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DAT transporter

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https://www.readbyqxmd.com/read/28734777/inhibitor-mechanisms-in-the-s1-binding-site-of-the-dopamine-transporter-defined-by-multi-site-molecular-tethering-of-photoactive-cocaine-analogs
#1
Danielle Krout, Akula Bala Pramod, Rejwi Acharya Dahal, Michael J Tomlinson, Babita Sharma, James D Foster, Mu-Fa Zou, Comfort Boatang, Amy Hauck Newman, John R Lever, Roxanne A Vaughan, L Keith Henry
Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints...
July 19, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28734204/molecular-dynamics-of-conformation-specific-dopamine-transporter-inhibitor-complexes
#2
Bernandie Jean, Christopher K Surratt, Jeffry D Madura
The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation...
July 11, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28734031/downregulation-of-dec1-contributes-to-the-neurotoxicity-induced-by-mpp-by-suppressing-pi3k-akt-gsk3%C3%AE-pathway
#3
Zhu Zhu, Yu-Wen Wang, Ding-Hao Ge, Ming Lu, Wei Liu, Jing Xiong, Gang Hu, Xiao-Ping Li, Jian Yang
AIM: Differentiated embryonic chondrocyte gene 1 (DEC1) is involved in the neuronal differentiation and development. The aim of this study is to investigate the role of DEC1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP(+) )-induced PD model. METHODS: The location of DEC1 and tyrosine hydroxylase (TH)-positive neurons were detected by immunofluorescence. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse subacute model of PD was established to evaluate the change of DEC1 expression in midbrain...
July 21, 2017: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/28727685/erbb4-signaling-in-dopaminergic-axonal-projections-increases-extracellular-dopamine-levels-and-regulates-spatial-working-memory-behaviors
#4
M Skirzewski, I Karavanova, A Shamir, L Erben, J Garcia-Olivares, J H Shin, D Vullhorst, V A Alvarez, S G Amara, A Buonanno
Genetic variants of Neuregulin 1 (NRG1) and its neuronal tyrosine kinase receptor ErbB4 are associated with risk for schizophrenia, a neurodevelopmental disorder characterized by excitatory/inhibitory imbalance and dopamine (DA) dysfunction. To date, most ErbB4 studies have focused on GABAergic interneurons in the hippocampus and neocortex, particularly fast-spiking parvalbumin-positive (PV+) basket cells. However, NRG has also been shown to modulate DA levels, suggesting a role for ErbB4 signaling in dopaminergic neuron function...
July 20, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28710426/targeting-of-dopamine-transporter-to-filopodia-requires-an-outward-facing-conformation-of-the-transporter
#5
Shiqi Ma, Mary H Cheng, Daryl A Guthrie, Amy H Newman, Ivet Bahar, Alexander Sorkin
Dopamine transporter (DAT) has been shown to accumulate in filopodia in neurons and non-neuronal cells. To examine the mechanisms of DAT filopodial targeting, we used quantitative live-cell fluorescence microscopy, and compared the effects of the DAT inhibitor cocaine and its fluorescent analog JHC1-64 on the plasma membrane distribution of wild-type DAT and two non-functional DAT mutants, R60A and W63A, that do not accumulate in filopodia. W63A did not bind JHC1-64, whereas R60A did, although less efficiently compared to the wild-type DAT...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28706191/aldehyde-dehydrogenase-1-positive-nigrostriatal-dopaminergic-fibers-exhibit-distinct-projection-pattern-and-dopamine-release-dynamics-at-mouse-dorsal-striatum
#6
Carmelo Sgobio, Junbing Wu, Wang Zheng, Xi Chen, Jing Pan, Armando G Salinas, Margaret I Davis, David M Lovinger, Huaibin Cai
Aldehyde dehydrogenase 1 (ALDH1A1)-positive dopaminergic (DA) neurons at the ventral substantia nigra pars compacta (SNpc) preferentially degenerate in Parkinson's disease (PD). Their projection pattern and dopamine release properties, however, remains uncharacterized. Here we show that ALDH1A1-positive axons project predominantly to the rostral two-thirds of dorsal striatum. A portion of these axons converge on a small fraction of striosome compartments restricted to the dorsolateral striatum (DLS), where less dopamine release was measured compared to the adjacent matrix enriched with the ALDH1A1-negative axons...
July 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28695985/intrastriatal-administration-of-botulinum-neurotoxin-a-normalizes-striatal-d2-r-binding-and-reduces-striatal-d1-r-binding-in-male-hemiparkinsonian-rats
#7
Franziska Wedekind, Angela Oskamp, Markus Lang, Alexander Hawlitschka, Karl Zilles, Andreas Wree, Andreas Bauer
Cerebral administration of botulinum neurotoxin A (BoNT-A) has been shown to improve disease-specific motor behavior in a rat model of Parkinson disease (PD). Since the dopaminergic system of the basal ganglia fundamentally contributes to motor function, we investigated the impact of BoNT-A on striatal dopamine receptor expression using in vitro and in vivo imaging techniques (positron emission tomography and quantitative autoradiography, respectively). Seventeen male Wistar rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and assigned to two treatment groups 7 weeks later: 10 rats were treated ipsilaterally with an intrastriatal injection of 1 ng BoNT-A, while the others received vehicle (n = 7)...
July 11, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28691722/potential-role-of-dopamine-transporter-in-behavioral-flexibility
#8
Anita Cybulska-Klosowicz, Julia Dabrowska, Sebastian Niedzielec, Renata Zakrzewska, Aleksandra Rozycka
Behavioral flexibility is subserved by the prefrontal cortex and the basal ganglia. Orbitofrontal cortex (OFC) and dorsomedial striatum (DMS) form a functional frontocorticostriatal circuit crucial for the mediation of flexibility during reversal learning via dopamine (DA) neurotransmission. The regulatory control in maintaining DA homeostasis and function is provided by the dopamine transporter (DAT), which therefore likely plays a significant role in controlling the influence of DA on cognitive processes...
2017: Acta Neurobiologiae Experimentalis
https://www.readbyqxmd.com/read/28689103/-123-i-meta-iodobenzylguanidine-mibg-myocardial-scintigraphy-in-patients-showing-scans-without-evidence-of-dopaminergic-deficits-swedds
#9
Fumihito Yoshii, Yusuke Moriya, Tomohide Ohnuki, Masafuchi Ryo, Wakoh Takahashi, Saori Kohara, Jun Hashimoto
OBJECTIVE: Scans without evidence of dopaminergic deficits (SWEDDs) in dopamine transporter single-photon emission computed tomography (DAT-SPECT) are found in 3.6-19.6% of patients with clinically suspected Parkinson's disease (PD). We investigated whether combined use of (123)I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy would be helpful to differentiate PD among SWEDDs patients. PATIENTS AND METHODS: 145 patients with clinically suspected PD underwent both DAT-SPECT and MIBG myocardial scintigraphy...
June 27, 2017: Clinical Neurology and Neurosurgery
https://www.readbyqxmd.com/read/28679601/prospective-clinical-and-dat-spect-imaging-in-premotor-lrrk2-g2019s-associated-parkinson-disease
#10
María Sierra, Isabel Martínez-Rodríguez, Pascual Sánchez-Juan, Isabel González-Aramburu, Mikel Jiménez-Alonso, Antonio Sánchez-Rodríguez, José Berciano, Ignacio Banzo, Jon Infante
OBJECTIVE: To assess the value of baseline clinical and imaging biomarkers in a cohort of asymptomatic LRRK2 G2019S carriers for predicting conversion to Parkinson disease (PD) at 4 years. METHODS: Thirty-two asymptomatic carriers of LRRK2 G2019S mutation underwent baseline and 4-year evaluation including clinical examination (Unified Parkinson's Disease Rating Scale, part III, olfaction University of Pennsylvania Smell Identification Test [UPSIT]) and dopamine transporter (DaT) SPECT ((123)I-ioflupane)...
July 5, 2017: Neurology
https://www.readbyqxmd.com/read/28679529/timing-of-caloric-intake-during-weight-loss-differentially-affects-striatal-dopamine-transporter-and-thalamic-serotonin-transporter-binding
#11
Ruth I Versteeg, Anouk Schrantee, Sofie M Adriaanse, Unga A Unmehopa, Jan Booij, Liesbeth Reneman, Eric Fliers, Susanne E la Fleur, Mireille J Serlie
Recent studies have shown that meal timing throughout the day contributes to maintaining or regaining weight after hypocaloric diets. Although brain serotonin and dopamine are well known to be involved in regulating feeding, it is unknown whether meal timing during energy restriction affects these neurotransmitter systems. We studied the effect of a 4 wk hypocaloric diet with either 50% of daily calories consumed at breakfast (BF group) or at dinner (D group) on hypothalamic and thalamic serotonin transporter (SERT) binding and on striatal dopamine transporter (DAT) binding...
July 5, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28673772/methyl-4-phenylpyridinium-mpp-differentially-affects-monoamine-release-and-re-uptake-in-murine-embryonic-stem-cell-derived-dopaminergic-and-serotonergic-neurons
#12
Yasmina Martí, Friederike Matthaeus, Thorsten Lau, Patrick Schloss
1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is known to selectively damage dopaminergic (DA) cells in the substantia nigra and to produce symptoms which are alike to those observed in Parkinson's disease (PD). Based on the similarity between MPTP-induced neurotoxicity and PD-related neuropathology, application of MPTP or its metabolite methyl-4-phenylpyridinium (MPP+) was successfully established in experimental rodent models to study PD-related neurodegenerative events. MPP+ is taken up by the dopamine transporter (DAT) into DA neurons where it exerts its neurotoxic action on mitochondria by affecting complex I of the respiratory chain...
June 30, 2017: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/28672806/phenotypic-discordance-in-siblings-with-identical-compound-heterozygous-park2-mutations
#13
David Isaacs, Daniel Claassen, Aaron B Bowman, Peter Hedera
PARK2 mutations are the most common cause of early-onset Parkinson's disease. No genotype-phenotype correlation exists, and phenotypic variability is quite common. We report two siblings with confirmed identical compound heterozygous mutations in the PARK2 gene manifesting strikingly different phenotypes. The older brother demonstrated marked parkinsonism by his mid-20's, whereas the younger brother developed exercise-induced dystonia in his mid-30's with no subsequent clinical progression, highlighting the clinical heterogeneity of the disease and implying the role of other genetic and/or environmental factors in disease progression...
June 24, 2017: Brain Sciences
https://www.readbyqxmd.com/read/28662820/survival-in-parkinson-s-disease-in-relation-to-striatal-dopamine-transporter-binding
#14
Elina Mäkinen, Juho Joutsa, Tero Vahlberg, Valtteri Kaasinen
OBJECTIVE: To investigate whether dopamine transporter (DAT) binding, as measured with single photon emission computed tomography (SPECT), can be used to predict mortality in patients with Parkinson's disease (PD). METHODS: A total of 162 patients with PD and abnormal [I-123]FP-CIT SPECT were clinically followed for a median of 5.8 years. A multivariate Cox regression model was used to investigate survival with the independent predictors of age, gender, severity of motor impairment, levodopa-equivalent daily dose of medication, presence of cognitive defects, and putaminal specific binding ratio (SBR) of [I-123]FP-CIT...
June 23, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28646469/the-cathinones-mdpv-and-%C3%AE-pvp-elicit-different-behavioral-and-molecular-effects-following-acute-exposure
#15
Giuseppe Giannotti, Isabella Canazza, Lucia Caffino, Sabrine Bilel, Andrea Ossato, Fabio Fumagalli, Matteo Marti
Since the mid-to-late 2000s, synthetic cathinones have gained popularity among drug users due to their psychostimulant effects greater than those produced by cocaine and amphetamine. Among them, 3,4-methylenedioxypyrovalerone (MDPV) and 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PVP) are ones of the most popular cathinones available in the clandestine market as "bath salts" or "fertilizers." Pre-clinical studies indicate that MDPV and α-PVP induced psychomotor stimulation, affected thermoregulation, and promoted reinforcing properties in rodents...
June 23, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28645061/the-neurochemical-consequences-of-methamphetamine-self-administration-in-male-and-female-rats
#16
Andrew Johansen, Lisa M McFadden
BACKGROUND: Methamphetamine (METH) is an addictive substance that is used in both males and females. Few preclinical studies have focused on understanding sex-differences in the neurochemical consequences of contingent METH. The purpose of the current study was to investigate potential sex-differences in the neurochemical consequences of METH self-administration. METHODS: Male and female adult rats were given extended access to METH or saline self-administration for 7d...
June 6, 2017: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/28644892/r-modafinil-exerts-weak-effects-on-spatial-memory-acquisition-and-dentate-gyrus-synaptic-plasticity
#17
Bharanidharan Shanmugasundaram, Yogesh D Aher, Jana Aradska, Marija Ilic, Daniel Daba Feyissa, Predrag Kalaba, Nilima Y Aher, Vladimir Dragacevic, Babak Saber Marouf, Thierry Langer, Harald H Sitte, Harald Hoeger, Gert Lubec, Volker Korz
Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO) is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP). Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO) or saline were administered for three days during the hole-board test and in in vivo DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT), and its phosphorylated form (ph-DAT) in DG tissue 4 h after LTP induction were quantified by western blot analysis...
2017: PloS One
https://www.readbyqxmd.com/read/28631404/structural-connectivity-differences-in-motor-network-between-tremor-dominant-and-nontremor-parkinson-s-disease
#18
Gaetano Barbagallo, Maria Eugenia Caligiuri, Gennarina Arabia, Andrea Cherubini, Angela Lupo, Rita Nisticò, Maria Salsone, Fabiana Novellino, Maurizio Morelli, Giuseppe Lucio Cascini, Domenico Galea, Aldo Quattrone
Motor phenotypes of Parkinson's disease (PD) are recognized to have different prognosis and therapeutic response, but the neural basis for this clinical heterogeneity remains largely unknown. The main aim of this study was to compare differences in structural connectivity metrics of the main motor network between tremor-dominant and nontremor PD phenotypes (TD-PD and NT-PD, respectively) using probabilistic tractography-based network analysis. A total of 63 PD patients (35 TD-PD patients and 28 NT-PD patients) and 30 healthy controls underwent a 3 T MRI...
June 20, 2017: Human Brain Mapping
https://www.readbyqxmd.com/read/28625719/atypical-dopamine-transporter-inhibitors-r-modafinil-and-jhw-007-differentially-affect-d2-autoreceptor-neurotransmission-and-the-firing-rate-of-midbrain-dopamine-neurons
#19
Alicia J Avelar, Jianjing Cao, Amy Hauck Newman, Michael J Beckstead
Abuse of psychostimulants like cocaine that inhibit dopamine (DA) reuptake through the dopamine transporter (DAT) represents a major public health issue, however FDA-approved pharmacotherapies have yet to be developed. Recently a class of ligands termed "atypical DAT inhibitors" has gained attention due to their range of effectiveness in increasing extracellular DA levels without demonstrating significant abuse liability. These compounds not only hold promise as therapeutic agents to treat stimulant use disorders but also as experimental tools to improve our understanding of DAT function...
June 15, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28623359/allosteric-modulatory-effects-of-sri-20041-and-sri-30827-on-cocaine-and-hiv-1-tat-protein-binding-to-human-dopamine-transporter
#20
Wei-Lun Sun, Pamela M Quizon, Yaxia Yuan, Wei Zhang, Subramaniam Ananthan, Chang-Guo Zhan, Jun Zhu
Dopamine transporter (DAT) is the target of cocaine and HIV-1 transactivator of transcription (Tat) protein. Identifying allosteric modulatory molecules with potential attenuation of cocaine and Tat binding to DAT are of great scientific and clinical interest. We demonstrated that tyrosine 470 and 88 act as functional recognition residues in human DAT (hDAT) for Tat-induced inhibition of DA transport and transporter conformational transitions. Here we investigated the allosteric modulatory effects of two allosteric ligands, SRI-20041 and SRI-30827 on cocaine binding on wild type (WT) hDAT, Y470 H and Y88 F mutants...
June 16, 2017: Scientific Reports
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