-
The Journal of Clinical Investigation May 2019The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA...
The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, Autism Spectrum Disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine to methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e. anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous dopamine efflux. Here we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation display impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.
Topics: Amino Acid Substitution; Animals; Autistic Disorder; Behavior, Animal; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drosophila Proteins; Drosophila melanogaster; Mice; Mice, Mutant Strains; Mutation, Missense; Synaptic Transmission
PubMed: 31094705
DOI: 10.1172/JCI127411 -
Translational Psychiatry Oct 2022Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and... (Randomized Controlled Trial)
Randomized Controlled Trial
Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [C]DASB and [C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.
Topics: Brain; Cognitive Behavioral Therapy; Dopamine; Dopamine Plasma Membrane Transport Proteins; Escitalopram; Humans; Phobia, Social; Serotonin; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 36202797
DOI: 10.1038/s41398-022-02187-3 -
Parkinsonism & Related Disorders Sep 2023Glymphatic dysfunction can contribute to α-synucleinopathies. We examined glymphatic function in idiopathic Parkinson's disease (PD) utilizing Diffusion Tensor Image...
INTRODUCTION
Glymphatic dysfunction can contribute to α-synucleinopathies. We examined glymphatic function in idiopathic Parkinson's disease (PD) utilizing Diffusion Tensor Image Analysis aLong the Perivascular Space (DTI-ALPS).
METHODS
This study enrolled consecutive patients diagnosed with de novo PD between June 2017 and March 2019 who underwent brain DTI with concurrent I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (I-FP-CIT) SPECT, and age- and sex-matched controls. From DTI-ALPS, the ALPS-index was calculated as a ratio of diffusivities along the x-axis in the region of neural fibers passing vertically to the diffusivities perpendicular to them, which reflected perivascular water motion at the lateral ventricular body level. The ALPS-index of the PD and control groups was compared using Student's t-test; its correlations with clinical scores for motor and cognition (UPDRS-III, MMSE, and MoCA) and striatal dopamine transporter uptake measured by I-FP-CIT specific binding ratios (SBRs) were examined using a correlation coefficient.
RESULTS
In all, 54 patients in the de novo PD group (31 women, 23 men; mean age, 68.9 ± 9.4 years) and 54 in the control group (mean age, 69.0 ± 10.5 years) were included. The ALPS-index was lower in the PD group than in the controls (1.51 ± 0.22 versus 1.66 ± 0.20; P < 0.001). In the PD group, the ALPS-index negatively correlated with the UPDRS-III score (r = -0.526), and positively correlated with the MMSE (r = 0.377) and MoCA scores (r = 0.382) (all, P < 0.05). No correlation was observed between the ALPS-index and striatal I-FP-CIT SBRs (P > 0.05).
CONCLUSIONS
DTI-ALPS can reveal glymphatic dysfunction in patients with PD, whose severity correlated with motor and cognitive dysfunction, but not striatal dopamine transporter uptake.
Topics: Male; Humans; Female; Middle Aged; Aged; Parkinson Disease; Dopamine Plasma Membrane Transport Proteins; Tropanes
PubMed: 37523953
DOI: 10.1016/j.parkreldis.2023.105767 -
Biomolecules Jan 2020The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors of human NET (hNET) play a...
The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors of human NET (hNET) play a major role in the treatment of many central and peripheral nervous system diseases. In this study, we focused on the spatial structure of a NET constructed by homology modeling on dopamine transporter templates. We further examined molecular construction of primary binding pocket (S1) together with secondary binding site (S2) and extracellular loop 4 (EL4). The next stage involved docking of transporter inhibitors: Reboxetine, duloxetine, desipramine, and other commonly used drugs. The procedure revealed the molecular orientation of residues and disclosed ones that are the most important for ligand binding: Phenylalanine F72, aspartic acid D75, tyrosine Y152, and phenylalanine F317. Aspartic acid D75 plays a key role in recognition of the basic amino group present in monoamine transporter inhibitors and substrates. The study also presents a comparison of hNET models with other related proteins, which could provide new insights into their interaction with therapeutics and aid future development of novel bioactive compounds.
Topics: Animals; Binding Sites; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drosophila Proteins; Drosophila melanogaster; Humans; Molecular Dynamics Simulation; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Protein Binding
PubMed: 31936154
DOI: 10.3390/biom10010102 -
The European Journal of Neuroscience Jan 2017Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine... (Review)
Review
Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) are regulators of dopamine homeostasis in the presynaptic neuron. DAT transports dopamine from the extracellular space into the cytosol of the presynaptic terminal. VMAT2 then packages this cytosolic dopamine into vesicular compartments for subsequent release upon neurotransmission. Thus, DAT and VMAT2 act in concert to move the transmitter efficiently throughout the neuron. Accumulation of dopamine in the neuronal cytosol can trigger oxidative stress and neurotoxicity, suggesting that the proper compartmentalization of dopamine is critical for neuron function and risk of disease. For decades, studies have examined the effects of reduced transporter function in mice (e.g. DAT-KO, VMAT2-KO, VMAT2-deficient). However, we have only recently been able to assess the effects of elevated transporter expression using BAC transgenic methods (DAT-tg, VMAT2-HI mice). Complemented with in vitro work and neurochemical techniques to assess dopamine compartmentalization, a new focus on the importance of transporter proteins as both models of human disease and potential drug targets has emerged. Here, we review the importance of DAT and VMAT2 function in the delicate balance of neuronal dopamine.
Topics: Animals; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Humans; Mesencephalon; Presynaptic Terminals; Synaptic Transmission
PubMed: 27520881
DOI: 10.1111/ejn.13357 -
Pharmacological Reviews Oct 2015Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are... (Review)
Review
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.
Topics: Adrenergic Uptake Inhibitors; Animals; Central Nervous System Diseases; Dopamine; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Glycosylation; Humans; Phosphorylation; Signal Transduction; Synaptic Transmission; Vesicular Monoamine Transport Proteins
PubMed: 26408528
DOI: 10.1124/pr.114.010397 -
Neurochemical Research Jun 2020Dopamine (DA) is critical for motivation, reward, movement initiation, and learning. Mechanisms that control DA signaling have a profound impact on these important... (Review)
Review
Dopamine (DA) is critical for motivation, reward, movement initiation, and learning. Mechanisms that control DA signaling have a profound impact on these important behaviors, and additionally play a role in DA-related neuropathologies. The presynaptic SLC6 DA transporter (DAT) limits extracellular DA levels by clearing released DA, and is potently inhibited by addictive and therapeutic psychostimulants. Decades of evidence support that the DAT is subject to acute regulation by a number of signaling pathways, and that endocytic trafficking strongly regulates DAT availability and function. DAT trafficking studies have been performed in a variety of model systems, including both in vitro and ex vivo preparations. In this review, we focus on the breadth of DAT trafficking studies, with specific attention to, and comparison of, how context may influence DAT's response to different stimuli. In particular, this overview highlights that stimulated DAT trafficking not only differs between in vitro and ex vivo environments, but also is influenced by both sex and anatomical subregions.
Topics: Animals; Brain; Dopamine; Dopamine Plasma Membrane Transport Proteins; GABA Plasma Membrane Transport Proteins; Humans; Protein Transport; Signal Transduction
PubMed: 32146647
DOI: 10.1007/s11064-020-03001-6 -
Biomolecules Jun 2022Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains,...
Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson's and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of ()-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered ()-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, ()-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, ()-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight ()-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for ()-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.
Topics: Animals; Dopamine; Dopamine Plasma Membrane Transport Proteins; Hippocampus; Humans; Motivation; Neuronal Plasticity; Rats
PubMed: 35883437
DOI: 10.3390/biom12070881 -
Brain and Behavior Jul 2023Gastrointestinal symptoms are common in Parkinson's disease (PD), but their neurophysiological correlates are not well understood. We recently reported that functional...
BACKGROUND
Gastrointestinal symptoms are common in Parkinson's disease (PD), but their neurophysiological correlates are not well understood. We recently reported that functional gastrointestinal symptoms were not associated with asymmetry per se but might be associated with lower left striatal dopamine transporter (DAT) binding. The purpose of this study was to further investigate if specific gastrointestinal symptoms associate with monoamine transporter changes in specific striatal or extrastriatal areas.
METHODS
Ninety PD patients, who underwent DAT ¹ I-FP-CIT SPECT imaging, were assessed using the MDS-Unified Parkinson's Disease Rating Scale part III, Rome III, and Wexner constipation score. DAT binding was calculated from striatal subregions using region-to-occipital cortex ratio. Voxel-wise analysis was used to assess the relationship between gastrointestinal symptoms and striatal DAT and extrastriatal serotonin transporter (SERT) binding.
RESULTS
Irritable bowel syndrome (IBS) criteria were fulfilled in 17 patients and were linked to higher ¹ I-FP-CIT binding in the right posterior putamen and adjacent areas as compared to patients without IBS. No other significant associations between gastrointestinal symptoms and DAT or SERT binding were found.
CONCLUSIONS
These findings suggest that PD patients with IBS may have higher DAT binding in the right hemisphere. This finding implicates alterations of brain neurotransmitter physiology in the gastrointestinal symptoms of PD patients.
Topics: Humans; Parkinson Disease; Dopamine Plasma Membrane Transport Proteins; Irritable Bowel Syndrome; Brain; Corpus Striatum; Serotonin Plasma Membrane Transport Proteins
PubMed: 37254594
DOI: 10.1002/brb3.3097 -
Annals of Neurology Dec 2017A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function... (Meta-Analysis)
Meta-Analysis Review
A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882.
Topics: Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Longitudinal Studies; Parkinson Disease; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon
PubMed: 29165839
DOI: 10.1002/ana.25103