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https://www.readbyqxmd.com/read/28530234/n-alkylated-analogs-of-4-methylamphetamine-4-ma-differentially-affect-monoamine-transporters-and-abuse-liability
#1
Ernesto Solis, John S Partilla, Farhana Sakloth, Iwona Ruchala, Kathryn L Schwienteck, Louis J De Felice, Jose M Eltit, Richard A Glennon, S Stevens Negus, Michael H Baumann
Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells co-expressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET and SERT...
May 22, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28520803/multiple-modality-biomarker-prediction-of-cognitive-impairment-in-prospectively-followed-de-novo-parkinson-disease
#2
Chelsea Caspell-Garcia, Tanya Simuni, Duygu Tosun-Turgut, I-Wei Wu, Yu Zhang, Mike Nalls, Andrew Singleton, Leslie A Shaw, Ju-Hee Kang, John Q Trojanowski, Andrew Siderowf, Christopher Coffey, Shirley Lasch, Dag Aarsland, David Burn, Lana M Chahine, Alberto J Espay, Eric D Foster, Keith A Hawkins, Irene Litvan, Irene Richard, Daniel Weintraub
OBJECTIVES: To assess the neurobiological substrate of initial cognitive decline in Parkinson's disease (PD) to inform patient management, clinical trial design, and development of treatments. METHODS: We longitudinally assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta [Aβ], tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition...
2017: PloS One
https://www.readbyqxmd.com/read/28511263/diagnosis-and-treatment-of-functional-psychogenic-parkinsonism
#3
Kathrin LaFaver, Alberto J Espay
Functional (psychogenic) parkinsonism (FP) is recognized by the mandatory combination of marked slowness without progressive decrement on repetitive manual tasks and variable resistance against passive movements in the absence of cogwheel rigidity. Other functional phenotypes, such as functional tremor and functional gait impairment, may coexist. Although neither necessary nor sufficient for the diagnosis of FP, supportive historical clues include the sudden onset of symptoms and absent or nonphysiologic response to levodopa...
April 2017: Seminars in Neurology
https://www.readbyqxmd.com/read/28506818/measuring-inhibition-of-monoamine-reuptake-transporters-by-new-psychoactive-substances-nps-in-real-time-using-a-high-throughput-fluorescence-based-assay
#4
Anne Zwartsen, Anouk H A Verboven, Regina G D M van Kleef, Fiona M J Wijnolts, Remco H S Westerink, Laura Hondebrink
The prevalence and use of new psychoactive substances (NPS) is increasing and currently over 600 NPS exist. Many illicit drugs and NPS increase brain monoamine levels by inhibition and/or reversal of monoamine reuptake transporters (DAT, NET and SERT). This is often investigated using labor-intensive, radiometric endpoint measurements. We investigated the applicability of a novel and innovative assay that is based on a fluorescent monoamine mimicking substrate. DAT, NET or SERT-expressing human embryonic kidney (HEK293) cells were exposed to common drugs (cocaine, dl-amphetamine or MDMA), NPS (4-fluoroamphetamine, PMMA, α-PVP, 5-APB, 2C-B, 25B-NBOMe, 25I-NBOMe or methoxetamine) or the antidepressant fluoxetine...
May 12, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28495886/the-sigma-1-receptor-modulates-dopamine-transporter-conformation-and-cocaine-binding-and-may-thereby-potentiate-cocaine-self-administration-in-rats
#5
Weimin Conrad Hong, Hideaki Yano, Takato Hiranita, Frederick T Chin, Christopher R McCurdy, Tsung-Ping Su, Susan G Amara, Jonathan L Katz
The dopamine transporter (DAT) regulates dopamine (DA) neurotransmission by recapturing DA into the presynaptic terminals, and is a principal target of the psychostimulant cocaine. The sigma-1 receptor (σ1R) is a molecular chaperone, and its ligands have been shown to modulate dopamine neuronal signaling, although their effects on DAT activity are unclear. Here, we report that the prototypical σ1R agonist (+)-pentazocine potentiated the dose response of cocaine self-administration in rats, consistent with effects of the σR agonists PRE-084 and DTG reported previously...
May 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28492278/direct-and-systemic-administration-of-a-cns-permeant-tamoxifen-analog-reduces-amphetamine-induced-dopamine-release-and-reinforcing-effects
#6
Colleen Carpenter, Alexander G Zestos, Rachel Altshuler, Roderick J Sorenson, Bipasha Guptaroy, Hollis D Showalter, Robert T Kennedy, Emily Jutkiewicz, Margaret E Gnegy
Amphetamines (AMPHs) are globally abused. With no effective treatment for AMPH addiction to date, there is urgent need for the identification of druggable targets that mediate the reinforcing action of this stimulant class. AMPH-stimulated dopamine efflux is modulated by protein kinase C (PKC) activation. Inhibition of PKC reduces AMPH-stimulated dopamine efflux and locomotor activity. The only known CNS-permeant PKC inhibitor is the selective estrogen receptor modulator tamoxifen. In this study we demonstrate that a tamoxifen analog, 6c, which more potently inhibits PKC than tamoxifen but lacks affinity for the estrogen receptor, reduces AMPH-stimulated increases in extracellular dopamine and reinforcement-related behavior...
May 11, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28466092/repeated-social-defeat-and-the-rewarding-effects-of-cocaine-in-adult-and-adolescent-mice-dopamine-transcription-factors-probdnf-signaling-pathways-and-the-trkb-receptor-in-the-mesolimbic-system
#7
Sandra Montagud-Romero, Cristina Nuñez, M Carmen Blanco-Gandia, Elena Martínez-Laorden, María A Aguilar, Javier Navarro-Zaragoza, Pilar Almela, Maria-Victoria Milanés, María-Luisa Laorden, José Miñarro, Marta Rodríguez-Arias
RATIONALE: Repeated social defeat (RSD) increases the rewarding effects of cocaine in adolescent and adult rodents. OBJECTIVE: The aim of the present study was to compare the long-term effects of RSD on the conditioned rewarding effects of cocaine and levels of the transcription factors Pitx3 and Nurr1 in the ventral tegmental area (VTA), the dopamine transporter (DAT), the D2 dopamine receptor (D2DR) and precursor of brain-derived neurotrophic factor (proBDNF) signaling pathways, and the tropomyosin-related kinase B (TrkB) receptor in the nucleus accumbens (NAc) in adult and adolescent mice...
May 2, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28458039/glucocorticoids-glucocorticoid-receptors-effect-on-dopaminergic-neurotransmitters-in-adhd-rats
#8
Yanhui Chen, Xiaolan Zheng, Linqi Xie, Liang Huang, Zhongling Ke, Jie Zheng, Hongzhu Lu, Jun Hu
Dexamethaone (DEX, glucocorticoid receptor agonist) and RU486 (glucocorticoid receptor inhibitor) may affect the behavior of attention deficit hyperactivity disorder (ADHD) rats, by changing the level of dopamine and noradrenaline and dopamine transporter in different regions of their brain. In this study, we have investigated the effect and the underlying mechanism of Glucocorticoids/Glucocorticoid receptors on dopaminergic neurotransmitters in ADHD Rats. Thirty male Wistar Kyoto rats (WKY) and 30 male spontaneously hypertensive rats (SHR) were respectively divided into 3 groups randomly as follows: a GR agonist group (DEX), a GR inhibitor group (RU486) and a control group (CON)...
April 27, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28456940/mptp-mouse-model-of-preclinical-and-clinical-parkinson-s-disease-as-an-instrument-for-translational-medicine
#9
Eduard R Mingazov, Gulnara R Khakimova, Elena A Kozina, Alexei E Medvedev, Olga A Buneeva, Ara S Bazyan, Michael V Ugrumov
Parkinson's disease (PD) is characterized by the appearance of motor symptoms many years after the onset of neurodegeneration, which explains low efficiency of therapy. Therefore, one of the priorities in neurology is to develop an early diagnosis and preventive treatment of PD, based on knowledge of molecular mechanisms of neurodegeneration and neuroplasticity in the nigrostriatal system. However, due to inability to diagnose PD at preclinical stage, research and development must be performed in animal models by comparing the nigrostriatal system in the models of asymptomatic and early symptomatic stages of PD...
April 29, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28454982/dopamine-transporter-dat-genetic-hypofunction-in-mice-produces-alterations-consistent-with-adhd-but-not-schizophrenia-or-bipolar-disorder
#10
M Mereu, G Contarini, E F Buonaguro, G Latte, F Managò, F Iasevoli, A de Bartolomeis, F Papaleo
ADHD, schizophrenia and bipolar disorder are psychiatric diseases with a strong genetic component which share dopaminergic alterations. Dopamine transporter (DAT) genetics might be potentially implicated in all these disorders. However, in contrast to DAT absence, the effects of DAT hypofunction especially in developmental trajectories have been scarcely addressed. Thus, we comprehensively studied DAT hypofunctional mice (DAT+/-) from adolescence to adulthood to disentangle DAT-dependent alterations in the development of psychiatric-relevant phenotypes...
April 26, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28454981/neuropharmacological-characterization-of-the-new-psychoactive-substance-methoxetamine
#11
Laura Hondebrink, Emma E J Kasteel, Anke M Tukker, Fiona M J Wijnolts, Anouk H A Verboven, Remco H S Westerink
The use of new psychoactive substances (NPS) is steadily increasing. One commonly used NPS is methoxetamine (MXE), a ketamine analogue. Several adverse effects have been reported following MXE exposure, while only limited data are available on its neuropharmacological modes of action. We investigated the effects of MXE and ketamine on several endpoints using multiple in vitro models. These included rat primary cortical cells, human SH-SY5Y cells, human induced pluripotent stem cell (hiPSC)-derived iCell(®) Neurons, DopaNeurons and astrocyte co-cultures, and human embryonic kidney (HEK293) cells...
April 25, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28445595/ventricular-fibrillation-cardiac-arrest-produces-a-chronic-striatal-hyperdopaminergic-state-that-is-worsened-by-methylphenidate-treatment
#12
Gerald J Nora, Rashed Harun, David F Fine, Daniel Hutchison, Adam C Grobart, Jason P Stezoski, Miranda Munoz, Patrick M Kochanek, Rehana K Leak, Tomas Drabek, Amy K Wagner
Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury. Currently, little is understood about chronic changes in striatal dopamine (DA) systems after hypoxic-ischemic brain injury. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches. We hypothesized that striatal DA neurotransmission would be altered chronically after ventricular fibrillation cardiac arrest (VF-CA)...
April 26, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28442581/sigma-receptor-effects-of-n-substituted-benztropine-analogs-implications-for-antagonism-of-cocaine-self-administration
#13
Takato Hiranita, Weimin C Hong, Theresa Kopajtic, Jonathan L Katz
Several N-substituted benztropine (BZT) analogs are atypical dopamine transport inhibitors as they have affinity for the dopamine transporter (DAT), but have minimal cocaine-like pharmacological effects and can block numerous effects of cocaine including its self-administration. Among these compounds, N-methyl (AHN1-055), N-allyl (AHN2-005), and N-butyl (JHW007) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane were more potent in antagonizing self-administration of cocaine and d-methamphetamine than in decreasing food-maintained responding...
April 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28441487/the-isomeric-preference-of-an-atypical-dopamine-transporter-inhibitor-contributes-to-its-selection-of-the-transporter-conformation
#14
Ara M Abramyan, Sebastian Stolzenberg, Zheng Li, Claus J Loland, Frank Noé, Lei Shi
Cocaine, a widely abused psychostimulant, inhibits the dopamine transporter (DAT) by trapping the protein in an outward-open conformation, whereas atypical DAT inhibitors such as benztropine have low abuse liability and prefer less outward-open conformations. Here, we use a spectrum of computational modeling and simulation approaches to obtain the underlying molecular mechanism in atomistic detail. Interestingly, our quantum mechanical calculations and molecular dynamics (MD) simulations suggest that a benztropine derivative JHW007 prefers a different stereoisomeric conformation of tropane in binding to DAT compared to that of a cocaine derivative, CFT...
May 4, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28437017/determination-of-the-enantiomeric-purity-of-the-selective-dopamine-transporter-inhibitor-r-r-4-2-benzhydryloxyethyl-1-4-fluorobenzyl-piperidin-3-ol
#15
Patrick Neiens, Georg Höfner, Klaus T Wanner
(+)-R,R-D-84 ((+)-R,R-4-(2-benzhydryloxyethyl)-1-(4-fluorobenzyl)piperidin-3-ol) is a promising pharmacological tool for the dopamine transporter (DAT), due to its high affinity and selectivity for this target. In this study, an analytical method to ascertain the enantiomeric purity of this compound was established. For this purpose, a high-performance liquid chromatographic (HPLC) method, based on a cellulose derived chiral stationary phase (CSP) was developed. The method was characterized concerning its specificity, linearity, and range...
April 24, 2017: Chirality
https://www.readbyqxmd.com/read/28428472/examination-of-a-method-to-determine-the-reference-region-for-calculating-the-specific-binding-ratio-in-dopamine-transporter-imaging
#16
Ayumi Watanabe, Yusuke Inoue, Yuji Asano, Kei Kikuchi, Hiroki Miyatake, Takanobu Tokushige
The specific binding ratio (SBR) was first reported by Tossici-Bolt et al. for quantitative indicators for dopamine transporter (DAT) imaging. It is defined as the ratio of the specific binding concentration of the striatum to the non-specific binding concentration of the whole brain other than the striatum. The non-specific binding concentration is calculated based on the region of interest (ROI), which is set 20 mm inside the outer contour, defined by a threshold technique. Tossici-Bolt et al. used a 50% threshold, but sometimes we couldn't define the ROI of non-specific binding concentration (reference region) and calculate SBR appropriately with a 50% threshold...
2017: Nihon Hoshasen Gijutsu Gakkai Zasshi
https://www.readbyqxmd.com/read/28417953/recombinant-adeno-associated-virus-mediated-rescue-of-function-in-a-mouse-model-of-dopamine-transporter-deficiency-syndrome
#17
P Illiano, C E Bass, L Fichera, L Mus, E A Budygin, T D Sotnikova, D Leo, S Espinoza, R R Gainetdinov
Dopamine Transporter Deficiency Syndrome (DTDS) is a rare autosomal recessive disorder caused by loss-of-function mutations in dopamine transporter (DAT) gene, leading to severe neurological disabilities in children and adults. DAT-Knockout (DAT-KO) mouse is currently the best animal model for this syndrome, displaying functional hyperdopaminergia and neurodegenerative phenotype leading to premature death in ~36% of the population. We used DAT-KO mouse as model for DTDS to explore the potential utility of a novel combinatorial adeno-associated viral (AAV) gene therapy by expressing DAT selectively in DA neurons and terminals, resulting in the rescue of aberrant striatal DA dynamics, reversal of characteristic phenotypic and behavioral abnormalities, and prevention of premature death...
April 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28410288/the-utility-of-the-combination-of-a-spect-study-with-123i-fp-cit-of-dopamine-transporters-and-123i-mibg-myocardial-scintigraphy-in-differentiating-parkinson-disease-from-other-degenerative-parkinsonian-syndromes
#18
Naoto Uyama, Hideki Otsuka, Takayoshi Shinya, Yoichi Otomi, Masafumi Harada, Wataru Sako, Yuishin Izumi, Ryuji Kaji, Yuya Watanabe, Satoru Takashi, Yamato Kunikane
OBJECTIVE: Molecular imaging of nigrostriatal dopamine transporters (DAT) and sympathetic cardiac innervation with single-photon emission computed tomography (SPECT) are useful tools for differentiating idiopathic Parkinson disease (PD) from other degenerative parkinsonian syndromes (non-PD). Nevertheless, these modalities are often insufficient for achieving a definite diagnosis. The aims of this study were to evaluate the diagnostic accuracy of the combination of these tools. MATERIALS AND METHODS: The SPECT radiotracers [I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)-nortropane (FP-CIT) and meta-[I]-iodobenzylguanidine (MIBG) were used to research presynaptic dopaminergic projections (DAT SPECT) and myocardial adrenergic innervation (MIBG scintigraphy), respectively...
June 2017: Nuclear Medicine Communications
https://www.readbyqxmd.com/read/28409113/axonal-damage-and-loss-of-connectivity-in-nigrostriatal-and-mesolimbic-dopamine-pathways-in-early-parkinson-s-disease
#19
Silvia Paola Caminiti, Luca Presotto, Damiano Baroncini, Valentina Garibotto, Rosa Maria Moresco, Luigi Gianolli, Maria Antonietta Volonté, Angelo Antonini, Daniela Perani
A progressive loss of dopamine neurons in the substantia nigra (SN) is considered the main feature of idiopathic Parkinson's disease (PD). Recent neuropathological evidence however suggests that the axons of the nigrostriatal dopaminergic system are the earliest target of α-synuclein accumulation in PD, thus the principal site for vulnerability. Whether this applies to in vivo PD, and also to the mesolimbic system has not been investigated yet. We used [(11)C]FeCIT PET to measure presynaptic dopamine transporter (DAT) activity in both nigrostriatal and mesolimbic systems, in 36 early PD patients (mean disease duration in months ± SD 21...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28408289/dopaminergic-control-of-anxiety-in-young-and-aged-zebrafish
#20
Victoria Kacprzak, Neil A Patel, Elizabeth Riley, Lili Yu, Jing-Ruey J Yeh, Irina V Zhdanova
Changes in the expression of the dopamine transporter (DAT), or the sensitivity of dopamine receptors, are associated with aging and substance abuse and may underlie some of the symptoms common to both conditions. In this study, we explored the role of the dopaminergic system in the anxiogenic effects of aging and acute cocaine exposure by comparing the behavioral phenotypes of wild type (WT) and DAT knockout zebrafish (DAT-KO) of different ages. To determine the involvement of specific dopamine receptors in anxiety states, antagonists to D1 (SCH23390) and D2/D3 (sulpiride) were employed...
April 10, 2017: Pharmacology, Biochemistry, and Behavior
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