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Movement Disorders Clinical Practice Apr 2023Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50-80%. Functional... (Review)
Review
BACKGROUND
Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50-80%. Functional neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly.
OBJECTIVE
To quantify dopamine transporter (DaT) activity by neuroimaging in early PD.
METHODS
Systematic review and novel analysis of DaT imaging studies in early PD.
RESULTS
In our systematic review, in 423 unique cases from 27 studies with disease duration of less than 6 years, mean age 58.0 (SD 11.5) years, and mean disease duration 1.8 (SD 1.2) years, striatal loss was 43.5% (95% CI 41.6, 45.4) contralaterally, and 36.0% (95% CI 33.6, 38.3) ipsilaterally. For unilateral PD, in 436 unique cases, mean age 57.5 (SD 10.2) years, and mean disease duration 1.8 (SD 1.4) years, striatal loss was 40.6% (95% CI 38.8, 42.4) contralaterally, and 31.6% (95% CI 29.4, 33.8) ipsilaterally. In our novel analysis of the Parkinson's Progressive Marker Initiative study, 413 cases had 1436 scans performed. For a disease duration of less than 1 year, age was 61.8 (SD 9.8) years, and striatal loss was 51.2% (95% CI 49.1, 53.3) contralaterally and 39.5% (36.9, 42.1) ipsilaterally, giving an overall striatal loss of 45.3% (43.0, 47.6).
CONCLUSIONS
Loss of striatal DaT activity in early PD is less at 35-45%, rather than the 50-80% striatal dopamine loss estimated to be present at the time of symptom onset, based on backwards extrapolation from autopsy studies.
PubMed: 37070042
DOI: 10.1002/mdc3.13687 -
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 -
Biomedicine & Pharmacotherapy =... Dec 2023Intracranial self-stimulation (ICSS) of the medial forebrain bundle in mice is an experimental model use to assess the relative potential of reward-seeking behaviors....
Abused drug-induced intracranial self-stimulation is correlated with the alteration of dopamine transporter availability in the medial prefrontal cortex and nucleus accumbens of mice.
Intracranial self-stimulation (ICSS) of the medial forebrain bundle in mice is an experimental model use to assess the relative potential of reward-seeking behaviors. Here, we used the ICSS model to evaluate the abuse potential of 18 abused drugs: 3-Fluoroethamphetamine (3-FEA); methylphenidate; cocaine; dextroamphetamine; alpha-Pyrrolidinobutyrophenone (α-PBT); 4'-Fluoro-4-methylaminorex (4-FPO); methamphetamine; larocaine; phentermine; paramethoxymethamphetamine (PMMA); phendimetrazine; N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48); Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (CB-13); 4-Ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210); Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018); N-(ortho-methoxybenzyl)-4-ethylamphetamine (4-EA-NBOMe); N-[(2-Methoxyphenyl)methyl]-N-methyl-1-(4-methylphenyl)propan-2-amine (4-MMA-NBOMe); and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine (4-MeO-PCP). We determined dopamine transporter (DAT) availability in the medial prefrontal cortex (mPFC), striatum, and nucleus accumbens (NAc) after drug treatment. DAT availability in the mPFC and NAc significantly correlated with the ICSS threshold after drug treatment. Extracellular dopamine and calcium levels in PC-12 cells were measured following drug treatment. After drug treatment, Spearman rank and Pearson correlation analyses showed a significant difference between the extracellular dopamine level and the ICSS threshold. After drug treatment, Spearman rank correlation analysis showed a significant correlation between Ca signaling and the ICSS threshold. A positive correlation exists between the ICSS threshold and DAT availability in the mPFC and NAc provoked by abused drugs. The relative potential of drug-induced reward-seeking behavior may be related to DAT availability-mediated extracellular dopamine levels in the mPFC and NAc.
Topics: Animals; Mice; Dopamine; Dopamine Plasma Membrane Transport Proteins; Nucleus Accumbens; Prefrontal Cortex; Self Stimulation
PubMed: 37948992
DOI: 10.1016/j.biopha.2023.115860 -
Brain and Behavior Feb 2020This study aims to establish a methamphetamine (METH)-induced behavioral sensitization model using tree shrews, as well as to measure the protein expression of the...
INTRODUCTION
This study aims to establish a methamphetamine (METH)-induced behavioral sensitization model using tree shrews, as well as to measure the protein expression of the dopamine D3 receptor (D3R) and dopamine transporter (DAT).
METHODS
Forty tree shrews were equally and randomly divided into four experimental groups: those administered with 1, 2, and 4 mg/kg METH and a control group (treated with an equal amount of normal saline). Each experimental group was repeatedly exposed to METH for nine consecutive days to induce the development of behavioral sensitization, followed by four days of withdrawal (without the METH treatment) to induce the transfer of behavioral sensitization, then given 0.5 mg/kg of METH to undergo the expression of behavioral sensitization. Altered locomotor and stereotypic behaviors were measured daily via open-field experiments during the development and expression stages, and weight changes were also recorded. Then, the Western blot method was used to detect the expression levels of D3R and DAT in three brain regions: the nucleus accumbens, prefrontal cortex, and dorsal striatum 24 hr after the last behavioral test.
RESULTS
METH administration augmented motor-stimulant responses and stereotypic behaviors in all experimental groups, and stereotypic behaviors intensified more in the groups treated with 2 and 4 mg/kg METH. Motion distance, speed, and trajectory were significantly elevated in all experimental, however, METH at 4 mg/kg induced more stereotypic behaviors, decreasing these locomotor activities as compared with the 2 mg/kg METH group. 2 and 4 mg/kg METH significantly upregulated and downregulated D3R and DAT expression levels, respectively, in three brain regions, and these changes are more pronounced in 2 mg/kg METH.
CONCLUSIONS
These results indicated that this animal model may be used to study the neurobiological mechanisms that underly the development and expression of behavioral sensitization to METH. Deregulated D3R and DAT expression may be involved in the METH-induced behavioral sensitization.
Topics: Animals; Behavior, Animal; Brain; Central Nervous System Sensitization; Central Nervous System Stimulants; Dopamine Plasma Membrane Transport Proteins; Locomotion; Methamphetamine; Receptors, Dopamine D3; Stereotyped Behavior; Tupaiidae
PubMed: 31943832
DOI: 10.1002/brb3.1533 -
Rhode Island Medical Journal (2013) Sep 2023The Dopamine Transporter Scan (DaT) is a radionuclear imaging technique which was approved by the FDA to differentiate essential tremor (ET) from Parkinson's disease... (Review)
Review
The Dopamine Transporter Scan (DaT) is a radionuclear imaging technique which was approved by the FDA to differentiate essential tremor (ET) from Parkinson's disease (PD). The scan is a crude indicator of the number of dopamine-secreting cells and is abnormal in presynaptic parkinsonian syndromes. In this article we review this and other possible clinical situations in which a DaT scan may be useful.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Parkinsonian Disorders; Parkinson Disease; Radionuclide Imaging
PubMed: 37643339
DOI: No ID Found -
The Journal of Biological Chemistry Apr 2020Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface...
Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface availability is dynamically regulated by endocytic trafficking, and direct protein kinase C (PKC) activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in DAergic terminals.
Topics: Animals; Binding Sites; Cell Line, Tumor; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Endocytosis; Female; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Monomeric GTP-Binding Proteins; Protein Binding; Protein Kinase C
PubMed: 32132171
DOI: 10.1074/jbc.RA120.012628 -
Journal of Neural Transmission (Vienna,... Apr 2023Both cerebrospinal fluid (CSF) homovanillic acid (HVA) and striatal dopamine transporter (DAT) binding on single-photon emission computed tomography (SPECT) reflect...
Both cerebrospinal fluid (CSF) homovanillic acid (HVA) and striatal dopamine transporter (DAT) binding on single-photon emission computed tomography (SPECT) reflect nigrostriatal dopaminergic function, but studies on the relationship between the two have been limited. It is also unknown whether the reported variance in striatal DAT binding among diseases reflects the pathophysiology or characteristics of the subjects. We included 70 patients with Parkinson's disease (PD), 12 with progressive supranuclear palsy (PSP), 12 with multiple system atrophy, six with corticobasal syndrome, and nine with Alzheimer's disease as disease control, who underwent both CSF analysis and I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (I-ioflupane) SPECT. We evaluated the correlation between CSF HVA concentration and the specific binding ratio (SBR) of striatal DAT binding. We also compared the SBR for each diagnosis, controlling for CSF HVA concentration. The correlations between the two were significant in patients with PD (r = 0.34, p = 0.004) and PSP (r = 0.77, p = 0.004). The mean SBR value was the lowest in patients with PSP and was significantly lower in patients with PSP than in those with PD (p = 0.037) after adjusting for CSF HVA concentration. Our study demonstrates that striatal DAT binding correlates with CSF HVA concentration in both PD and PSP, and striatal DAT reduction would be more advanced in PSP than in PD at an equivalent dopamine level. Striatal DAT binding may correlate with dopamine levels in the brain. The pathophysiology of each diagnosis may explain this difference.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Homovanillic Acid; Dopamine; Parkinsonian Disorders; Tomography, Emission-Computed, Single-Photon; Parkinson Disease
PubMed: 36871130
DOI: 10.1007/s00702-023-02611-y -
Neurochemical Research Jan 2022The dopamine transporter (DAT) mediates the inactivation of released dopamine (DA) through its reuptake, and thereby plays an important homeostatic role in dopaminergic...
The dopamine transporter (DAT) mediates the inactivation of released dopamine (DA) through its reuptake, and thereby plays an important homeostatic role in dopaminergic neurotransmission. Amphetamines exert their stimulant effects by targeting DAT and inducing the reverse transport of DA, leading to a dramatic increase of extracellular DA. Animal models have proven critical to investigating the molecular and cellular mechanisms underlying transporter function and its modulation by psychostimulants such as amphetamine. Here we establish a behavioral model for amphetamine action using adult Drosophila melanogaster. We use it to characterize the effects of amphetamine on sleep and sleep architecture. Our data show that amphetamine induces hyperactivity and disrupts sleep in a DA-dependent manner. Flies that do not express a functional DAT (dDAT null mutants) have been shown to be hyperactive and to exhibit significantly reduced sleep at baseline. Our data show that, in contrast to its action in control flies, amphetamine decreases the locomotor activity of dDAT null mutants and restores their sleep by modulating distinct aspects of sleep structure. To begin to explore the circuitry involved in the actions of amphetamine on sleep, we also describe the localization of dDAT throughout the fly brain, particularly in neuropils known to regulate sleep. Together, our data establish Drosophila as a robust model for studying the regulatory mechanisms that govern DAT function and psychostimulant action.
Topics: Amphetamine; Animals; Dopamine Plasma Membrane Transport Proteins; Drosophila; Drosophila melanogaster; Sleep
PubMed: 33630236
DOI: 10.1007/s11064-021-03275-4 -
Scientific Reports Jul 2022The human placenta represents a unique non-neuronal site of monoamine transporter expression, with pathophysiological relevance during the prenatal period. Monoamines...
The human placenta represents a unique non-neuronal site of monoamine transporter expression, with pathophysiological relevance during the prenatal period. Monoamines (serotonin, dopamine, norepinephrine) are crucial neuromodulators for proper placenta functions and fetal development, including cell proliferation, differentiation, and neuronal migration. Accumulating evidence suggests that even a transient disruption of monoamine balance during gestation may lead to permanent changes in the fetal brain structures and functions, projecting into adulthood. Nonetheless, little is known about the transfer of dopamine and norepinephrine across the placental syncytiotrophoblast. Employing the method of isolated membranes from the human term placenta, here we delineate the transport mechanisms involved in dopamine and norepinephrine passage across the apical microvillous (MVM) and basal membranes. We show that the placental uptake of dopamine and norepinephrine across the mother-facing MVM is mediated via the high-affinity and low-capacity serotonin (SERT/SLC6A4) and norepinephrine (NET/SLC6A2) transporters. In the fetus-facing basal membrane, however, the placental uptake of both monoamines is controlled by the organic cation transporter 3 (OCT3/SLC22A3). Our findings thus provide insights into physiological aspects of dopamine and norepinephrine transport across both the maternal and fetal sides of the placenta. As monoamine transporters represent targets for several neuroactive drugs such as antidepressants, our findings are pharmacologically relevant to ensure the safety of drug use during pregnancy.
Topics: Adult; Cell Membrane; Dopamine; Female; Humans; Norepinephrine; Placenta; Pregnancy; Serotonin; Serotonin Plasma Membrane Transport Proteins; Trophoblasts
PubMed: 35804076
DOI: 10.1038/s41598-022-15790-7 -
Parkinsonism & Related Disorders Mar 2020Non-motor symptoms (NMS) are common in Parkinson's disease (PD), but their relationships to nigrostriatal degeneration remain largely unexplored.
BACKGROUND
Non-motor symptoms (NMS) are common in Parkinson's disease (PD), but their relationships to nigrostriatal degeneration remain largely unexplored.
METHODS
We evaluated 18 NMS scores covering 5 major domains in relation to concurrent and future dopamine transporter (DAT) imaging in 344 PD patients from the Parkinson's Progression and Markers Initiative (PPMI). We standardized NMS assessments into z-scores for side-by-side comparisons. Patients underwent sequential DaTSCAN imaging at enrollment and at months 12, 24, and 48. Specific binding ratios (SBR) were calculated using the occipital lobe reference region. We evaluated the association of striatal DAT binding at the four time points with each baseline NMS using mixed-effects regression models.
RESULTS
Multiple baseline NMS were significantly associated with DAT binding at baseline and at follow-up scans. REM sleep behavior disorder (RBD) symptoms showed the strongest association - mean striatal SBR declined with increasing RBD symptom z-score (average of time-point-specific slopes per unit change in z-score: β = -0.083, SE = 0.017; p < 0.0001). In addition, striatal DAT binding was linearly associated with increasing baseline z-scores: positively for the memory (β=0.055, SE = 0.022; p = 0.01) and visuospatial (β=0.044, SE = 0.020; p = 0.03) cognitive domains, and negatively for total anxiety (β= -0.059, SE = 0.018; p = 0.001). Striatal DAT binding showed curvilinear associations with odor identification, verbal discrimination recognition, and autonomic dysfunction z-scores (p = 0.001, p = 0.0009, and p = 0.0002, respectively). Other NMS were not associated with DAT binding.
CONCLUSIONS
Multiple NMS, RBD symptoms in particular, are associated with nigrostriatal dopaminergic changes in early PD.
Topics: Aged; Anxiety; Autonomic Nervous System Diseases; Cognitive Dysfunction; Depression; Disruptive, Impulse Control, and Conduct Disorders; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Longitudinal Studies; Male; Middle Aged; Neostriatum; Olfaction Disorders; Parkinson Disease; REM Sleep Behavior Disorder; Substantia Nigra; Tomography, Emission-Computed, Single-Photon
PubMed: 32092703
DOI: 10.1016/j.parkreldis.2020.02.001