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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 -
Molecular Psychiatry Jul 2023Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases...
Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol's actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.
Topics: Mice; Animals; Dopamine; Ethanol; Carrier Proteins; Cocaine-Related Disorders; Cocaine; Serotonin; Mice, Knockout; Cations; Dopamine Plasma Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins
PubMed: 37308680
DOI: 10.1038/s41380-023-02064-5 -
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 -
Journal of Biomedical Science Aug 2023Parkinson's disease (PD) is the second most frequent age-related neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Both environmental...
BACKGROUND
Parkinson's disease (PD) is the second most frequent age-related neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Both environmental and genetic aspects are involved in the pathogenesis of PD. Osmotin is a structural and functional homolog of adiponectin, which regulates the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) via adiponectin receptor 1 (AdipoR1), thus attenuating PD-associated pathology. Therefore, the current study investigated the neuroprotective effects of osmotin using in vitro and in vivo models of PD.
METHODS
The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and neuron-specific enolase promoter human alpha-synuclein (NSE-hαSyn) transgenic mouse models and 1-methyl-4-phenylpyridinium (MPP)- or alpha-synuclein A53T-treated cell models. MPTP was injected at a dose of 30 mg/kg/day for five days, and osmotin was injected twice a week at a dose of 15 mg/kg for five weeks. We performed behavioral tests and analyzed the biochemical and molecular changes in the substantia nigra pars compacta (SNpc) and the striatum.
RESULTS
Based on our study, osmotin mitigated MPTP- and α-synuclein-induced motor dysfunction by upregulating the nuclear receptor-related 1 protein (Nurr1) transcription factor and its downstream markers tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2). From a pathological perspective, osmotin ameliorated neuronal cell death and neuroinflammation by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, osmotin alleviated the accumulation of α-synuclein by promoting the AMPK/mammalian target of rapamycin (mTOR) autophagy signaling pathway. Finally, in nonmotor symptoms of PD, such as cognitive deficits, osmotin restored synaptic deficits, thereby improving cognitive impairment in MPTP- and α-synuclein-induced mice.
CONCLUSIONS
Therefore, our findings indicated that osmotin significantly rescued MPTP/α-synuclein-mediated PD neuropathology. Altogether, these results suggest that osmotin has potential neuroprotective effects in PD neuropathology and may provide opportunities to develop novel therapeutic interventions for the treatment of PD.
Topics: Humans; Mice; Animals; Parkinson Disease; alpha-Synuclein; Neuroprotective Agents; AMP-Activated Protein Kinases; Substantia Nigra; Signal Transduction; Dopaminergic Neurons; TOR Serine-Threonine Kinases; Mice, Inbred C57BL; Disease Models, Animal; Mammals
PubMed: 37568205
DOI: 10.1186/s12929-023-00961-z -
Cell Research Jan 2024Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent...
Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington's Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occluded, and cytosol-facing conformations. Notably, tetrabenazine induces a substantial rearrangement of TM2 and TM7, extending beyond the typical rocker-switch movement. These functionally dynamic snapshots, complemented by biochemical analysis, unveil the essential components responsible for ligand recognition, elucidate the proton-driven exchange cycle, and provide a framework to design improved pharmaceutics targeting VMAT2.
Topics: Humans; Reserpine; Serotonin; Synaptic Vesicles; Tetrabenazine; Vesicular Monoamine Transport Proteins
PubMed: 38163846
DOI: 10.1038/s41422-023-00906-z -
Brain : a Journal of Neurology Aug 2023Postural instability and freezing of gait are the most debilitating dopamine-refractory motor impairments in advanced stages of Parkinson's disease because of increased...
Postural instability and freezing of gait are the most debilitating dopamine-refractory motor impairments in advanced stages of Parkinson's disease because of increased risk of falls and poorer quality of life. Recent findings suggest an inability to efficaciously utilize vestibular information during static posturography among people with Parkinson's disease who exhibit freezing of gait, with associated changes in cholinergic system integrity as assessed by vesicular acetylcholine transporter PET. There is a lack of adequate understanding of how postural control varies as a function of available sensory information in patients with Parkinson's disease with freezing of gait. The goal of this cross-sectional study was to examine cerebral cholinergic system changes that associate with inter-sensory postural control processing features as assessed by dynamic computerized posturography and acetylcholinesterase PET. Seventy-five participants with Parkinson's disease, 16 of whom exhibited freezing of gait, underwent computerized posturography on the NeuroCom© Equitest sensory organization test platform, striatal dopamine, and acetylcholinesterase PET scanning. Findings demonstrated that patients with Parkinson's disease with freezing of gait have greater difficulty maintaining balance in the absence of reliable proprioceptive cues as compared to those without freezing of gait [β = 0.28 (0.021, 0.54), P = 0.034], an effect that was independent of disease severity [β = 0.16 (0.062, 0.26), P < 0.01] and age [β = 0.092 (-0.005, 0.19), P = 0.062]. Exploratory voxel-based analysis revealed an association between postural control and right hemispheric cholinergic network related to visual-vestibular integration and self-motion perception. High anti-cholinergic burden predicted postural control impairment in a manner dependent on right hemispheric cortical cholinergic integrity [β = 0.34 (0.065, 0.61), P < 0.01]. Our findings advance the perspective that cortical cholinergic system might play a role in supporting postural control after nigro-striatal dopaminergic losses in Parkinson's disease. Failure of cortex-dependent visual-vestibular integration may impair detection of postural instability in absence of reliable proprioceptive cues. Better understanding of how the cholinergic system plays a role in this process may augur novel treatments and therapeutic interventions to ameliorate debilitating symptoms in patients with advanced Parkinson's disease.
Topics: Humans; Parkinson Disease; Acetylcholinesterase; Dopamine; Gait Disorders, Neurologic; Cross-Sectional Studies; Quality of Life; Postural Balance
PubMed: 37086478
DOI: 10.1093/brain/awad134 -
Proceedings of the National Academy of... Oct 2023The burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. At many synapses, however, high firing rates...
The burst firing of midbrain dopamine neurons releases a phasic dopamine signal that mediates reinforcement learning. At many synapses, however, high firing rates deplete synaptic vesicles (SVs), resulting in synaptic depression that limits release. What accounts for the increased release of dopamine by stimulation at high frequency? We find that adaptor protein-3 (AP-3) and its coat protein VPS41 promote axonal dopamine release by targeting vesicular monoamine transporter VMAT2 to the axon rather than dendrites. AP-3 and VPS41 also produce SVs that respond preferentially to high-frequency stimulation, independent of their role in axonal polarity. In addition, conditional inactivation of VPS41 in dopamine neurons impairs reinforcement learning, and this involves a defect in the frequency dependence of release rather than the amount of dopamine released. Thus, AP-3 and VPS41 promote the axonal polarity of dopamine release but enable learning by producing a distinct population of SVs tuned specifically to high firing frequency that confers the phasic release of dopamine.
Topics: Dopamine; Synaptic Vesicles; Vesicular Monoamine Transport Proteins; Axons; Mesencephalon
PubMed: 37812725
DOI: 10.1073/pnas.2309843120 -
The Kaohsiung Journal of Medical... Oct 2023Butyrate (BU), a gut microbiota-derived metabolite, has been reported to play a neuroprotective role in Parkinson's disease (PD). However, the specific molecular...
Butyrate (BU), a gut microbiota-derived metabolite, has been reported to play a neuroprotective role in Parkinson's disease (PD). However, the specific molecular mechanism of BU has not been fully interpreted. This work aimed to verify the protective effects of BU against MPTP/MPP -induced neurotoxicity and explore the mechanisms involved. The results showed that BU protected against MPTP-induced motor dysfunction and decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels. Additionally, BU pretreatment improved PC12 cell viability and reduced MPP -induced PC12 cell apoptosis. BU treatment also attenuated MPP -stimulated oxidative stress and inflammatory response in PC12 cells. Furthermore, BU inhibited MPTP/MPP -induced hyperactivation of the JAK2/STAT3 signaling in mice and PC12 cells. Besides, a JAK2 agonist, Coumermycin A1 (C-A1), substantially reversed BU-mediated inhibition on JAK2/STAT3 phosphorylation in MPP -challenged PC12 cells and abated BU-induced repression on MPP -triggered apoptosis, oxidative stress, and inflammatory response in PC12 cells. To sum up, BU might exert neuroprotective effects against MPP /MPTP-induced neurotoxicity by inactivating the JAK2/STAT3 signaling.
Topics: Rats; Mice; Animals; Parkinson Disease; Butyrates; Gastrointestinal Microbiome; MPTP Poisoning; Neuroprotective Agents; Signal Transduction; PC12 Cells; Mice, Inbred C57BL
PubMed: 37807941
DOI: 10.1002/kjm2.12745 -
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