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Neuron May 2023Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric...
Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia. Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations.
Topics: Mice; Animals; Dopamine; Propofol; Dopamine Plasma Membrane Transport Proteins; Molecular Docking Simulation; Receptors, Dopamine D1; Nucleus Accumbens; Anhedonia; Mice, Inbred C57BL
PubMed: 36917979
DOI: 10.1016/j.neuron.2023.02.017 -
Alzheimer's & Dementia : the Journal of... Apr 2023Lysosomes are degradative organelles that maintain cellular homeostasis and protein quality control. Transcription factor EB (TFEB)-mediated lysosome biogenesis enhances...
INTRODUCTION
Lysosomes are degradative organelles that maintain cellular homeostasis and protein quality control. Transcription factor EB (TFEB)-mediated lysosome biogenesis enhances lysosome-dependent degradation and alleviates neurodegenerative diseases, but the mechanisms underlying TFEB regulation and modification are still poorly understood.
METHODS
By screening novel small-molecule compounds, we identified a group of lysosome-enhancing compounds (LYECs) that promote TFEB activation and lysosome biogenesis.
RESULTS
One of these compounds, LH2-051, significantly inhibited the function of the dopamine transporter (DAT) and subsequently promoted lysosome biogenesis. We uncovered cyclin-dependent kinase 9 (CDK9) as a novel regulator of DAT-mediated lysosome biogenesis and identified six novel CDK9-phosphorylated sites on TFEB. We observed that signal transduction by the DAT-CDK9-TFEB axis occurs on lysosomes. Finally, we found that LH2-051 enhanced the degradation of amyloid beta plaques and improved the memory of amyloid precursor protein (APP)/Presenilin 1 (PS1) mice.
DISCUSSION
We identified the DAT-CDK9-TFEB signaling axis as a novel regulator of lysosome biogenesis. Our study sheds light on the mechanisms of protein quality control under pathophysiological conditions.
Topics: Mice; Animals; Alzheimer Disease; Amyloid beta-Peptides; Dopamine Plasma Membrane Transport Proteins; Amyloid beta-Protein Precursor; Lysosomes; Autophagy
PubMed: 36130073
DOI: 10.1002/alz.12776 -
Handbook of Experimental Pharmacology 2020There is a plethora of amphetamine derivatives exerting stimulant, euphoric, anti-fatigue, and hallucinogenic effects; all structural properties allowing these effects... (Review)
Review
There is a plethora of amphetamine derivatives exerting stimulant, euphoric, anti-fatigue, and hallucinogenic effects; all structural properties allowing these effects are contained within the amphetamine structure. In the first part of this review, the interaction of amphetamine with the dopamine transporter (DAT), crucially involved in its behavioral effects, is covered, as well as the role of dopamine synthesis, the vesicular monoamine transporter VMAT2, and organic cation 3 transporter (OCT3). The second part deals with requirements in amphetamine's effect on the kinases PKC, CaMKII, and ERK, whereas the third part focuses on where we are in developing anti-amphetamine therapeutics. Thus, treatments are discussed that target DAT, VMAT2, PKC, CaMKII, and OCT3. As is generally true for the development of therapeutics for substance use disorder, there are multiple preclinically promising specific compounds against (meth)amphetamine, for which further development and clinical trials are badly needed.
Topics: Amphetamine; Central Nervous System Stimulants; Dopamine Plasma Membrane Transport Proteins; Humans; Organic Cation Transport Proteins; Vesicular Monoamine Transport Proteins
PubMed: 31286212
DOI: 10.1007/164_2019_251 -
Handbook of Clinical Neurology 2016Single-photon emission computed tomography (SPECT) is a functional nuclear imaging technique that allows visualization and quantification of different in vivo... (Review)
Review
Single-photon emission computed tomography (SPECT) is a functional nuclear imaging technique that allows visualization and quantification of different in vivo physiologic and pathologic features of brain neurobiology. It has been used for many years in diagnosis of several neurologic and psychiatric disorders. In this chapter, we discuss the current state-of-the-art of SPECT imaging of brain perfusion and dopamine transporter (DAT) imaging. Brain perfusion SPECT imaging plays an important role in the localization of the seizure onset zone in patients with refractory epilepsy. In cerebrovascular disease, it can be useful in determining the cerebrovascular reserve. After traumatic brain injury, SPECT has shown perfusion abnormalities despite normal morphology. In the context of organ donation, the diagnosis of brain death can be made with high accuracy. In neurodegeneration, while amyloid or (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) are the nuclear diagnostic tools of preference for early and differential diagnosis of dementia, perfusion SPECT imaging can be useful, albeit with slightly lower accuracy. SPECT imaging of the dopamine transporter system is widely available in Europe and Asia, but since recently also in the USA, and has been accepted as an important diagnostic tool in the early and differential diagnosis of parkinsonism in patients with unclear clinical features. The combination of perfusion SPECT (or FDG-PET) and DAT imaging provides differential diagnosis between idiopathic Parkinson's disease, Parkinson-plus syndromes, dementia with Lewy bodies, and essential tremor.
Topics: Brain; Brain Diseases; Dopamine Plasma Membrane Transport Proteins; Humans; Magnetic Resonance Imaging; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon
PubMed: 27432669
DOI: 10.1016/B978-0-444-53485-9.00013-1 -
Cells Jun 2023Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function... (Review)
Review
Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the gene. Advances in genomic analysis have revealed an evolving spectrum of -related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy.
Topics: Dopamine Plasma Membrane Transport Proteins; Precision Medicine; Phenotype
PubMed: 37443770
DOI: 10.3390/cells12131737 -
Synapse (New York, N.Y.) Jan 2023The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability and... (Meta-Analysis)
Meta-Analysis
The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability and dopamine transporter (DAT) availability, measured using positron emission tomography, and obesity. We performed a systematic search of MEDLINE (from inception to November 2020) and EMBASE (from inception to November 2020) for articles published in English using the keywords "dopamine receptor," "dopamine transporter," "obesity," and "neuroimaging." Body mass index (BMI) and the corresponding binding potential (BP ) were extracted from figures in each study using Engauge Digitizer, version 12.1, and plotted for radiopharmaceuticals and regions of interest (ROIs). Five studies involving 119 subjects with DR and five studies including 421 subjects with DAT were eligible for inclusion in this study. In overweight or obese subjects with BMI of 25 kg/m or higher, DR availability from C-Racloprie was negatively associated with BMI. However, DR availability from C-PHNO was positively associated with BMI. DAT ratio was calculated after dividing DAT availabilities of overweight/obese BMI with mean DAT availabilities of normal BMI. The association between DAT ratio and BMI was not significant regardless of radiopharmaceuticals. In conclusion, dopamine plays a main role in the reward system with regard to obesity. Overweight and obese subjects had negative association between DR availability from C-Raclopride and BMI. However, the association of DR availability with BMI was dependent on radiopharmaceuticals. DAT availability did not show the significant relationship with BMI regardless of radiopharmaceuticals.
Topics: Humans; Dopamine Plasma Membrane Transport Proteins; Radiopharmaceuticals; Overweight; Obesity; Receptors, Dopamine D2
PubMed: 36099576
DOI: 10.1002/syn.22254 -
Biomolecules May 2023The key element of dopamine (DA) neurotransmission is undoubtedly DA transporter (DAT), a transmembrane protein responsible for the synaptic reuptake of the mediator.... (Review)
Review
The key element of dopamine (DA) neurotransmission is undoubtedly DA transporter (DAT), a transmembrane protein responsible for the synaptic reuptake of the mediator. Changes in DAT's function can be a key mechanism of pathological conditions associated with hyperdopaminergia. The first strain of gene-modified rodents with a lack of DAT were created more than 25 years ago. Such animals are characterized by increased levels of striatal DA, resulting in locomotor hyperactivity, increased levels of motor stereotypes, cognitive deficits, and other behavioral abnormalities. The administration of dopaminergic and pharmacological agents affecting other neurotransmitter systems can mitigate those abnormalities. The main purpose of this review is to systematize and analyze (1) known data on the consequences of changes in DAT expression in experimental animals, (2) results of pharmacological studies in these animals, and (3) to estimate the validity of animals lacking DAT as models for discovering new treatments of DA-related disorders.
Topics: Animals; Rodentia; Dopamine Plasma Membrane Transport Proteins; Corpus Striatum; Dopamine; Synaptic Transmission
PubMed: 37238676
DOI: 10.3390/biom13050806 -
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 -
Vitamins and Hormones 2015In this chapter, we explore the basic science of the dopamine transporter (DAT), an integral component of a system that regulates dopamine homeostasis. Dopamine is a key... (Review)
Review
In this chapter, we explore the basic science of the dopamine transporter (DAT), an integral component of a system that regulates dopamine homeostasis. Dopamine is a key neurotransmitter for several brain functions including locomotor control and reward systems. The transporter structure, function, mechanism of action, localization, and distribution, in addition to gene regulation, are discussed. Over many years, a wealth of information concerning the DAT has been accrued and has led to increased interest in the role of the DAT in a plethora of central nervous system diseases. These DAT characteristics are explored in relation to a range of neurological and neuropsychiatric diseases, with a particular focus on the genetics of the DAT. In addition, we discuss the pharmacology of the DAT and how this relates to disease and addiction.
Topics: Animals; Central Nervous System Diseases; Dopamine; Dopamine Plasma Membrane Transport Proteins; Homeostasis; Humans; Time Factors
PubMed: 25817874
DOI: 10.1016/bs.vh.2014.12.009 -
Ageing Research Reviews Sep 2016The dopamine transporter (DAT) is responsible for clearance of dopamine from the synaptic cleft after its release. Imaging DAT availability provides a measure of... (Review)
Review
The dopamine transporter (DAT) is responsible for clearance of dopamine from the synaptic cleft after its release. Imaging DAT availability provides a measure of dopamine terminal function and a method for detecting the striatal dopamine terminal dysfunction present in idiopathic Parkinson's disease (PD) and atypical neurodegenerative parkinsonian disorders such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). DAT imaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT) can be used to support or refute a diagnosis of dopamine deficient parkinsonism in cases where this is unclear and rationalise a trial of dopamine replacement agents as therapy. It can also detect subclinical dopaminergic dysfunction when present in subjects at risk for PD such as relatives of patients, susceptibility gene mutation carriers, and subjects with late onset hyposmia or sleep disorders. The presence of normal DAT availability on imaging can help categorise "subjects without evidence of dopamine deficiency" (SWEDDs) who on occasion mimic PD and include dystonic tremors, drug-induced and psychogenic parkinsonism in their ranks. Reduced levels of baseline striatal DAT availability on PET or SPECT scanning, however, should be regarded as supportive rather than diagnostic of dopamine deficient parkinsonism.
Topics: Animals; Dementia; Dopamine Plasma Membrane Transport Proteins; Humans; Molecular Imaging; Parkinson Disease; Parkinson Disease, Secondary
PubMed: 26802555
DOI: 10.1016/j.arr.2015.12.009