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Frontiers in Neurology 2021Bipolar disorder (BD) has been suggested to be a risk factor for the development of Parkinson's disease (PD). Standard treatment of BD includes drugs that are known to...
Bipolar disorder (BD) has been suggested to be a risk factor for the development of Parkinson's disease (PD). Standard treatment of BD includes drugs that are known to induce drug-induced parkinsonism (DIP). Clinical differentiation between PD and DIP is crucial and might be aided by functional neuroimaging of the dopaminergic nigrostriatal pathway. Twenty consecutive BD patients with parkinsonism were clinically assessed and underwent I-ioflupane dopamine transporter single-photon emission computer tomography (SPECT). Imaging data of BD patients with pathological scans were further compared to a population of 40 PD patients. Four BD patients had abnormal scans, but their clinical features and cumulative exposure to both antipsychotic drugs and lithium were similar to those of BD patients with normal dopamine transporter imaging. BD patients with pathological scans had putaminal binding ratio and putamen-to-caudate ratios higher than those of PD patients despite a similar motor symptom burden. Up to 20% of BD patients with parkinsonism might have an underlying dopaminergic deficit, which would not be due to cumulative exposure to offending drugs and is ostensibly higher than expected in the general population. This supports the evidence that BD represents a risk factor for subsequent development of neurodegenerative parkinsonism, the nature of which needs to be elucidated.
PubMed: 33927683
DOI: 10.3389/fneur.2021.652375 -
Scientific Reports Feb 2024The progression of neuroinflammation after anti-parkinsonian therapy on the Parkinson's disease (PD) brain and in vivo evidence of the therapy purporting neuroprotection... (Randomized Controlled Trial)
Randomized Controlled Trial
The progression of neuroinflammation after anti-parkinsonian therapy on the Parkinson's disease (PD) brain and in vivo evidence of the therapy purporting neuroprotection remain unclear. To elucidate this, we examined changes in microglial activation, nigrostriatal degeneration, and clinical symptoms longitudinally after dopamine replacement therapy in early, optimally-controlled PD patients with and without zonisamide treatment using positron emission tomography (PET). We enrolled sixteen PD patients (Hoehn and Yahr stage 1-2), and age-matched normal subjects. PD patients were randomly divided into two groups: one (zonisamide) that did and one (zonisamide) that did not undergo zonisamide therapy. Annual changes in neuroinflammation ([C]DPA713 PET), dopamine transporter availability ([C]CFT PET) and clinical severity were examined. Voxelwise differentiations in the binding of [C]DPA713 (BP) and [C]CFT (SUVR) were compared with normal data and between the zonisamide and zonisamide PD groups. The cerebral [C]DPA713 BP increased with time predominantly over the parieto-occipital region in PD patients. Comparison of the zonisamide group with the zonisamide group showed lower levels in the cerebral [C]DPA713 BP in the zonisamide group. While the striatal [C]CFT SUVR decreased longitudinally, the [C]CFT SUVR in the nucleus accumbens showed a higher binding in the zonisamide group. A significant annual increase in attention score were found in the zonisamide group. The current results indicate neuroinflammation proceeds to the whole brain even after anti-parkinsonian therapy, but zonisamide coadministration might have the potential to ameliorate proinflammatory responses, exerting a neuroprotective effect in more damaged nigrostriatal regions with enhanced attention in PD.
Topics: Humans; Parkinson Disease; Zonisamide; Neuroinflammatory Diseases; Positron-Emission Tomography; Brain; Dopamine Plasma Membrane Transport Proteins
PubMed: 38409373
DOI: 10.1038/s41598-024-55233-z -
Journal of Cerebral Blood Flow and... Jul 2023The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3...
Striatal dopamine transporter and receptor availability correlate with relative cerebral blood flow measured with [C]PE2I, [F]FE-PE2I and [C]raclopride PET in healthy individuals.
The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [C]PE2I (n = 20) and [F]FE-PE2I (n = 20) and the D2/3 tracer [C]raclopride (n = 18). Subjects with a [C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [C]DASB. Binding potential (BP) and relative tracer delivery (R) values were calculated on regional and voxel-level. Striatal R and BP values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BP image. An inter-tracer comparison between [C]PE2I BP and [C]DASB R was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BP and R for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [C]PE2I BP and [C]DASB R. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.
Topics: Humans; Raclopride; Dopamine; Dopamine Plasma Membrane Transport Proteins; Retrospective Studies; Positron-Emission Tomography; Cerebrovascular Circulation
PubMed: 36912083
DOI: 10.1177/0271678X231160881 -
Neuropharmacology Dec 2019Recent work demonstrated the propensity of dopamine transporters (DATs) to form trimers or higher oligomers, enhanced upon binding a furopyrimidine, AIM-100. AIM-100...
Recent work demonstrated the propensity of dopamine transporters (DATs) to form trimers or higher oligomers, enhanced upon binding a furopyrimidine, AIM-100. AIM-100 binding promotes DAT endocytosis and thereby moderates dopaminergic transmission. Despite the neurobiological significance of these events, the molecular mechanisms that underlie the stabilization of DAT trimer and the key interactions that modulate the trimerization of DAT, and not serotonin transporter SERT, remain unclear. In the present study, we determined three structural models, termed trimer-W238, -C306 and -Y303, for possible trimerization of DATs . To this aim, we used structural data resolved for DAT and its structural homologs that share the LeuT fold, advanced computational modeling and simulations, site-directed mutagenesis experiments and live-cell imaging assays. The models are in accord with the versatility of LeuT fold to stabilize dimeric or higher order constructs. Selected residues show a high propensity to occupy interfacial regions. Among them, D231-W238 in the extracellular loop EL2, including the intersubunit salt-bridge forming pair D231/D232-R237 (not present in SERT) (in trimer-W238), the loop EL3 (trimers-C306 and -Y303), and W497 on the intracellularly exposed IL5 loop (trimer-C306) and its spatial neighbors (e.g. K525) near the C-terminus are computationally predicted and experimentally confirmed to play important roles in enabling the correct folding and/or oligomerization of DATs in the presence of AIM-100. The study suggests the possibility of controlling the effective transport of dopamine by altering the oligomerization state of DAT upon small molecule binding, as a possible intervention strategy to modulate dopaminergic signaling. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
Topics: Binding Sites; Cells, Cultured; Computer Simulation; Dopamine Plasma Membrane Transport Proteins; Furans; Humans; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Protein Binding; Protein Folding; Pyrimidines; Serotonin Plasma Membrane Transport Proteins
PubMed: 31228486
DOI: 10.1016/j.neuropharm.2019.107676 -
Molecular Brain Jun 2021Reductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While...
Reductions in the GABAergic neurotransmitter system exist across multiple brain regions in schizophrenia and encompass both pre- and postsynaptic components. While reduced midbrain GABAergic inhibitory neurotransmission may contribute to the hyperdopaminergia thought to underpin psychosis in schizophrenia, molecular changes consistent with this have not been reported. We hypothesised that reduced GABA-related molecular markers would be found in the midbrain of people with schizophrenia and that these would correlate with dopaminergic molecular changes. We hypothesised that downregulation of inhibitory neuron markers would be exacerbated in schizophrenia cases with high levels of neuroinflammation. Eight GABAergic-related transcripts were measured with quantitative PCR, and glutamate decarboxylase (GAD) 65/67 and GABA alpha 3 (α3) (GABRA3) protein were measured with immunoblotting, in post-mortem midbrain (28/28 and 28/26 control/schizophrenia cases for mRNA and protein, respectively), and analysed by both diagnosis and inflammatory subgroups (as previously defined by higher levels of four pro-inflammatory cytokine transcripts). We found reductions (21 - 44%) in mRNA encoding both presynaptic and postsynaptic proteins, vesicular GABA transporter (VGAT), GAD1, and parvalbumin (PV) mRNAs and four alpha subunits (α1, α2, α3, α5) of the GABA receptor in people with schizophrenia compared to controls (p < 0.05). Gene expression of somatostatin (SST) was unchanged (p = 0.485). We confirmed the reduction in GAD at the protein level (34%, p < 0.05). When stratifying by inflammation, only GABRA3 mRNA exhibited more pronounced changes in high compared to low inflammatory subgroups in schizophrenia. GABRA3 protein was expressed by 98% of tyrosine hydroxylase-positive neurons and was 23% lower in schizophrenia, though this did not reach statistical significance (p > 0.05). Expression of transcripts for GABA receptor alpha subunits 2 and 3 (GABRA2, GABRA3) were positively correlated with tyrosine hydroxylase (TH) and dopamine transporter (DAT) transcripts in schizophrenia cases (GABRA2; r > 0.630, GABRA3; r > 0.762, all p < 0.001) but not controls (GABRA2; r < - 0.200, GABRA3; r < 0.310, all p > 0.05). Taken together, our results support a profound disruption to inhibitory neurotransmission in the substantia nigra regardless of inflammatory status, which provides a potential mechanism for disinhibition of nigrostriatal dopamine neurotransmission.
Topics: Adult; Aged; Biomarkers; Cohort Studies; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Female; GABAergic Neurons; Gene Expression Regulation; Glutamate Decarboxylase; Humans; Inflammation; Male; Mesencephalon; Middle Aged; Neuroinflammatory Diseases; Parvalbumins; Protein Subunits; RNA, Messenger; Receptors, GABA-A; Schizophrenia; Somatostatin; Tyrosine 3-Monooxygenase; Vesicular Inhibitory Amino Acid Transport Proteins; Young Adult; gamma-Aminobutyric Acid
PubMed: 34174930
DOI: 10.1186/s13041-021-00805-7 -
No link between striatal dopaminergic axons and dopamine transporter imaging in Parkinson's disease.Movement Disorders : Official Journal... Oct 2019Brain dopamine transporter binding has been considered a possible biomarker for nigrostriatal degeneration in PD.
BACKGROUND
Brain dopamine transporter binding has been considered a possible biomarker for nigrostriatal degeneration in PD.
OBJECTIVE
To investigate whether dopamine transporter binding is associated with the number of dopaminergic neurites in the putamen.
METHODS
Tyrosine hydroxylase-positive nerve fibers were counted from postmortem putamen sections taken from 14 parkinsonism patients who had been scanned with dopamine transporter single-photon emission computed tomography antemortem. Fiber counts were correlated with putamen dopamine transporter binding and SN neuron counts.
RESULTS
The putamen dopamine transporter specific binding ratio did not correlate with the putamen tyrosine hydroxylase-positive axon counts (r = 0.00; P = 1.0; PD patients: r = 0.07; P = 0.86). The nigra neuron counts had a positive correlation with the putamen tyrosine hydroxylase-positive axon counts.
CONCLUSIONS
Striatal dopamine transporter imaging does not associate with axonal nor somal loss of the nigrostriatal neurons in PD. It may reflect dopaminergic activity rather than number of surviving neurons or their striatal projection axons. © 2019 International Parkinson and Movement Disorder Society.
Topics: Aged; Aged, 80 and over; Axons; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Male; Middle Aged; Neurons; Parkinson Disease; Putamen; Substantia Nigra; Tomography, Emission-Computed, Single-Photon
PubMed: 31234224
DOI: 10.1002/mds.27777 -
The Journal of Biological Chemistry Feb 2023Extracellular dopamine (DA) levels are constrained by the presynaptic DA transporter (DAT), a major psychostimulant target. Despite its necessity for DA...
Extracellular dopamine (DA) levels are constrained by the presynaptic DA transporter (DAT), a major psychostimulant target. Despite its necessity for DA neurotransmission, DAT regulation in situ is poorly understood, and it is unknown whether regulated DAT trafficking impacts dopaminergic signaling and/or behaviors. Leveraging chemogenetics and conditional gene silencing, we found that activating presynaptic Gq-coupled receptors, either hM3Dq or mGlu5, drove rapid biphasic DAT membrane trafficking in ex vivo striatal slices, with region-specific differences between ventral and dorsal striata. DAT insertion required D2 DA autoreceptors and intact retromer, whereas DAT retrieval required PKC activation and Rit2. Ex vivo voltammetric studies revealed that DAT trafficking impacts DA clearance. Furthermore, dopaminergic mGlu5 silencing elevated DAT surface expression and abolished motor learning, which was rescued by inhibiting DAT with a subthreshold CE-158 dose. We discovered that presynaptic DAT trafficking is complex, multimodal, and region specific, and for the first time, we identified cell autonomous mechanisms that govern presynaptic DAT tone. Importantly, the findings are consistent with a role for regulated DAT trafficking in DA clearance and motor function.
Topics: Dopamine; Dopamine Plasma Membrane Transport Proteins; Receptors, Presynaptic; Animals; Mice; Corpus Striatum
PubMed: 36640864
DOI: 10.1016/j.jbc.2023.102900 -
Neuroscience Jan 2021Recent work indicates a role for RING finger protein 11 (RNF11) in Parkinson disease (PD) pathology, which involves the loss of dopaminergic neurons. However, the role...
Recent work indicates a role for RING finger protein 11 (RNF11) in Parkinson disease (PD) pathology, which involves the loss of dopaminergic neurons. However, the role of RNF11 in regulating dopamine neurotransmission has not been studied. In this work, we tested the effect of RNF11 RNAi knockdown or overexpression on stimulated dopamine release in the larval Drosophila central nervous system. Dopamine release was stimulated using optogenetics and monitored in real-time using fast-scan cyclic voltammetry at an electrode implanted in an isolated ventral nerve cord. RNF11 knockdown doubled dopamine release, but there was no decrease in dopamine from RNF11 overexpression. RNF11 knockdown did not significantly increase stimulated serotonin or octopamine release, indicating the effect is dopamine specific. Dopamine clearance was also changed, as RNF11 RNAi flies had a higher V and RNF11 overexpressing flies had a lower V than control flies. RNF11 RNAi flies had increased mRNA levels of dopamine transporter (DAT) in RNF11, confirming changes in DAT. In RNF11 RNAi flies, release was maintained better for stimulations repeated at short intervals, indicating increases in the recycled releasable pool of dopamine. Nisoxetine, a DAT inhibitor, and flupenthixol, a D2 antagonist, did not affect RNF11 RNAi or overexpressing flies differently than control. Thus, RNF11 knockdown causes early changes in dopamine neurotransmission, and this is the first work to demonstrate that RNF11 affects both dopamine release and uptake. RNF11 expression decreases in human dopaminergic neurons during PD, and that decrease may be protective by increasing dopamine neurotransmission in the surviving dopaminergic neurons.
Topics: Animals; Central Nervous System; DNA-Binding Proteins; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Drosophila; Drosophila Proteins; Humans; Serotonin
PubMed: 33176188
DOI: 10.1016/j.neuroscience.2020.10.021 -
Brain Research Jul 2023L-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to L-DOPA-induced dyskinesia (LID). LID involves a complex...
L-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to L-DOPA-induced dyskinesia (LID). LID involves a complex interaction between the remaining dopamine (DA) system and the semi-homologous serotonin (5-HT) system. Since serotonin transporters (SERT) have some affinity for DA uptake, they may serve as a functional compensatory mechanism when DA transporters (DAT) are scant. DAT and SERT's functional contributions in the dyskinetic brain have not been well delineated. The current investigation sought to determine how DA depletion and L-DOPA treatment affect DAT and SERT transcriptional processes, translational processes, and functional DA uptake in the 6-hydroxydopamine-lesioned hemi-parkinsonian rat. Rats were counterbalanced for motor impairment into equally lesioned treatment groups then given daily L-DOPA (0 or 6 mg/kg) for 2 weeks. At the end of treatment, the substantia nigra was processed for tyrosine hydroxylase (TH) and DAT gene expression and dorsal raphe was processed for SERT gene expression. The striatum was processed for synaptosomal DAT and SERT protein expression and ex vivo DA uptake. Nigrostriatal DA loss severely reduced DAT mRNA and protein expression in the striatum with minimal changes in SERT. L-DOPA treatment, while not significantly affecting DAT or SERT alone, did increase striatal SERT:DAT protein ratios. Using ex vivo microdialysis, L-DOPA treatment increased DA uptake via SERT when DAT was depleted. Overall, these results suggest that DA loss and L-DOPA treatment uniquely alter DAT and SERT, revealing implications for monoamine transporters as potential biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.
Topics: Rats; Animals; Levodopa; Serotonin Plasma Membrane Transport Proteins; Serotonin; Gain of Function Mutation; Rats, Sprague-Dawley; Dopamine; Corpus Striatum; Parkinson Disease; Oxidopamine
PubMed: 37127174
DOI: 10.1016/j.brainres.2023.148381 -
Neurochemistry International Jul 2020Dopamine (DA) signaling is critical to the modulation of multiple brain functions including locomotion, reinforcement, attention and cognition. The literature provides... (Review)
Review
Dopamine (DA) signaling is critical to the modulation of multiple brain functions including locomotion, reinforcement, attention and cognition. The literature provides strong evidence that altered DA availability and actions can impact normal neurodevelopment, with both early and enduring consequences on anatomy, physiology and behavior. An appreciation for the developmental contributions of DA signaling to brain development is needed to guide efforts to preclude and remedy neurobehavioral disorders, such as attention-deficit/hyperactivity disorder, addiction, bipolar disorder, schizophrenia and autism spectrum disorder, each of which exhibits links to DA via genetic, cellular and/or pharmacological findings. In this review, we highlight research pursued in preclinical models that use genetic and pharmacological approaches to manipulate DA signaling at sensitive developmental stages, leading to changes at molecular, circuit and/or behavioral levels. We discuss how these alterations can be aligned with traits displayed by neuropsychiatric diseases. Lastly, we review human studies that evaluate contributions of developmental perturbations of DA systems to increased risk for neuropsychiatric disorders.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Schizophrenia; Signal Transduction
PubMed: 32325191
DOI: 10.1016/j.neuint.2020.104747