-
Signal Transduction and Targeted Therapy Sep 2023Substance use disorder remains a major challenge, with an enduring need to identify and evaluate new, translational targets for effective treatment. Here, we report the...
Substance use disorder remains a major challenge, with an enduring need to identify and evaluate new, translational targets for effective treatment. Here, we report the upregulation of Hypoxia-inducible factor-1α (HIF-1α) expression by roxadustat (Rox), a drug developed for renal anemia that inhibits HIF prolyl hydroxylase to prevent degradation of HIF-1α, administered either systemically or locally into selected brain regions, suppressed morphine (Mor)-induced conditioned place preference (CPP). A similar effect was observed with methamphetamine (METH). Moreover, Rox also inhibited the expression of both established and reinstated Mor-CPP and promoted the extinction of Mor-CPP. Additionally, the elevation of HIF-1α enhanced hepcidin/ferroportin 1 (FPN1)-mediated iron efflux and resulted in cellular iron deficiency, which led to the functional accumulation of the dopamine transporter (DAT) in plasma membranes due to iron deficiency-impaired ubiquitin degradation. Notably, iron-deficient mice generated via a low iron diet mimicked the effect of Rox on the prevention of Mor- or METH-CPP formation, without affecting other types of memory. These data reveal a novel mechanism for HIF-1α and iron involvement in substance use disorder, which may represent a potential novel therapeutic strategy for the treatment of drug abuse. The findings also repurpose Rox by suggesting a potential new indication for the treatment of substance use disorder.
Topics: Animals; Mice; Up-Regulation; Iron; Brain; Homeostasis; Iron Deficiencies; Hypoxia
PubMed: 37718358
DOI: 10.1038/s41392-023-01578-2 -
Environmental Pollution (Barking, Essex... Nov 2023Caenorhabditis elegans is a useful model for examining metabolic processes and related mechanisms. We here examined the effect of exposure to...
Caenorhabditis elegans is a useful model for examining metabolic processes and related mechanisms. We here examined the effect of exposure to N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) on dopamine metabolism and underling molecular basis in nematodes. The dopamine content was reduced by 6-PPDQ (1 and 10 μg/L). Meanwhile, dopamine related behaviors (basal slowing response and area restricted searching) were changed by 6-PPDQ (1 and 10 μg/L). Exposure to 6-PPDQ (1 and 10 μg/L) decreased expressions of genes (cat-2 and bas-1) encoding enzymes governing dopamine synthesis and cat-1 encoding dopamine transporter. Development of dopaminergic neurons was also affected by 10 μg/L 6-PPDQ as reflected by decrease in fluorescence intensity, neuronal loss, and defect in dendrite development. Exposure to 6-PPDQ (1 and 10 μg/L) altered expressions of ast-1 and rcat-1 encoding upregulators of cat-2 and bas-1. The dopamine content and expressions of cat-2 and bas-1 were inhibited by RNAi of ast-1 and increased by RNAi of rcat-1 in 6-PPDQ exposed nematodes. Using endpoints of locomotion behavior and brood size, in 6-PPDQ exposed nematodes, the susceptibility to toxicity was caused by RNAi of ast-1, cat-2, bas-1, and cat-1, and the resistance to toxicity was induced by RNAi of rcat-1. Therefore, 6-PPDQ exposure disrupted dopamine metabolism and the altered molecular basis for dopamine metabolism was associated with 6-PPDQ toxicity induction. Moreover, the defects in dopamine related behaviors and toxicity on locomotion and reproduction could be rescued by treatment with 0.1 mM dopamine.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Dopamine; Oxidative Stress; Phenylenediamines; Benzoquinones
PubMed: 37777057
DOI: 10.1016/j.envpol.2023.122649 -
Parkinsonism & Related Disorders Oct 2023According to the cognitive-reserve concept, higher educated dementia patients tolerate more brain pathology than lower educated patients with similar impairment. Here,...
BACKGROUND
According to the cognitive-reserve concept, higher educated dementia patients tolerate more brain pathology than lower educated patients with similar impairment. Here, we examined whether higher education is associated with more severe dopamine terminal loss at the diagnosis of Parkinson's disease (PD).
METHODS
Dopamine transporter (DaT) SPECT information of 352 de novo PD patients and 172 healthy controls (HC) were retrieved from PPMI. Correlation analyses were performed between education years and regional DaT signal (i.e., putamen, caudate, striatum), correcting for UPDRS-III, age, sex and MoCA. Second, using a median split on education (Md = 16 yrs), high and low education groups were determined, which were matched for demographic and/or clinical scores and compared based on regional DaT signals. Finally, moderation analyses were conducted in the PD cohort, assessing the effect of education on the relation between putaminal DaT capacity and UPDRS-III. All analyses were performed across the entire cohorts and separately for three age ranges (sixth, seventh and eighth life decade).
RESULTS
Only PD patients in their eighth life decade presented a positive association between education and regional dopamine signalling. A significant moderation effect of education on the association between putaminal DaT signal loss and motor symptom severity was observed in this group (B=3.377, t=3.075, p = .003). The remaining analyses did not yield any significant results, neither in the PD nor HC cohort.
CONCLUSION
Higher education is not related with greater tolerance against dopamine loss in PD, but may nonetheless assert protective effects at more advanced age.
PubMed: 37690218
DOI: 10.1016/j.parkreldis.2023.105844 -
Parkinsonism & Related Disorders Oct 2023Physical activity benefits patients with Parkinson's disease (PD) and is assumed to possess disease-modifying potential. PD-related biomarkers, such as dopamine...
INTRODUCTION
Physical activity benefits patients with Parkinson's disease (PD) and is assumed to possess disease-modifying potential. PD-related biomarkers, such as dopamine transporter (DAT) imaging and cerebrospinal fluid (CSF) α-synuclein (α-syn) and amyloid β (Aβ), correlate with disease severity and, to some extent, reflect disease progression and pathology. However, the association between regular physical activity and PD biomarker changes remains unknown. This study aimed to investigate the association between physical activity and longitudinal trajectories of PD biomarkers.
METHODS
This retrospective study included 444 patients with a median follow-up time of 5 years from the Parkinson's Progression Markers Initiative cohort. Data collection included physical activity as scaled by the Physical Activity Scale for the Elderly questionnaire, dopamine transporter imaging, CSF assessment, and serum biomarkers. We analyzed the data using a linear mixed regression model.
RESULTS
Regular physical activity was associated with a slower decline of DAT uptake in the caudate (β = 0.063, p = 0.011) and the putamen (β = 0.062, p = 0.023). No association was detected between regular physical activity and CSF, as well as serum biomarkers.
CONCLUSION
Regular physical activity is associated with favorable PD biomarker progression, indicating a potential disease-modifying effect.
Topics: Humans; Aged; Parkinson Disease; Retrospective Studies; Amyloid beta-Peptides; alpha-Synuclein; Biomarkers; Patient Acuity
PubMed: 37648587
DOI: 10.1016/j.parkreldis.2023.105820 -
Journal of Psychopharmacology (Oxford,... Nov 2023Major depressive disorder (MDD) is a leading cause of global disability. Several lines of evidence implicate the dopamine system in its pathophysiology. However, the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major depressive disorder (MDD) is a leading cause of global disability. Several lines of evidence implicate the dopamine system in its pathophysiology. However, the magnitude and consistency of the findings are unknown. We address this by systematically reviewing in vivo imaging evidence for dopamine measures in MDD and meta-analysing these where there are sufficient studies.
METHODS
Studies investigating the dopaminergic system using positron emission tomography or single photon emission computed tomography in MDD and a control group were included. Demographic, clinical and imaging measures were extracted from each study, and meta-analyses and sensitivity analyses were conducted.
RESULTS
We identified 43 studies including 662 patients and 801 controls. Meta-analysis of 38 studies showed no difference in mean or mean variability of striatal D receptor availability ( = 0.06, = 0.620), or combined dopamine synthesis and release capacity ( = 0.19, = 0.309). Dopamine transporter (DAT) availability was lower in the MDD group in studies using DAT selective tracers ( = -0.56, = 0.006), but not when tracers with an affinity for serotonin transporters were included ( = -0.21, = 0.420). Subgroup analysis showed greater dopamine release ( = 0.49, = 0.030), but no difference in dopamine synthesis capacity ( = -0.21, = 0.434) in the MDD group. Striatal D receptor availability was lower in patients with MDD in two studies.
CONCLUSIONS
The meta-analysis indicates striatal DAT availability is lower, but D receptor availability is not altered in people with MDD compared to healthy controls. There may be greater dopamine release and lower striatal D receptors in MDD, although further studies are warranted. We discuss factors associated with these findings, discrepancies with preclinical literature and implications for future research.
Topics: Humans; Dopamine; Depressive Disorder, Major; Tomography, Emission-Computed, Single-Photon; Positron-Emission Tomography; Receptors, Dopamine D2; Dopamine Plasma Membrane Transport Proteins
PubMed: 37811803
DOI: 10.1177/02698811231200881 -
The Journal of Biological Chemistry Aug 2023Amphetamines (AMPHs) are substrates of the dopamine transporter (DAT) and reverse the direction of dopamine (DA) transport. This has been suggested to depend on...
Amphetamines (AMPHs) are substrates of the dopamine transporter (DAT) and reverse the direction of dopamine (DA) transport. This has been suggested to depend on activation of Ca-dependent pathways, but the mechanism underlying reverse transport via endogenously expressed DAT is still unclear. Here, to enable concurrent visualization by live imaging of extracellular DA dynamics and cytosolic Ca levels, we employ the fluorescent Ca sensor jRGECO1a expressed in cultured dopaminergic neurons together with the fluorescent DA sensor GRAB expressed in cocultured "sniffer" cells. In the presence of the Na-channel blocker tetrodotoxin to prevent exocytotic DA release, AMPH induced in the cultured neurons a profound dose-dependent efflux of DA that was blocked both by inhibition of DAT with cocaine and by inhibition of the vesicular monoamine transporter-2 with Ro-4-1284 or reserpine. However, the AMPH-induced DA efflux was not accompanied by an increase in cytosolic Ca and was unaffected by blockade of voltage-gated calcium channels or chelation of cytosolic Ca. The independence of cytosolic Ca was further supported by activation of N-methyl-D-aspartate-type ionotropic glutamate receptors leading to a marked increase in cytosolic Ca without affecting AMPH-induced DA efflux. Curiously, AMPH elicited spontaneous Ca spikes upon blockade of the D2 receptor, suggesting that AMPH can regulate intracellular Ca in an autoreceptor-dependent manner regardless of the apparent independence of Ca for AMPH-induced efflux. We conclude that AMPH-induced DA efflux in dopaminergic neurons does not require cytosolic Ca but is strictly dependent on the concerted action of AMPH on both vesicular monoamine transporter-2 and DAT.
Topics: Amphetamine; Cocaine; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Vesicular Monoamine Transport Proteins; Humans; Cell Line, Tumor
PubMed: 37468107
DOI: 10.1016/j.jbc.2023.105063 -
Human Brain Mapping Feb 2024Attention network theory proposes three distinct types of attention-alerting, orienting, and control-that are supported by separate brain networks and modulated by...
Attention network theory proposes three distinct types of attention-alerting, orienting, and control-that are supported by separate brain networks and modulated by different neurotransmitters, that is, norepinephrine, acetylcholine, and dopamine. Here, we explore the extent of cortical, genetic, and molecular dissociation of these three attention systems using multimodal neuroimaging. We evaluated the spatial overlap between fMRI activation maps from the attention network test (ANT) and cortex-wide gene expression data from the Allen Human Brain Atlas. The goal was to identify genes associated with each of the attention networks in order to determine whether specific groups of genes were co-expressed with the corresponding attention networks. Furthermore, we analyzed publicly available PET-maps of neurotransmitter receptors and transporters to investigate their spatial overlap with the attention networks. Our analyses revealed a substantial number of genes (3871 for alerting, 6905 for orienting, 2556 for control) whose cortex-wide expression co-varied with the activation maps, prioritizing several molecular functions such as the regulation of protein biosynthesis, phosphorylation, and receptor binding. Contrary to the hypothesized associations, the ANT activation maps neither aligned with the distribution of norepinephrine, acetylcholine, and dopamine receptor and transporter molecules, nor with transcriptomic profiles that would suggest clearly separable networks. Independence of the attention networks appeared additionally constrained by a high level of spatial dependency between the network maps. Future work may need to reconceptualize the attention networks in terms of their segregation and reevaluate the presumed independence at the neural and neurochemical level.
Topics: Humans; Orientation; Acetylcholine; Brain; Magnetic Resonance Imaging; Norepinephrine
PubMed: 38401136
DOI: 10.1002/hbm.26588 -
Movement Disorders : Official Journal... Jul 2023Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD).
OBJECTIVE
The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity.
METHODS
We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo-controlled, double-blind, 6-month main study followed by an active-treatment 6-month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [ F]FE-PE2I.
RESULTS
Drug-related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies.
CONCLUSIONS
Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Animals; Parkinson Disease; Dopamine; Nerve Growth Factors; Dopaminergic Neurons; Drug Delivery Systems; Double-Blind Method
PubMed: 37212361
DOI: 10.1002/mds.29426 -
Movement Disorders : Official Journal... Sep 2023It has been suggested that the loss of nigrostriatal dopaminergic axon terminals occurs before the loss of dopaminergic neurons in the substantia nigra (SN) in...
BACKGROUND
It has been suggested that the loss of nigrostriatal dopaminergic axon terminals occurs before the loss of dopaminergic neurons in the substantia nigra (SN) in Parkinson's disease (PD). This study aimed to use free-water imaging to evaluate microstructural changes in the dorsoposterior putamen (DPP) of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) patients, which is considered a prodromal stage of synucleinopathies.
METHODS
Free water values in the DPP, dorsoanterior putamen (DAP), and posterior SN were compared between the healthy controls (n = 48), iRBD (n = 43) and PD (n = 47) patients. In iRBD patients, the relationships between baseline and longitudinal free water values and clinical manifestations or dopamine transporter (DAT) striatal binding ratio (SBR) were analyzed.
RESULTS
Free water values were significantly higher in the DPP and posterior substantia nigra (pSN), but not in the DAP, in the iRBD and PD groups than in controls. In iRBD patients, free water values in the DPP were progressively increased and correlated with the progression of clinical manifestations and the striatal DAT SBR. Baseline free water in the DPP was negatively correlated with striatal DAT SBR and hyposmia and positively correlated with motor deficits.
CONCLUSIONS
This study demonstrates that free water values in the DPP are increased cross-sectionally and longitudinally and associated with clinical manifestations and the function of the dopaminergic system in the prodromal stage of synucleinopathies. Our findings indicate that free-water imaging of the DPP has the potential to be a valid marker of early diagnosis and progression of synucleinopathies. © 2023 International Parkinson and Movement Disorder Society.
Topics: Humans; REM Sleep Behavior Disorder; Putamen; Synucleinopathies; Prodromal Symptoms; Parkinson Disease; Dopamine; Water
PubMed: 37342973
DOI: 10.1002/mds.29499 -
Frontiers in Neuroscience 2023One of the hallmarks of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons and associated dopamine depletion. Several mechanisms, previously... (Review)
Review
One of the hallmarks of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons and associated dopamine depletion. Several mechanisms, previously considered in isolation, have been proposed to contribute to the pathophysiology of dopaminergic degeneration: dopamine oxidation-mediated neurotoxicity, high dopamine transporter (DAT) expression density per neuron, and autophagy-lysosome pathway (ALP) dysfunction. However, the interrelationships among these mechanisms remained unclear. Our recent research bridges this gap, recognizing autophagy as a novel dopamine homeostasis regulator, unifying these concepts. I propose that autophagy modulates dopamine reuptake by selectively degrading DAT. In PD, ALP dysfunction could increase DAT density per neuron, and enhance dopamine reuptake, oxidation, and neurotoxicity, potentially contributing to the progressive loss of dopaminergic neurons. This integrated understanding may provide a more comprehensive view of aspects of PD pathophysiology and opens new avenues for therapeutic interventions.
PubMed: 37694119
DOI: 10.3389/fnins.2023.1219441