporters, which are misfolded and thus cause diseases in the affected individuals. Prominent examples include mutations in the transporters for dopamine (DAT, SLC6A3), for creatine (CT1, SLC6A8), and for glycine (GlyT2, SLC6A5), which result in infantile dystonia, mental retardation, and hyperekplexia, respectively. Thus, there is an obvious unmet medical need to identify compounds, which can remedy the folding deficit. The pharmacological correction of folding defects was originally explored in mutants of the serotonin transporter (SERT, SLC6A4), which were created to study the COPII-dependent export from the endoplasmic reticulum. This led to the serendipitous discovery of the pharmacochaperoning action of ibogaine. Ibogaine and its metabolite noribogaine also rescue several disease-relevant mutants of DAT. Because the pharmacology of DAT and SERT is exceptionally rich, it is not surprising that additional compounds have been identified, which rescue folding-deficient mutants. These compounds are not only of interest for restoring DAT function in the affected children. They are also likely to serve as useful tools to interrogate the folding trajectory of the transporter. This is likely to initiate a virtuous cycle: if the principles underlying folding of SLC6 transporters are understood, the design of pharmacochaperones ought to be facilitated.
Topics: Animals; Dopamine Plasma Membrane Transport Proteins; Drug Discovery; Humans; Molecular Chaperones; Mutation; Protein Folding; Proteostasis Deficiencies; Serotonin Plasma Membrane Transport Proteins; Solute Carrier Proteins
PubMed: 29086036
DOI: 10.1007/164_2017_71 -
Current Topics in Behavioral... 2022The dopamine transporter (DAT) is the main target of methylphenidate (MPH), which remains the number one drug prescribed worldwide for the treatment of Attention-Deficit...
The dopamine transporter (DAT) is the main target of methylphenidate (MPH), which remains the number one drug prescribed worldwide for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). In addition, abnormalities of the DAT have been widely associated with ADHD. Based on clinical and preclinical studies, the direction of DAT abnormalities in ADHD are, however, still unclear. Moreover, chronic treatment of MPH has been shown to increase brain DAT expression in both animals and ADHD patients, suggesting that findings of overexpressed levels of DAT in ADHD patients are possibly attributable to the effects of long-term MPH treatment rather than the pathology of the condition itself. In this chapter, we will discuss some of the effects exerted by MPH, which are related to its actions on catecholamine protein targets and brain metabolites, together with genes and proteins mediating neuronal plasticity. For this purpose, we present data from biochemical, proton nuclear magnetic resonance spectroscopy (H-NMR) and gene/protein expression studies. Overall, results of the studies discussed in this chapter show that MPH has a complex biological/pharmacological action well beyond the DAT.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Brain; Central Nervous System Stimulants; Dopamine Plasma Membrane Transport Proteins; Methylphenidate
PubMed: 35507284
DOI: 10.1007/7854_2022_333 -
Journal of Nuclear Medicine Technology Mar 2019Idiopathic Parkinson disease (PD) is a progressive neurologic condition that affects the dopamine transporters in the substantia nigra of the brain. Currently, more than... (Review)
Review
Idiopathic Parkinson disease (PD) is a progressive neurologic condition that affects the dopamine transporters in the substantia nigra of the brain. Currently, more than 10 million people are living with this disease worldwide, with thousands of newly diagnosed and undiagnosed cases added every year. The disease is difficult to differentiate from other similar disorders, as symptoms widely vary and can mimic other conditions. Classic PD symptoms may look similar to essential tremor and other parkinsonian syndromes. The I-ioflupane dopamine transporter (DaT) protocol differentiates PD from essential tremor through in vivo testing with SPECT imaging. The DaT protocol commonly relies on a semiquantitative analysis and visual interpretations of the images, which may produce inaccurate results due to human error. DaTQUANT software (GE Healthcare) was created in 2013 as an adjunct processing tool with advanced quantitative uptake methods and a designated normals database for a more accurate assessment of a patient's case. DaTQUANT has proven to be a vital protocol component for an accurate differentiation of PD from essential tremor. Current use of the software has been rather limited, so a greater push for education and implementation will be key for its success.
Topics: Dopamine Plasma Membrane Transport Proteins; Humans; Image Processing, Computer-Assisted; Parkinson Disease; Software
PubMed: 30683690
DOI: 10.2967/jnmt.118.222349