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NeuroImage. Clinical 2021To evaluate possible differences between brain dopamine transporter (DAT) binding in a group of symptomatic parkinsonism patients without dopaminergic degeneration and...
OBJECTIVE
To evaluate possible differences between brain dopamine transporter (DAT) binding in a group of symptomatic parkinsonism patients without dopaminergic degeneration and healthy individuals.
BACKGROUND
Dopaminergic neuroimaging studies of Parkinson's disease (PD) have often used control groups formed from symptomatic patients with apparently normal striatal dopamine function. We sought to investigate whether symptomatic patients can be used to represent dopaminergically normal healthy controls.
METHODS
Forty healthy elderly individuals were scanned with DAT [I]FP-CIT SPECT and compared to 69 age- and sex-matched symptomatic patients with nondegenerative conditions (including essential tremor, drug-induced parkinsonism and vascular parkinsonism). An automated region-of-interest based analysis of the caudate nucleus and the anterior/posterior putamen was performed. Specific binding ratios (SBR = [ROI-occ]/occ) were compared between the groups.
RESULTS
DAT binding in symptomatic patients was 8.6% higher in the posterior putamen than in healthy controls (p = 0.03). Binding correlated negatively with age in both groups but not with motor symptom severity, cognitive function or depression ratings.
CONCLUSIONS
Putaminal DAT binding, as measured with [I]FP-CIT SPECT, was higher in symptomatic controls than in healthy individuals. The reason for the difference is unclear but can include selection bias when DAT binding is used to aid clinical diagnosis and possible self-selection bias in healthy volunteerism. This effect should be taken into consideration when designing and interpreting neuroimaging trials investigating the dopamine system with [I]FP-CIT SPECT.
Topics: Aged; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Humans; Neuroimaging; Parkinson Disease; Tomography, Emission-Computed, Single-Photon
PubMed: 34482280
DOI: 10.1016/j.nicl.2021.102807 -
Pharmacogenetics and Genomics Aug 2019
Review
Topics: Attention Deficit Disorder with Hyperactivity; Carboxylic Ester Hydrolases; Dopamine Plasma Membrane Transport Proteins; Humans; Methylphenidate; Norepinephrine Plasma Membrane Transport Proteins; Pharmacogenetics; Pharmacogenomic Variants
PubMed: 30950912
DOI: 10.1097/FPC.0000000000000376 -
ELife Feb 2022The striatum receives dense dopaminergic projections, making it a key region of the dopaminergic system. Its dysfunction has been implicated in various conditions...
The striatum receives dense dopaminergic projections, making it a key region of the dopaminergic system. Its dysfunction has been implicated in various conditions including Parkinson's disease (PD) and substance use disorder. However, the investigation of dopamine-specific functioning in humans is problematic as current MRI approaches are unable to differentiate between dopaminergic and other projections. Here, we demonstrate that 'connectopic mapping' - a novel approach for characterizing fine-grained, overlapping modes of functional connectivity - can be used to map dopaminergic projections in striatum. We applied connectopic mapping to resting-state functional MRI data of the Human Connectome Project (population cohort; N = 839) and selected the second-order striatal connectivity mode for further analyses. We first validated its specificity to dopaminergic projections by demonstrating a high spatial correlation ( = 0.884) with dopamine transporter availability - a marker of dopaminergic projections - derived from DaT SPECT scans of 209 healthy controls. Next, we obtained the subject-specific second-order modes from 20 controls and 39 PD patients scanned under placebo and under dopamine replacement therapy (L-DOPA), and show that our proposed dopaminergic marker tracks PD diagnosis, symptom severity, and sensitivity to L-DOPA. Finally, across 30 daily alcohol users and 38 daily smokers, we establish strong associations with self-reported alcohol and nicotine use. Our findings provide evidence that the second-order mode of functional connectivity in striatum maps onto dopaminergic projections, tracks inter-individual differences in PD symptom severity and L-DOPA sensitivity, and exhibits strong associations with levels of nicotine and alcohol use, thereby offering a new biomarker for dopamine-related (dys)function in the human brain.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Brain; Cohort Studies; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Levodopa; Magnetic Resonance Imaging; Male; Middle Aged; Neural Pathways; Parkinson Disease
PubMed: 35113016
DOI: 10.7554/eLife.71846 -
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 -
The Journal of Biological Chemistry 2021The dopamine transporter (DAT) is essential for the reuptake of the released neurotransmitter dopamine (DA) in the brain. Psychostimulants, methamphetamine and cocaine,...
The dopamine transporter (DAT) is essential for the reuptake of the released neurotransmitter dopamine (DA) in the brain. Psychostimulants, methamphetamine and cocaine, have been reported to induce the formation of DAT multimeric complexes in vivo and in vitro. The interpretation of DAT multimer function has been primarily in the context of compounds that induce structural and functional modifications of the DAT, complicating the understanding of the significance of DAT multimers. To examine multimerization in the absence of DAT ligands as well as in their presence, we developed a novel, optogenetic fusion chimera of cryptochrome 2 and DAT with an mCherry fluorescent reporter (Cry2-DAT). Using blue light to induce Cry2-DAT multimeric protein complex formation, we were able to simultaneously test the functional contributions of DAT multimerization in the absence or presence of substrates or inhibitors with high spatiotemporal precision. We found that blue light-stimulated Cry2-DAT multimers significantly increased IDT307 uptake and MFZ 9-18 binding in the absence of ligands as well as after methamphetamine and nomifensine treatment. Blue light-induced Cry2-DAT multimerization increased colocalization with recycling endosomal marker Rab11 and had decreased presence in Rab5-positive early endosomes and Rab7-positive late endosomes. Our data suggest that the increased uptake and binding results from induced and rapid trafficking of DAT multimers to the plasma membrane. Our data suggest that DAT multimers may function to help maintain DA homeostasis.
Topics: Animals; Biological Transport; Cell Membrane; Dopamine; Dopamine Plasma Membrane Transport Proteins; Gene Expression; HEK293 Cells; Humans; Neurons; Optogenetics; Protein Multimerization
PubMed: 34015332
DOI: 10.1016/j.jbc.2021.100787 -
Neuropharmacology Dec 2021Clandestine chemists are currently exploiting the pyrrolidinophenone scaffold to develop new designer drugs that carry the risk of abuse and overdose. These drugs...
Clandestine chemists are currently exploiting the pyrrolidinophenone scaffold to develop new designer drugs that carry the risk of abuse and overdose. These drugs promote addiction through the rewarding effects of increased dopaminergic neurotransmission. 3,4-Methylenedioxypyrovalerone (MDPV) and its analogs are illicit psychostimulants of this class that are ∼50-fold more potent than cocaine at inhibiting the human dopamine transporter (hDAT). In contrast, MDPV is a weak inhibitor at both the human serotonin transporter (hSERT) and, as it is shown here, the Drosophila melanogaster DAT (dDAT). We studied three conserved residues between hSERT and dDAT that are unique in hDAT (A117, F318, and P323 in dDAT), and one residue that is different in all three transporters (D121 in dDAT). hDAT residues were replaced in the dDAT sequence at these positions using site-directed mutagenesis and stable cell lines were generated expressing these mutant transporters. The potencies of MDPV and two of its analogs were determined using a Ca-mobilization assay. In this assay, voltage-gated Ca channels are expressed to sense the membrane electrical depolarization evoked when dopamine is transported through DAT. Each individual mutant slightly improved MDPV's potency, but the combination of all four increased its potency ∼100-fold (2 log units) in inhibiting dDAT activity. Molecular modeling and docking studies were conducted to explore the possible mode of interaction between MDPV and DAT in silico. Two of the studied residues (F318 and P323) are at the entrance of the S1 binding site, whereas the other two (A117 and D121) face the aryl moiety of MDPV when bound to this site. Therefore, these four non-conserved residues can influence MDPV selectivity not only by stabilizing binding, but also by controlling access to its binding site at DAT.
Topics: Animals; Benzodioxoles; Biological Transport; Calcium Channels; Cell Line; Designer Drugs; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Drosophila melanogaster; Molecular Docking Simulation; Pyrrolidines; Serotonin Plasma Membrane Transport Proteins; Synthetic Cathinone
PubMed: 34619165
DOI: 10.1016/j.neuropharm.2021.108820 -
Movement Disorders : Official Journal... Aug 2021Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine... (Meta-Analysis)
Meta-Analysis Review
Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine receptors emerge as a consequence of the loss of dopamine nerve terminals or dopaminergic pharmacotherapy. We performed a systematic review and meta-analysis of the available PET and single-photon emission computed tomography studies that have investigated dopamine receptors in PD, PSP and MSA. The inclusion criteria were studies including human PET or single-photon emission computed tomography imaging; dopamine receptor tracers (D1-like or D2-like) and idiopathic PD, PSP, or MSA patients compared with healthy controls. The 67 included D2-like studies had 1925 patients. Data were insufficient for an analysis of D1-like studies. PD patients had higher striatal binding early in the disease, but after a disease duration of 4.36 years, PD patients had lower binding values than healthy controls. Striatal D2R binding was highest in unmedicated early PD patients and in the striatum contralateral to the predominant motor symptoms. PSP and MSA-P patients had lower striatal D2R binding than PD patients (14.2% and 21.8%, respectively). There is initial upregulation of striatal D2Rs in PD, which downregulate on average 4 years after motor symptom onset, possibly because of agonist-induced effects. The consistent upregulation of D2Rs in the PD striatum contralateral to the predominant motor symptoms indicates that receptor changes are driven by neurodegeneration and loss of striatal neuropil. Both PSP and MSA patients have clearly lower striatal D2R binding values than PD patients, which offers an opportunity for differential diagnostics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Parkinson Disease; Receptors, Dopamine D2; Tomography, Emission-Computed, Single-Photon
PubMed: 33955044
DOI: 10.1002/mds.28632 -
International Journal of Molecular... Aug 2022The trace amine-associated receptor 1 (TAAR1) is a Gs protein-coupled, intracellularly located metabotropic receptor. Trace and classic amines, amphetamines, act as...
The trace amine-associated receptor 1 (TAAR1) is a Gs protein-coupled, intracellularly located metabotropic receptor. Trace and classic amines, amphetamines, act as agonists on TAAR1; they activate downstream signal transduction influencing neurotransmitter release via intracellular phosphorylation. Our aim was to check the effect of the catecholaminergic activity enhancer compound ((-)BPAP, ()-(-)-1-(benzofuran-2-yl)-2-propylaminopentane) on neurotransmitter release via the TAAR1 signaling. Rat striatal slices were prepared and the resting and electrical stimulation-evoked [H]dopamine release was measured. The releaser (±)methamphetamine evoked non-vesicular [H]dopamine release in a TAAR1-dependent manner, whereas (-)BPAP potentiated [H]dopamine release with vesicular origin via TAAR1 mediation. (-)BPAP did not induce non-vesicular [H]dopamine release. N-Ethylmaleimide, which inhibits SNARE core complex disassembly, potentiated the stimulatory effect of (-)BPAP on vesicular [H]dopamine release. Subsequent analyses indicated that the dopamine-release stimulatory effect of (-)BPAP was due to an increase in PKC-mediated phosphorylation. We have hypothesized that there are two binding sites present on TAAR1, one for the releaser and one for the enhancer compounds, and they activate different PKC-mediated phosphorylation leading to the evoking of non-vesicular and vesicular dopamine release. (-)BPAP also increased VMAT2 operation enforcing vesicular [H]dopamine accumulation and release. Vesicular dopamine release promoted by TAAR1 evokes activation of D2 dopamine autoreceptor-mediated presynaptic feedback inhibition. In conclusion, TAAR1 possesses a triggering role in both non-vesicular and vesicular dopamine release, and the mechanism of action of (-)BPAP is linked to the activation of TAAR1 and the signal transduction attached.
Topics: Animals; Corpus Striatum; Dopamine; Dopamine Agents; Dopamine Plasma Membrane Transport Proteins; Methamphetamine; Rats; Receptors, G-Protein-Coupled
PubMed: 35955676
DOI: 10.3390/ijms23158543 -
Heliyon Jun 2021The present study used a binding assay to identify novel target biomolecules of -menthol ([-]-menthol) that promote mouse ambulation. Among 88 different ligands to...
The present study used a binding assay to identify novel target biomolecules of -menthol ([-]-menthol) that promote mouse ambulation. Among 88 different ligands to specific biomolecules examined, 0.1 mM -menthol inhibited the binding of 13 ligands with relatively high inhibition rates. The assays showed that -menthol acts on calcium channels, sodium channels, γ-aminobutyric acid type A (GABA) receptor, GABA transporter, dopamine transporter, dopamine D4 receptor, adenosine A2a receptor, α2A-adrenergic receptor, histamine H2 receptor, bombesin receptor, angiotensin AT1 receptor, vasopressin V2 receptor, and leukotriene B4 receptor over a similar concentration range. The inhibition constant (K) for -menthol inhibition of binding of [H]-WIN35,428 to the human recombinant dopamine transporter was 6.15 × 10 mol/L. The K for -menthol inhibition of binding of [H]-ethynylbicycloorthobenzoate (EBOB), a ligand of GABA receptor picrotoxin site, was 2.88 × 10 mol/L. These results should aid future research by providing clues for investigating the mechanisms underlying -menthol activities, including the ambulation-promoting effect. The present results suggest that the dopamine transporter, adenosine A2a receptor, dopamine D4 receptor, α2A-adrenergic receptor, and GABA receptor are promising candidate molecules that are involved in the mechanisms underlying the psychostimulant-like effect of -menthol.
PubMed: 34195432
DOI: 10.1016/j.heliyon.2021.e07329 -
Journal of Neurochemistry Oct 2021Methcathinone (MCAT) is a psychostimulant of abuse that can cause both persistent striatal dopaminergic and serotonergic, as well as hippocampal serotonergic, deficits....
Methcathinone (MCAT) is a psychostimulant of abuse that can cause both persistent striatal dopaminergic and serotonergic, as well as hippocampal serotonergic, deficits. Evidence suggests that the rapid effects of stimulants that are structurally and mechanistically similar to MCAT on monoamine transporter function may contribute to the abuse liability and/or persistent monoaminergic deficits caused by these agents. Thus, effects of MCAT on 1) striatal dopamine (DA) transporter (DAT); and 2) striatal and hippocampal serotonin transporter (SERT) function, as determined in tissues from adult male rats, were assessed. As reported previously, a single administration of MCAT rapidly (within 1 hr) decreases striatal [ H]DA uptake. Similarly, incubation of rat synaptosomes with MCAT at 37℃ (but not 4˚C) decreased striatal [ H]DA uptake. Incubation with MCAT likewise decreased [ H]5HT but not vesicular [ H]DA uptake. MCAT incubation in vitro was without effect on [ H]DA uptake in striatal synaptosomes prepared from MCAT-treated rats. The decrease in [ H]DA uptake caused by MCAT incubation: (a) reflected a decrease in V , with minimal change in K , and (b) was attenuated by co-incubation with the cell-permeable calcium chelator, N,N'-[1,2-ethanediylbis(oxy-2,1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]-1,1'-bis[(acetyloxy)methyl] ester-glycine (BAPTA-AM), as well as the non-selective protein kinase-C (PKC) inhibitors bisindolylmaleimide-1 (BIM-1) and 2-[1-3(Aminopropyl)indol-3-yl]-3(1-methyl-1H-indol-3-yl)maleimide (or Bisindolylmaleimide VIII; Ro-31-7549). Taken together, these results suggest that in vitro MCAT incubation may model important aspects of MCAT administration in vivo, and that calcium and PKC contribute to the in vitro effects of MCAT on DAT.
Topics: Animals; Central Nervous System Stimulants; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Male; Propiophenones; Protein Kinase C; Rats; Rats, Sprague-Dawley; Synaptosomes
PubMed: 34320222
DOI: 10.1111/jnc.15483