Activation of Phosphatidylinositol-Linked Dopamine Receptors Induces a Facilitation of Glutamate-Mediated Synaptic Transmission in the Lateral Entorhinal Cortex.

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Iulia Glovaci

Full Text Available The lateral entorhinal cortex receives strong inputs from midbrain dopamine neurons that can modulate its sensory and mnemonic function. We have previously demonstrated that 1 µM dopamine facilitates synaptic transmission in layer II entorhinal cortex cells via activation of D1-like receptors, increased cAMP-PKA activity, and a resulting enhancement of AMPA-receptor mediated currents. The present study assessed the contribution of phosphatidylinositol (PI-linked D1 receptors to the dopaminergic facilitation of transmission in layer II of the rat entorhinal cortex, and the involvement of phospholipase C activity and release of calcium from internal stores. Whole-cell patch-clamp recordings of glutamate-mediated evoked excitatory postsynaptic currents were obtained from pyramidal and fan cells. Activation of D1-like receptors using SKF38393, SKF83959, or 1 µM dopamine induced a reversible facilitation of EPSCs which was abolished by loading cells with either the phospholipase C inhibitor U-73122 or the Ca2+ chelator BAPTA. Neither the L-type voltage-gated Ca2+ channel blocker nifedipine, nor the L/N-type channel blocker cilnidipine, blocked the facilitation of synaptic currents. However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3 receptors or ryanodine receptors. Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36 completely blocked the dopamine-induced facilitation. Overall, in addition to our previous report indicating a role for the cAMP-PKA pathway in dopamine-induced facilitation of synaptic transmission, we demonstrate here that the dopaminergic facilitation of synaptic responses in layer II entorhinal neurons also relies on a signaling cascade dependent on PI-linked D1 receptors, PLC, release of Ca2+ from internal stores, and PKC activation which is

Dopamine-induced apoptosis in human neuronal cells: inhibition by nucleic acides antisense to the dopamine transporter

International Nuclear Information System (INIS)

Porat, S.; Gabbay, M.; Tauber, M.; Ratovitski, T.; Blinder, E.; Simantov, R.

1996-01-01

Human neuroblastoma NMB cells take up [ 3 H]dopamine in a selective manner indicating that dopamine transporters are responsible for this uptake. These cells were therefore used as a model to study dopamine neurotoxicity, and to elucidate the role of dopamine transporters in controlling cell death. Treatment with 0.05-0.4 mM dopamine changed cells' morphology within 4 h, accompanied by retraction of processes, shrinkage, apoptosis-like atrophy, accumulation of apoptotic particles, DNA fragmentation and cell death. Cycloheximide inhibited dopamine's effect, suggesting that induction of apoptosis by dopamine was dependent upon protein synthesis. Dopamine cytotoxicity, monitored morphologically by flow cytometric analysis, and by lactate dehydrogenase released, was blocked by cocaine but not by the noradrenaline and serotonin uptake blockers desimipramine and imipramine, respectively. Attempting to inhibit dopamine transport and toxicity in a drug-free and highly selective way, three 18-mer dopamine transporter antisense phosphorothioate oligonucleotides (numbers 1, 2 and 3) and a new plasmid vector expressing the entire rat dopamine transporter complementary DNA in the antisense orientation were prepared and tested. Antisense phosphorothioate oligonucleotide 3 inhibited [ 3 H]dopamine uptake in a time- and dose-dependent manner. Likewise, transient transfection of NMB cells with the plasmid expressing dopamine transporter complementary DNA in the antisense orientation partially blocked [ 3 H]dopamine uptake. Antisense phosphorothioate oligonucleotide 3 also decreased, dose-dependently, the toxic effect of dopamine and 6-hydroxydopamine. Western blot analysis with newly prepared anti-human dopamine transporter antibodies showed that antisense phosphorothioate oligonucleotide 3 decreased the transporter protein level. These studies contribute to better understand the mechanism of dopamine-induced apoptosis and neurotoxicity. (Copyright (c) 1996 Elsevier Science B

D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans.

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Fazio, Leonardo; Blasi, Giuseppe; Taurisano, Paolo; Papazacharias, Apostolos; Romano, Raffaella; Gelao, Barbara; Ursini, Gianluca; Quarto, Tiziana; Lo Bianco, Luciana; Di Giorgio, Annabella; Mancini, Marina; Popolizio, Teresa; Rubini, Giuseppe; Bertolino, Alessandro

2011-02-14

Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 G>T) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [(123)I] FP-CIT SPECT. Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [(123)I]FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease. Copyright © 2010 Elsevier Inc. All rights reserved.

The Human Dopamine Transporter: Investigating the Role of the C Terminus in Surface Targeting

DEFF Research Database (Denmark)

Vægter, Christian Bjerggaard

2005-01-01

Dopaminergic neurotransmission is involved in the modulation of locomotor activity, emotional behavior, memory and cognition. Hence, imbalances in the dopaminergic system in humans have been hypothesized to contribute to the pathogenesis of a number of illnesses, including Parkinson's disease......, schizophrenia, ADHD (attention deficit hyperactivity disorder) and addiction. The dopamine transporter (DAT) is a presynaptic protein of dopaminergic nerve terminals that terminate dopaminergic signaling by rapidly sequestering released dopamine from the synaptic cleft. The DAT therefore plays an important role....... New data suggest a potential role of the PDZ interaction in the regulation of DAT internalization and recycling: we found that iv disrupting the PDZ domain-binding sequence affected the regulation of constitutive internalization, degradation and potentially also recycling of DAT in Neuro2A cells. We...

Study and development of retinal dopamine nervous system in experimental myopia

International Nuclear Information System (INIS)

Zhao Juan; Liu Xingdang

2007-01-01

Myopia is the most familiar ametropia. Animal experimental models include form deprivation myopia and defocus myopia. Experimental animals we often use are chicken and mammals. The retinal dopamine system and vision experience have close relations with the regulation of eyeball's growth after birth, while the change of dopamine transporter may reflect the change of dopamine in the synaptic cleft more directly. (authors)

Exclusion of close linkage between the synaptic vesicular monoamine transporter locus and schizophrenia spectrum disorders

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Persico, A.M.; Uhl, G.R. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Wang, Zhe Wu [Universitario Campus Bio-Medico, Rome (Italy)] [and others

1995-12-18

The principal brain synaptic vesicular monoamine transporter (VMAT2) is responsible for the reuptake of serotonin, dopamine, norepinephrine, epinephrine, and histamine from the cytoplasm into synaptic vesicles, thus contributing to determination of the size of releasable neurotransmitter vesicular pools. Potential involvement of VMAT2 gene variants in the etiology of schizophrenia and related disorders was tested using polymorphic VMAT2 gene markers in 156 subjects from 16 multiplex pedigrees with schizophrenia, schizophreniform, schizoaffective, and schizotypal disorders and mood incongruent psychotic depression. Assuming genetic homogeneity, complete ({theta} = 0.0) linkage to the schizophrenia spectrum was excluded under both dominant and recessive models. Allelic variants at the VMAT2 locus do not appear to provide major genetic contributions to the etiology of schizophrenia spectrum disorders in these pedigrees. 16 refs.

The binding sites for cocaine and dopamine in the dopamine transporter overlap

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Beuming, Thijs; Kniazeff, Julie; Bergmann, Marianne L

2008-01-01

Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog Leu......T. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed...... inhibition of dopamine transport by cocaine....

Phenyl Ring-Substituted Lobelane Analogs: Inhibition of [3H]Dopamine Uptake at the Vesicular Monoamine Transporter-2

OpenAIRE

Nickell, Justin R.; Zheng, Guangrong; Deaciuc, Agripina G.; Crooks, Peter A.; Dwoskin, Linda P.

2011-01-01

Lobeline attenuates the behavioral effects of methamphetamine via inhibition of the vesicular monoamine transporter (VMAT2). To increase selectivity for VMAT2, chemically defunctionalized lobeline analogs, including lobelane, were designed to eliminate nicotinic acetylcholine receptor affinity. The current study evaluated the ability of lobelane analogs to inhibit [3H]dihydrotetrabenazine (DTBZ) binding to VMAT2 and [3H]dopamine (DA) uptake into isolated synaptic vesicles and determined the m...

Membrane permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release

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Rickhag, Karl Mattias; Owens, WA; Winkler, Marie-Therese

2013-01-01

The dopamine transporter (DAT) is responsible for sequestration of extracellular dopamine (DA). The psychostimulant amphetamine (AMPH) is a DAT substrate, which is actively transported into the nerve terminal, eliciting vesicular depletion and reversal of DA transport via DAT. Here, we investigate......-terminal protein-protein interactions are critical for AMPH-evoked DA efflux and suggest that it may be possible to target protein-protein interactions to modulate transporter function and interfere with psychostimulant effects....

Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease.

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Dunn, Amy R; Stout, Kristen A; Ozawa, Minagi; Lohr, Kelly M; Hoffman, Carlie A; Bernstein, Alison I; Li, Yingjie; Wang, Minzheng; Sgobio, Carmelo; Sastry, Namratha; Cai, Huaibin; Caudle, W Michael; Miller, Gary W

2017-03-14

Members of the synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, although SV2C with its restricted basal ganglia distribution is poorly characterized. SV2C is emerging as a potentially relevant protein in Parkinson disease (PD), because it is a genetic modifier of sensitivity to l-DOPA and of nicotine neuroprotection in PD. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of PD. Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted α-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Furthermore, SV2C expression is dramatically altered in postmortem brain tissue from PD cases but not in Alzheimer disease, progressive supranuclear palsy, or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-synuclein. These data establish SV2C as a mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction.

Mechanisms of glycine release, which build up synaptic and extrasynaptic glycine levels: the role of synaptic and non-synaptic glycine transporters.

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Harsing, Laszlo G; Matyus, Peter

2013-04-01

Glycine is an amino acid neurotransmitter that is involved in both inhibitory and excitatory neurochemical transmission in the central nervous system. The role of glycine in excitatory neurotransmission is related to its coagonist action at glutamatergic N-methyl-D-aspartate receptors. The glycine levels in the synaptic cleft rise many times higher during synaptic activation assuring that glycine spills over into the extrasynaptic space. Another possible origin of extrasynaptic glycine is the efflux of glycine occurring from astrocytes associated with glutamatergic synapses. The release of glycine from neuronal or glial origins exhibits several differences compared to that of biogenic amines or other amino acid neurotransmitters. These differences appear in an external Ca(2+)- and temperature-dependent manner, conferring unique characteristics on glycine as a neurotransmitter. Glycine transporter type-1 at synapses may exhibit neural and glial forms and plays a role in controlling synaptic glycine levels and the spill over rate of glycine from the synaptic cleft into the extrasynaptic biophase. Non-synaptic glycine transporter type-1 regulates extrasynaptic glycine concentrations, either increasing or decreasing them depending on the reverse or normal mode operation of the carrier molecule. While we can, at best, only estimate synaptic glycine levels at rest and during synaptic activation, glycine concentrations are readily measurable via brain microdialysis technique applied in the extrasynaptic space. The non-synaptic N-methyl-D-aspartate receptor may obtain glycine for activation following its spill over from highly active synapses or from its release mediated by the reverse operation of non-synaptic glycine transporter-1. The sensitivity of non-synaptic N-methyl-D-aspartate receptors to glutamate and glycine is many times higher than that of synaptic N-methyl-D-aspartate receptors making the former type of receptor the primary target for drug action. Synaptic

The dopamine transporter: role in neurotoxicity and human disease

International Nuclear Information System (INIS)

Bannon, Michael J.

2005-01-01

The dopamine transporter (DAT) is a plasma membrane transport protein expressed exclusively within a small subset of CNS neurons. It plays a crucial role in controlling dopamine-mediated neurotransmission and a number of associated behaviors. This review focuses on recent data elucidating the role of the dopamine transporter in neurotoxicity and a number of CNS disorders, including Parkinson disease, drug abuse, and attention deficit hyperactivity disorder (ADHD)

The dopamine transporter: role in neurotoxicity and human disease

Energy Technology Data Exchange (ETDEWEB)

Bannon, Michael J [Department of Psychiatry and Behavioral Neuroscience, Pharmacology, and Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201 (United States)

2005-05-01

The dopamine transporter (DAT) is a plasma membrane transport protein expressed exclusively within a small subset of CNS neurons. It plays a crucial role in controlling dopamine-mediated neurotransmission and a number of associated behaviors. This review focuses on recent data elucidating the role of the dopamine transporter in neurotoxicity and a number of CNS disorders, including Parkinson disease, drug abuse, and attention deficit hyperactivity disorder (ADHD)

Infantile parkinsonism-dystonia: a dopamine “transportopathy”

OpenAIRE

Blackstone, Craig

2009-01-01

The dopamine transporter (DAT) retrieves the neurotransmitter dopamine from the synaptic cleft at dopaminergic synapses. Variations in solute carrier family 6A, member 3 (SLC6A3/DAT1), the human gene encoding DAT, have been implicated in attention deficit hyperactivity and bipolar disorders, and DAT is a prominent site of action for drugs such as amphetamines and cocaine. In this issue of the JCI, Kurian et al. report that an autosomal recessive infantile parkinsonism-dystonia is caused by lo...

Presence and function of dopamine transporter (DAT in stallion sperm: dopamine modulates sperm motility and acrosomal integrity.

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Javier A Urra

Full Text Available Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT, serotonin (SERT and norepinephrine (NET transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylaminostyryl]-N-methylpyridinium iodide (ASP(+, as substrate. In addition, we also showed that dopamine (1 mM treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909 and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility.

Effect of nerve activity on transport of nerve growth factor and dopamine β-hydroxylase antibodies in sympathetic neurones

International Nuclear Information System (INIS)

Lees, G.; Chubb, I.; Freeman, C.; Geffen, L.; Rush, R.

1981-01-01

The effect of nerve activity on the uptake and retrograde transport of nerve growth factor (NGF) and dopamine β-hydroxylase (DBH) antibodies was studied by injecting 125 I-labelled NGF and anti-DBH into the anterior eye chamber of guinea-pigs. Decentralization of the ipsilateral superior cervical ganglion (SCG) had no significant effect on the retrograde transport of either NGF or anti-DBH. Phenoxybenzamine produced a 50% increase in anti-DBH but not NGF accumulation and this effect was prevented by prior decentralization. This demonstrates that NGF is taken up independently of the retrieval of synaptic vesicle components. (Auth.)

Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors.

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Cartier, Etienne; Hamilton, Peter J; Belovich, Andrea N; Shekar, Aparna; Campbell, Nicholas G; Saunders, Christine; Andreassen, Thorvald F; Gether, Ulrik; Veenstra-Vanderweele, Jeremy; Sutcliffe, James S; Ulery-Reynolds, Paula G; Erreger, Kevin; Matthies, Heinrich J G; Galli, Aurelio

2015-02-01

Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD). Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis. We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD.

SEP-225289 serotonin and dopamine transporter occupancy: a PET study.

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DeLorenzo, Christine; Lichenstein, Sarah; Schaefer, Karen; Dunn, Judith; Marshall, Randall; Organisak, Lisa; Kharidia, Jahnavi; Robertson, Brigitte; Mann, J John; Parsey, Ramin V

2011-07-01

SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy. Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events. Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC(50) (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported. At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about

Adenosine A2A receptors modulate the dopamine D2 receptor-mediated inhibition of synaptic transmission in the mouse prefrontal cortex.

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Real, Joana I; Simões, Ana Patrícia; Cunha, Rodrigo A; Ferreira, Samira G; Rial, Daniel

2018-05-01

Prefrontal cortex (PFC) circuits are modulated by dopamine acting on D 1 - and D 2 -like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A 2A receptors (A 2 A R) also control PFC-related responses and A 2 A R antagonists are potential anti-psychotic drugs. As tight antagonistic A 2 A R-D 2 R and synergistic A 2 A R-D 1 R interactions occur in other brain regions, we now investigated the crosstalk between A 2 A R and D 1 /D 2 R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired-pulse responses. Dopamine inhibition was prevented by the D 2 R-like antagonist sulpiride but not by the D 1 R antagonist SCH23390 and was mimicked by the D 2 R agonist sumanirole, but not by the agonists of either D 4 R (A-412997) or D 3 R (PD128907). Dopamine inhibition was prevented by the A 2 A R antagonist, SCH58261, and attenuated in A 2 A R knockout mice. Accordingly, triple-labelling immunocytochemistry experiments revealed the co-localization of A 2 A R and D 2 R immunoreactivity in glutamatergic (vGluT1-positive) nerve terminals of the PFC. This reported positive A 2 A R-D 2 R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti-psychotic potential of A 2 A R antagonists. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Limited distal organelles and synaptic function in extensive monoaminergic innervation.

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Tao, Juan; Bulgari, Dinara; Deitcher, David L; Levitan, Edwin S

2017-08-01

Organelles such as neuropeptide-containing dense-core vesicles (DCVs) and mitochondria travel down axons to supply synaptic boutons. DCV distribution among en passant boutons in small axonal arbors is mediated by circulation with bidirectional capture. However, it is not known how organelles are distributed in extensive arbors associated with mammalian dopamine neuron vulnerability, and with volume transmission and neuromodulation by monoamines and neuropeptides. Therefore, we studied presynaptic organelle distribution in Drosophila octopamine neurons that innervate ∼20 muscles with ∼1500 boutons. Unlike in smaller arbors, distal boutons in these arbors contain fewer DCVs and mitochondria, although active zones are present. Absence of vesicle circulation is evident by proximal nascent DCV delivery, limited impact of retrograde transport and older distal DCVs. Traffic studies show that DCV axonal transport and synaptic capture are not scaled for extensive innervation, thus limiting distal delivery. Activity-induced synaptic endocytosis and synaptic neuropeptide release are also reduced distally. We propose that limits in organelle transport and synaptic capture compromise distal synapse maintenance and function in extensive axonal arbors, thereby affecting development, plasticity and vulnerability to neurodegenerative disease. © 2017. Published by The Company of Biologists Ltd.

Pre-synaptic glycine GlyT1 transporter--NMDA receptor interaction: relevance to NMDA autoreceptor activation in the presence of Mg2+ ions.

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Musante, Veronica; Summa, Maria; Cunha, Rodrigo A; Raiteri, Maurizio; Pittaluga, Anna

2011-05-01

Rat hippocampal glutamatergic terminals possess NMDA autoreceptors whose activation by low micromolar NMDA elicits glutamate exocytosis in the presence of physiological Mg(2+) (1.2 mM), the release of glutamate being significantly reduced when compared to that in Mg(2+)-free condition. Both glutamate and glycine were required to evoke glutamate exocytosis in 1.2 mM Mg(2+), while dizocilpine, cis-4-[phosphomethyl]-piperidine-2-carboxylic acid and 7-Cl-kynurenic acid prevented it, indicating that occupation of both agonist sites is needed for receptor activation. D-serine mimicked glycine but also inhibited the NMDA/glycine-induced release of [(3H]D-aspartate, thus behaving as a partial agonist. The NMDA/glycine-induced release in 1.2 mM Mg(2+) strictly depended on glycine uptake through the glycine transporter type 1 (GlyT1), because the GlyT1 blocker N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine hydrochloride, but not the GlyT2 blocker Org 25534, prevented it. Accordingly, [(3)H]glycine was taken up during superfusion, while lowering the external concentration of Na(+), the monovalent cation co-transported with glycine by GlyT1, abrogated the NMDA-induced effect. Western blot analysis of subsynaptic fractions confirms that GlyT1 and NMDA autoreceptors co-localize at the pre-synaptic level, where GluN3A subunits immunoreactivity was also recovered. It is proposed that GlyT1s coexist with NMDA autoreceptors on rat hippocampal glutamatergic terminals and that glycine taken up by GlyT1 may permit physiological activation of NMDA pre-synaptic autoreceptors. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Practical Approach for the Clinical Use of Dopamine Transporter Imaging

International Nuclear Information System (INIS)

Kim, Jae Seung

2008-01-01

Dopamine transporter imaging is useful in the diagnosis of Parkinson's disease and the most successful technique in the clinical use of neuroreceptor imaging. Recently, several radiopharmaceuticals including I-123 FP-CIT, Tc-99m TRODAT, and F-18 FP-CIT for dopamine transporter imaging have been approved for the routine clinical use in several European countries, Taiwan and Korea, respectively. This review summarized the practical issue for the routine clinical examination of dopamine transporter imaging

Forebrain deletion of αGDI in adult mice worsens the pre-synaptic deficit at cortico-lateral amygdala synaptic connections.

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Veronica Bianchi

Full Text Available The GDI1 gene encodes αGDI, which retrieves inactive GDP-bound RAB from membranes to form a cytosolic pool awaiting vesicular release. Mutations in GDI1 are responsible for X-linked Intellectual Disability. Characterization of the Gdi1-null mice has revealed alterations in the total number and distribution of hippocampal and cortical synaptic vesicles, hippocampal short-term synaptic plasticity and specific short-term memory deficits in adult mice, which are possibly caused by alterations of different synaptic vesicle recycling pathways controlled by several RAB GTPases. However, interpretation of these studies is complicated by the complete ablation of Gdi1 in all cells in the brain throughout development. In this study, we generated conditionally gene-targeted mice in which the knockout of Gdi1 is restricted to the forebrain, hippocampus, cortex and amygdala and occurs only during postnatal development. Adult mutant mice reproduce the short-term memory deficit previously reported in Gdi1-null mice. Surprisingly, the delayed ablation of Gdi1 worsens the pre-synaptic phenotype at cortico-amygdala synaptic connections compared to Gdi1-null mice. These results suggest a pivotal role of αGDI via specific RAB GTPases acting specifically in forebrain regions at the pre-synaptic sites involved in memory formation.

Reduced dopamine transporter binding predates impulse control disorders in Parkinson's disease.

Science.gov (United States)

Vriend, Chris; Nordbeck, Anna H; Booij, Jan; van der Werf, Ysbrand D; Pattij, Tommy; Voorn, Pieter; Raijmakers, Pieter; Foncke, Elisabeth M J; van de Giessen, Elsmarieke; Berendse, Henk W; van den Heuvel, Odile A

2014-06-01

Impulse control disorders (ICD) are relatively common in Parkinson's disease (PD) and generally are regarded as adverse effects of dopamine replacement therapy, although certain demographic and clinical risk factors are also involved. Previous single-photon emission computed tomography (SPECT) studies showed reduced ventral striatal dopamine transporter binding in Parkinson patients with ICD compared with patients without. Nevertheless, these studies were performed in patients with preexisting impulse control impairments, which impedes clear-cut interpretation of these findings. We retrospectively procured follow-up data from 31 medication-naïve PD patients who underwent dopamine transporter SPECT imaging at baseline and were subsequently treated with dopamine replacement therapy. We used questionnaires and a telephone interview to assess medication status and ICD symptom development during the follow-up period (31.5 ± 12.0 months). Eleven patients developed ICD symptoms during the follow-up period, eight of which were taking dopamine agonists. The PD patients with ICD symptoms at follow-up had higher baseline depressive scores and lower baseline dopamine transporter availability in the right ventral striatum, anterior-dorsal striatum, and posterior putamen compared with PD patients without ICD symptoms. No baseline between-group differences in age and disease stage or duration were found. The ICD symptom severity correlated negatively with baseline dopamine transporter availability in the right ventral and anterior-dorsal striatum. The results of this preliminary study show that reduced striatal dopamine transporter availability predates the development of ICD symptoms after dopamine replacement therapy and may constitute a neurobiological risk factor related to a lower premorbid dopamine transporter availability or a more pronounced dopamine denervation in PD patients susceptible to ICD. © 2014 International Parkinson and Movement Disorder Society.

Synaptic contacts impaired by styrene-7,8-oxide toxicity

International Nuclear Information System (INIS)

Corsi, P.; D'Aprile, A.; Nico, B.; Costa, G.L.; Assennato, G.

2007-01-01

Styrene-7,8-oxide (SO), a chemical compound widely used in industrial applications, is a potential hazard for humans, particularly in occupational settings. Neurobehavioral changes are consistently observed in occupationally exposed individuals and alterations of neurotransmitters associated with neuronal loss have been reported in animal models. Although the toxic effects of styrene have been extensively documented, the molecular mechanisms responsible for SO-induced neurotoxicity are still unclear. A possible dopamine-mediated effect of styrene neurotoxicity has been previously demonstrated, since styrene oxide alters dopamine neurotransmission in the brain. Thus, the present study hypothesizes that styrene neurotoxicity may involve synaptic contacts. Primary striatal neurons were exposed to styrene oxide at different concentrations (0.1-1 mM) for different time periods (8, 16, and 24 h) to evaluate the dose able to induce synaptic impairments. The expression of proteins crucial for synaptic transmission such as Synapsin, Synaptophysin, and RAC-1 were considered. The levels of Synaptophysin and RAC-1 decreased in a dose-dependent manner. Accordingly, morphological alterations, observed at the ultrastructural level, primarily involved the pre-synaptic compartment. In SO-exposed cultures, the biochemical cascade of caspases was activated affecting the cytoskeleton components as their target. Thus the impairments in synaptic contacts observed in SO-exposed cultures might reflect a primarily morphological alteration of neuronal cytoskeleton. In addition, our data support the hypothesis developed by previous authors of reactive oxygen species (ROS) initiating events of SO cytotoxicity

Synaptically evoked glutamate transporter currents in Spinal Dorsal Horn Astrocytes

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Dougherty Patrick M

2009-07-01

Full Text Available Abstract Background Removing and sequestering synaptically released glutamate from the extracellular space is carried out by specific plasma membrane transporters that are primarily located in astrocytes. Glial glutamate transporter function can be monitored by recording the currents that are produced by co-transportation of Na+ ions with the uptake of glutamate. The goal of this study was to characterize glutamate transporter function in astrocytes of the spinal cord dorsal horn in real time by recording synaptically evoked glutamate transporter currents. Results Whole-cell patch clamp recordings were obtained from astrocytes in the spinal substantia gelatinosa (SG area in spinal slices of young adult rats. Glutamate transporter currents were evoked in these cells by electrical stimulation at the spinal dorsal root entry zone in the presence of bicuculline, strychnine, DNQX and D-AP5. Transporter currents were abolished when synaptic transmission was blocked by TTX or Cd2+. Pharmacological studies identified two subtypes of glutamate transporters in spinal astrocytes, GLAST and GLT-1. Glutamate transporter currents were graded with stimulus intensity, reaching peak responses at 4 to 5 times activation threshold, but were reduced following low-frequency (0.1 – 1 Hz repetitive stimulation. Conclusion These results suggest that glutamate transporters of spinal astrocytes could be activated by synaptic activation, and recording glutamate transporter currents may provide a means of examining the real time physiological responses of glial cells in spinal sensory processing, sensitization, hyperalgesia and chronic pain.

Computational systems analysis of dopamine metabolism.

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Zhen Qi

2008-06-01

Full Text Available A prominent feature of Parkinson's disease (PD is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metabolism is preliminary, future extensions and refinements may eventually serve as an in silico platform for prescreening potential therapeutics, identifying immediate side effects, screening for biomarkers, and assessing the impact of risk factors of the disease.

Impulse control disorders in Parkinson's disease: decreased striatal dopamine transporter levels.

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Voon, Valerie; Rizos, Alexandra; Chakravartty, Riddhika; Mulholland, Nicola; Robinson, Stephanie; Howell, Nicholas A; Harrison, Neil; Vivian, Gill; Ray Chaudhuri, K

2014-02-01

Impulse control disorders are commonly associated with dopaminergic therapy in Parkinson's disease (PD). PD patients with impulse control disorders demonstrate enhanced dopamine release to conditioned cues and a gambling task on [(11)C]raclopride positron emission tomography (PET) imaging and enhanced ventral striatal activity to reward on functional MRI. We compared PD patients with impulse control disorders and age-matched and gender-matched controls without impulse control disorders using [(123)I]FP-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT), to assess striatal dopamine transporter (DAT) density. The [(123)I]FP-CIT binding data in the striatum were compared between 15 PD patients with and 15 without impulse control disorders using independent t tests. Those with impulse control disorders showed significantly lower DAT binding in the right striatum with a trend in the left (right: F(1,24)=5.93, p=0.02; left: F(1,24)=3.75, p=0.07) compared to controls. Our findings suggest that greater dopaminergic striatal activity in PD patients with impulse control disorders may be partly related to decreased uptake and clearance of dopamine from the synaptic cleft. Whether these findings are related to state or trait effects is not known. These findings dovetail with reports of lower DAT levels secondary to the effects of methamphetamine and alcohol. Although any regulation of DAT by antiparkinsonian medication appears to be modest, PD patients with impulse control disorders may be differentially sensitive to regulatory mechanisms of DAT expression by dopaminergic medications.

Decreased lymphocyte dopamine transporter in romantic lovers.

Science.gov (United States)

Marazziti, Donatella; Baroni, Stefano; Giannaccini, Gino; Piccinni, Armando; Mucci, Federico; Catena-Dell'Osso, Mario; Rutigliano, Grazia; Massimetti, Gabriele; Dell'Osso, Liliana

2017-06-01

The role of dopamine (DA) in romantic love is suggested by different evidence and is supported by the findings of some brain imaging studies. The DA transporter (DAT) is a key structure in regulating the concentration of the neurotransmitter in the synaptic cleft. Given the presence of DAT in blood cells, the present study aimed to explore it in resting lymphocytes of 30 healthy subjects of both sexes in the early stage of romantic love (no longer than 6 months), as compared with 30 subjects involved in a long-lasting relationship. All subjects had no physical or psychiatric illness. The DAT was measured by means of the [3H]-WIN 35,428 binding and the [3H]-DA reuptake to resting lymphocytes membranes. Romantic love was assessed by a specific questionnaire developed by us. The results showed that the subjects in the early phase of romantic love had a global alteration of the lymphocyte DAT involving both a decreased number of proteins (Bmax) and a reduced functionality (Vmax). Taken together, these findings would indicate the presence of increased levels of DA in romantic love that, if paralleled by similar concentrations in the brain, would explain some peculiar features of this human feeling.

Synaptic Democracy and Vesicular Transport in Axons

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Bressloff, Paul C.; Levien, Ethan

2015-04-01

Synaptic democracy concerns the general problem of how regions of an axon or dendrite far from the cell body (soma) of a neuron can play an effective role in neuronal function. For example, stimulated synapses far from the soma are unlikely to influence the firing of a neuron unless some sort of active dendritic processing occurs. Analogously, the motor-driven transport of newly synthesized proteins from the soma to presynaptic targets along the axon tends to favor the delivery of resources to proximal synapses. Both of these phenomena reflect fundamental limitations of transport processes based on a localized source. In this Letter, we show that a more democratic distribution of proteins along an axon can be achieved by making the transport process less efficient. This involves two components: bidirectional or "stop-and-go" motor transport (which can be modeled in terms of advection-diffusion), and reversible interactions between motor-cargo complexes and synaptic targets. Both of these features have recently been observed experimentally. Our model suggests that, just as in human societies, there needs to be a balance between "efficiency" and "equality".

Functional characterization of dopamine transporter in vivo using Drosophila melanogaster behavioral analysis.

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Taro eUeno

2014-09-01

Full Text Available Dopamine mediates diverse functions such as motivation, reward, attention, learning/memory and sleep/arousal. Recent studies using model organisms including the fruit fly, have elucidated various physiological functions of dopamine, and identified specific neural circuits for these functions. Flies with mutations in the Drosophila dopamine transporter (dDAT gene show enhanced dopamine signaling, and short sleep and memory impairment phenotypes. However, understanding the mechanism by which dopamine signaling causes these phenotypes requires an understanding of the dynamics of dopamine release. Here we report the effects of dDAT expression on behavioral traits. We show that dDAT expression in a subset of dopaminergic neurons is sufficient for normal sleep. dDAT expression in other cell types such as Kenyon cells and glial cells can also rescue the short sleep phenotype of dDAT mutants. dDAT mutants also show a down-regulation of the D1-like dopamine receptor dDA1, and this phenotype is rescued when dDAT is expressed in the same cell types in which it rescues sleep. On the other hand, dDAT overexpression in mushroom bodies, which are the target of memory forming dopamine neurons, abolishes olfactory aversive memory. Our data demonstrate that expression of extrasynaptic dopamine transporters can rescue some aspects of dopamine signaling in dopamine transporter mutants. These results provide novel insights into regulatory systems that modulate dopamine signaling.

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease.

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German, Christopher L; Baladi, Michelle G; McFadden, Lisa M; Hanson, Glen R; Fleckenstein, Annette E

2015-10-01

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

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Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

2016-06-15

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

Intranasal dopamine reduces in vivo [123I]FP-CIT binding to striatal dopamine transporter: correlation with behavioral changes and evidence for Pavlovian conditioned dopamine response

OpenAIRE

Maria A de Souza Silva; C. eMattern; C. eMattern; C.I. eDecheva; Joseph P. Huston; A. eSadile; M. eBeu; H.W. eMüller; Susanne eNikolaus

2016-01-01

Purpose: Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We ...

A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

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Razavi, Asghar M.; Khelashvili, George; Weinstein, Harel

2017-01-01

The dopamine transporter (DAT) belongs to the neurotransmitter:sodium symporter (NSS) family of membrane proteins that are responsible for reuptake of neurotransmitters from the synaptic cleft to terminate a neuronal signal and enable subsequent neurotransmitter release from the presynaptic neuron. The release of one sodium ion from the crystallographically determined sodium binding site Na2 had been identified as an initial step in the transport cycle which prepares the transporter for substrate translocation by stabilizing an inward-open conformation. We have constructed Markov State Models (MSMs) from extensive molecular dynamics simulations of human DAT (hDAT) to explore the mechanism of this sodium release. Our results quantify the release process triggered by hydration of the Na2 site that occurs concomitantly with a conformational transition from an outward-facing to an inward-facing state of the transporter. The kinetics of the release process are computed from the MSM, and transition path theory is used to identify the most probable sodium release pathways. An intermediate state is discovered on the sodium release pathway, and the results reveal the importance of various modes of interaction of the N-terminus of hDAT in controlling the pathways of release.

Blockade of dopamine D1-family receptors attenuates the mania-like hyperactive, risk-preferring, and high motivation behavioral profile of mice with low dopamine transporter levels.

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Milienne-Petiot, Morgane; Groenink, Lucianne; Minassian, Arpi; Young, Jared W

2017-10-01

Patients with bipolar disorder mania exhibit poor cognition, impulsivity, risk-taking, and goal-directed activity that negatively impact their quality of life. To date, existing treatments for bipolar disorder do not adequately remediate cognitive dysfunction. Reducing dopamine transporter expression recreates many bipolar disorder mania-relevant behaviors (i.e. hyperactivity and risk-taking). The current study investigated whether dopamine D 1 -family receptor blockade would attenuate the risk-taking, hypermotivation, and hyperactivity of dopamine transporter knockdown mice. Dopamine transporter knockdown and wild-type littermate mice were tested in mouse versions of the Iowa Gambling Task (risk-taking), Progressive Ratio Breakpoint Test (effortful motivation), and Behavioral Pattern Monitor (activity). Prior to testing, the mice were treated with the dopamine D 1 -family receptor antagonist SCH 23390 hydrochloride (0.03, 0.1, or 0.3 mg/kg), or vehicle. Dopamine transporter knockdown mice exhibited hyperactivity and hyperexploration, hypermotivation, and risk-taking preference compared with wild-type littermates. SCH 23390 hydrochloride treatment decreased premature responding in dopamine transporter knockdown mice and attenuated their hypermotivation. SCH 23390 hydrochloride flattened the safe/risk preference, while reducing activity and exploratory levels of both genotypes similarly. Dopamine transporter knockdown mice exhibited mania-relevant behavior compared to wild-type mice. Systemic dopamine D 1 -family receptor antagonism attenuated these behaviors in dopamine transporter knockdown, but not all effects were specific to only the knockdown mice. The normalization of behavior via blockade of dopamine D 1 -family receptors supports the hypothesis that D 1 and/or D 5 receptors could contribute to the mania-relevant behaviors of dopamine transporter knockdown mice.

Normalization of markers for dopamine innervation in striatum of MPTP-lesioned miniature pigs with intrastriatal grafts

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Cumming, P; Danielsen, E H; Vafaee, M

2001-01-01

, both pre-synaptic markers of dopamine fibres were normal in striatum. Dopamine depletion or grafting were without effect on the cerebral perfusion rate, measured with [15O]-water, did not alter the rate of oxygen metabolism (CMRO2) in brain, and did not alter the binding potential of tracers...... for dopamine D1 or D2 receptors in pig striatum. However, the grafting was associated with a local increase in the binding of [11C]PK 11195, a tracer for reactive gliosis, suggesting that an immunological reaction occurs at the site of graft, which might potentially have reduced the graft patency. However...

Serotonin transporters in dopamine transporter imaging: a head-to-head comparison of dopamine transporter SPECT radioligands 123I-FP-CIT and 123I-PE2I

DEFF Research Database (Denmark)

Ziebell, Morten; Holm-Hansen, Signe; Thomsen, Gerda

2010-01-01

Current SPECT radioligands available for in vivo imaging of the dopamine transporter (DAT) also show affinity for monoamine transporters other than DAT, especially the serotonin transporter (SERT). The effect of this lack of selectivity for in vivo imaging is unknown. In this study, we compared...

An Investigation of the Stoichiometry of Na+ Cotransport with Dopamine in Rat and Human Dopamine Transporters Expressed in Human Embryonic Kidney Cells

National Research Council Canada - National Science Library

Schumacher, Paul

2001-01-01

The neuronal membrane transporter for dopamine (DAT) is a member of the Na+ and Cl dependent family of transporters and concentrates dopamine intracellularly up to 106 fold over extracellular levels...

GABA Metabolism and Transport: Effects on Synaptic Efficacy

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Fabian C. Roth

2012-01-01

Full Text Available GABAergic inhibition is an important regulator of excitability in neuronal networks. In addition, inhibitory synaptic signals contribute crucially to the organization of spatiotemporal patterns of network activity, especially during coherent oscillations. In order to maintain stable network states, the release of GABA by interneurons must be plastic in timing and amount. This homeostatic regulation is achieved by several pre- and postsynaptic mechanisms and is triggered by various activity-dependent local signals such as excitatory input or ambient levels of neurotransmitters. Here, we review findings on the availability of GABA for release at presynaptic terminals of interneurons. Presynaptic GABA content seems to be an important determinant of inhibitory efficacy and can be differentially regulated by changing synthesis, transport, and degradation of GABA or related molecules. We will discuss the functional impact of such regulations on neuronal network patterns and, finally, point towards pharmacological approaches targeting these processes.

Long-term stimulant treatment affects brain dopamine transporter level in patients with attention deficit hyperactive disorder.

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Wang, Gene-Jack; Volkow, Nora D; Wigal, Timothy; Kollins, Scott H; Newcorn, Jeffrey H; Telang, Frank; Logan, Jean; Jayne, Millard; Wong, Christopher T; Han, Hao; Fowler, Joanna S; Zhu, Wei; Swanson, James M

2013-01-01

Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated. We used positron emission tomography and [(11)C]cocaine (dopamine transporter radioligand) to measure dopamine transporter availability in the brains of 18 never-medicated adult ADHD subjects prior to and after 12 months of treatment with methylphenidate and in 11 controls who were also scanned twice at 12 months interval but without stimulant medication. Dopamine transporter availability was quantified as non-displaceable binding potential using a kinetic model for reversible ligands. Twelve months of methylphenidate treatment increased striatal dopamine transporter availability in ADHD (caudate, putamen and ventral striatum: +24%, p<0.01); whereas there were no changes in control subjects retested at 12-month interval. Comparisons between controls and ADHD participants revealed no significant difference in dopamine transporter availability prior to treatment but showed higher dopamine transporter availability in ADHD participants than control after long-term treatment (caudate: p<0.007; putamen: p<0.005). Upregulation of dopamine transporter availability during long-term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication. Our findings also suggest that the discrepancies in the literature regarding dopamine transporter availability in ADHD participants (some studies reporting increases, other no changes and other decreases) may reflect, in part, differences in treatment histories.

NOVEL FLUORESCENT PROBES FOR THE DOPAMINE TRANSPORTER

DEFF Research Database (Denmark)

Cha, J; Vægter, Christian Bjerggaard; Adkins, Erica

-reactive rhodamine red derivatives. The resulting N-substituted (JHC 1-64) and 2-substituted (JHC 1-53) ligands showed high affinity binding to DAT expressed in HEK 293 cells (Ki= 6.4 and 29 nM, respectively). Their ability to selectively label the DAT was demonstrated by confocal laser scanning microscopy of HEK......To enable visualization of the dopamine transporter (DAT) through fluorescence technologies we have synthesized a novel series of fluorescently tagged analogs of cocaine. Previous structure-activity relationship (SAR) studies have demonstrated that the dopamine transporter (DAT) can tolerate...... in untransfected control cells. The possibility of using these ligands for direct labeling of the DAT in living cells represents a new and important approach for understanding cellular targeting and trafficking of the DAT. Moreover, these fluorescent ligands might also provide the molecular tools...

SAD-B kinase regulates pre-synaptic vesicular dynamics at hippocampal Schaffer collateral synapses and affects contextual fear memory.

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Watabe, Ayako M; Nagase, Masashi; Hagiwara, Akari; Hida, Yamato; Tsuji, Megumi; Ochiai, Toshitaka; Kato, Fusao; Ohtsuka, Toshihisa

2016-01-01

Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, such as axon specifications and maturation in central and peripheral nervous systems. At mature pre-synaptic terminals, SAD-B is associated with synaptic vesicles and the active zone cytomatrix; however, how SAD-B regulates neurotransmission and synaptic plasticity in vivo remains unclear. Thus, we used SAD-B knockout (KO) mice to study the function of this pre-synaptic kinase in the brain. We found that the paired-pulse ratio was significantly enhanced at Shaffer collateral synapses in the hippocampal CA1 region in SAD-B KO mice compared with wild-type littermates. We also found that the frequency of the miniature excitatory post-synaptic current was decreased in SAD-B KO mice. Moreover, synaptic depression following prolonged low-frequency synaptic stimulation was significantly enhanced in SAD-B KO mice. These results suggest that SAD-B kinase regulates vesicular release probability at pre-synaptic terminals and is involved in vesicular trafficking and/or regulation of the readily releasable pool size. Finally, we found that hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice. These observations suggest that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. Synapses of amphids defective (SAD)-A/B kinases control various steps in neuronal development and differentiation, but their roles in mature brains were only partially known. Here, we demonstrated, at mature pre-synaptic terminals, that SAD-B regulates vesicular release probability and synaptic plasticity. Moreover, hippocampus-dependent contextual fear learning was significantly impaired in SAD-B KO mice, suggesting that SAD-B kinase plays pivotal roles in controlling vesicular release properties and regulating hippocampal function in the mature brain. © 2015 International

The binding sites for benztropines and dopamine in the dopamine transporter overlap

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Jensen, Heidi Bisgaard; Larsen, M Andreas B; Mazier, Sonia

2011-01-01

Analogs of benztropines (BZTs) are potent inhibitors of the dopamine transporter (DAT) but are less effective than cocaine as behavioral stimulants. As a result, there have been efforts to evaluate these compounds as leads for potential medication for cocaine addiction. Here we use computational...

Dopamine D1/D5, but not D2/D3, receptor dependency of synaptic plasticity at hippocampal mossy fiber synapses that is enabled by patterned afferent stimulation, or spatial learning

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Hardy Hagena

2016-09-01

Full Text Available Although the mossy fiber (MF synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24h synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH-CA1 and perforant path (PP-dentate gyrus (DG synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP and long-term depression (LTD. These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about spatial experience effectively occurs and the neuromodulator dopamine plays a key role in motivation-based learning. Prior research on the regulation by dopamine receptors of long-term synaptic plasticity in CA1 and dentate gyrus synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of these receptors in persistent (>24h forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data

Association of attention-deficit disorder and the dopamine transporter gene

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Cook, E.H. Jr.; Stein, M.A.; Krasowski, M.D.; Cox, N.J.; Olkon, D.M.; Kieffer, J.E.; Leventhal, B.L. [Univ. of Chicago, IL (United States)

1995-04-01

Attention-deficit hyperactivity disorder (ADHD) has been shown to be familial and heritable, in previous studies. As with most psychiatric disorders, examination of pedigrees has not revealed a consistent Mendelian mode of transmission. The response of ADHD patients to medications that inhibit the dopamine transporter, including methylphenidate, amphetamine, pemoline, and bupropion, led us to consider the dopamine transporter as a primary candidate gene for ADHD. To avoid effects of population stratification and to avoid the problem of classification of relatives with other psychiatric disorders as affected or unaffected, we used the haplotype-based haplotype relative risk (HHRR) method to test for association between a VNTR polymorphism at the dopamine transporter locus (DAT1) and DSM-III-R-diagnosed ADHD (N = 49) and undifferentiated attention-deficit disorder (UADD) (N = 8) in trios composed of father, mother, and affected offspring. HHRR analysis revealed significant association between ADHS/UADD and the 480-bp DAT1 allele (X{sup 2} 7.51, 1 df, P = .006). When cases of UADD were dropped from the analysis, similar results were found (X{sup 2} 7.29, 1 df, P = .007). If these findings are replicated, molecular analysis of the dopamine transporter gene may identify mutations that increase susceptibility to ADHD/UADD. Biochemical analysis of such mutations may lead to development of more effective therapeutic interventions. 36 refs., 4 tabs.

Brain serotonin and dopamine transporter bindings in adults with high-functioning autism.

Science.gov (United States)

Nakamura, Kazuhiko; Sekine, Yoshimoto; Ouchi, Yasuomi; Tsujii, Masatsugu; Yoshikawa, Etsuji; Futatsubashi, Masami; Tsuchiya, Kenji J; Sugihara, Genichi; Iwata, Yasuhide; Suzuki, Katsuaki; Matsuzaki, Hideo; Suda, Shiro; Sugiyama, Toshiro; Takei, Nori; Mori, Norio

2010-01-01

Autism is a neurodevelopmental disorder that is characterized by repetitive and/or obsessive interests and behavior and by deficits in sociability and communication. Although its neurobiological underpinnings are postulated to lie in abnormalities of the serotoninergic and dopaminergic systems, the details remain unknown. To determine the occurrence of changes in the binding of serotonin and dopamine transporters, which are highly selective markers for their respective neuronal systems. Using positron emission tomography, we measured the binding of brain serotonin and dopamine transporters in each individual with the radioligands carbon 11 ((11)C)-labeled trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652) and 2beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane ([(11)C]WIN-35,428), respectively. Statistical parametric mapping was used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. Participants recruited from the community. Twenty men (age range, 18-26 years; mean [SD] IQ, 99.3 [18.1]) with autism and 20 age- and IQ-matched control subjects. Serotonin transporter binding was significantly lower throughout the brain in autistic individuals compared with controls (P dopamine transporter binding was significantly higher in the orbitofrontal cortex of the autistic group (P dopamine transporter binding was significantly inversely correlated with serotonin transporter binding (r = -0.61; P = .004). The brains of autistic individuals have abnormalities in both serotonin transporter and dopamine transporter binding. The present findings indicate that the gross abnormalities in these neurotransmitter systems may underpin the neurophysiologic mechanism of autism. Our sample was not characteristic or representative of a typical sample of adults with autism in the community.

No association between striatal dopamine transporter binding and body mass index

DEFF Research Database (Denmark)

van de Giessen, Elsmarieke; Hesse, Swen; Caan, Matthan W A

2013-01-01

Dopamine is one among several neurotransmitters that regulate food intake and overeating. Thus, it has been linked to the pathophysiology of obesity and high body mass index (BMI). Striatal dopamine D(2) receptor availability is lower in obesity and there are indications that striatal dopamine...... transporter (DAT) availability is also decreased. In this study, we tested whether BMI and striatal DAT availability are associated....

Early diagnosis of Parkinson's disease: neurospect by trodat-1Tc99m, dopamine transporter marker

International Nuclear Information System (INIS)

Mena, Ismael; Diaz, Fernando; Gomez, Ariel

2001-01-01

Information: We have recently preliminarily reported that NeuroSPECT (NSP) of the Dopamine Transporter (DAT) is a highly sensitive method for early diagnosis of Parkinson disease (27). Objectives: To evaluate the sensitivity of NSP of DAT in patients with de novo hemiparkinsonism and compare the contralateral Vs ipsilateral to the symptomatic side results and also Vs. normal controls, in order to assess the sensitivity to detect pre symptomatic and symptomatic impairment of concentration of DAT (Au)

Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts

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Marco Emanuele

2016-05-01

Full Text Available Alpha-synuclein (αSyn interferes with multiple steps of synaptic activity at pre-and post-synaptic terminals, however the mechanism/s by which αSyn alters neurotransmitter release and synaptic potentiation is unclear. By atomic force microscopy we show that human αSyn, when incubated with reconstituted membrane bilayer, induces lipid rafts' fragmentation. As a consequence, ion channels and receptors are displaced from lipid rafts with consequent changes in their activity. The enhanced calcium entry leads to acute mobilization of synaptic vesicles, and exhaustion of neurotransmission at later stages. At the post-synaptic terminal, an acute increase in glutamatergic transmission, with increased density of PSD-95 puncta, is followed by disruption of the interaction between N-methyl-d-aspartate receptor (NMDAR and PSD-95 with ensuing decrease of long term potentiation. While cholesterol loading prevents the acute effect of αSyn at the presynapse; inhibition of casein kinase 2, which appears activated by reduction of cholesterol, restores the correct localization and clustering of NMDARs.

Protective actions of the vesicular monoamine transporter 2 (VMAT2) in monoaminergic neurons.

Science.gov (United States)

Guillot, Thomas S; Miller, Gary W

2009-04-01

Vesicular monoamine transporters (VMATs) are responsible for the packaging of neurotransmitters such as dopamine, serotonin, norepinephrine, and epinephrine into synaptic vesicles. These proteins evolved from precursors in the major facilitator superfamily of transporters and are among the members of the toxin extruding antiporter family. While the primary function of VMATs is to sequester neurotransmitters within vesicles, they can also translocate toxicants away from cytosolic sites of action. In the case of dopamine, this dual role of VMAT2 is combined-dopamine is more readily oxidized in the cytosol where it can cause oxidative stress so packaging into vesicles serves two purposes: neurotransmission and neuroprotection. Furthermore, the deleterious effects of exogenous toxicants on dopamine neurons, such as MPTP, can be attenuated by VMAT2 activity. The active metabolite of MPTP can be kept within vesicles and prevented from disrupting mitochondrial function thereby sparing the dopamine neuron. The highly addictive drug methamphetamine is also neurotoxic to dopamine neurons by using dopamine itself to destroy the axon terminals. Methamphetamine interferes with vesicular sequestration and increases the production of dopamine, escalating the amount in the cytosol and leading to oxidative damage of terminal components. Vesicular transport seems to resist this process by sequestering much of the excess dopamine, which is illustrated by the enhanced methamphetamine neurotoxicity in VMAT2-deficient mice. It is increasingly evident that VMAT2 provides neuroprotection from both endogenous and exogenous toxicants and that while VMAT2 has been adapted by eukaryotes for synaptic transmission, it is derived from phylogenetically ancient proteins that originally evolved for the purpose of cellular protection.

Endogenous Glucagon-like Peptide-1 Suppresses High-Fat Food Intake by Reducing Synaptic Drive onto Mesolimbic Dopamine Neurons

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Xue-Feng Wang

2015-08-01

Full Text Available Glucagon-like peptide-1 (GLP-1 and its analogs act as appetite suppressants and have been proven to be clinically efficacious in reducing body weight in obese individuals. Central GLP-1 is expressed in a small population of brainstem cells located in the nucleus tractus solitarius (NTS, which project to a wide range of brain areas. However, it remains unclear how endogenous GLP-1 released in the brain contributes to appetite regulation. Using chemogenetic tools, we discovered that central GLP-1 acts on the midbrain ventral tegmental area (VTA and suppresses high-fat food intake. We used integrated pathway tracing and synaptic physiology to further demonstrate that activation of GLP-1 receptors specifically reduces the excitatory synaptic strength of dopamine (DA neurons within the VTA that project to the nucleus accumbens (NAc medial shell. These data suggest that GLP-1 released from NTS neurons can reduce highly palatable food intake by suppressing mesolimbic DA signaling.

Synaptic Cell Adhesion

OpenAIRE

Missler, Markus; Südhof, Thomas C.; Biederer, Thomas

2012-01-01

Chemical synapses are asymmetric intercellular junctions that mediate synaptic transmission. Synaptic junctions are organized by trans-synaptic cell adhesion molecules bridging the synaptic cleft. Synaptic cell adhesion molecules not only connect pre- and postsynaptic compartments, but also mediate trans-synaptic recognition and signaling processes that are essential for the establishment, specification, and plasticity of synapses. A growing number of synaptic cell adhesion molecules that inc...

Organic cation transporter 2 (SLC22A2), a low-affinity and high-capacity choline transporter, is preferentially enriched on synaptic vesicles in cholinergic neurons.

Science.gov (United States)

Nakata, T; Matsui, T; Kobayashi, K; Kobayashi, Y; Anzai, N

2013-11-12

Organic cation transporters (OCTs) are expressed mainly in the kidney and liver. OCTs transport intrinsic organic cations, including monoamine, dopamine, serotonine and choline, across the plasma membrane. Here, we demonstrate that OCT2 (SLC22A2) is expressed in cholinergic neurons, motoneurons in the anterior horn of the spinal cord, and is implicated in acetylcholine (Ach) recycling in presynaptic terminals. Application of rabbit anti-peptide antibody revealed that OCT2 was expressed in the anterior horn of the spinal cord. Double immunostaining of muscle sections with anti-OCT2 and alpha-bungarotoxin (BTX) revealed that OCT2 was localized in the neuromuscular junctions (NMJs). Immunoelectron microscopy revealed that OCT2 was localized both in synaptic vesicles (SVs) in presynaptic terminals around the motoneurons (C-terminals) and in SVs in nerve terminals in NMJs. The similarity in the distribution of OCT2 in cholinergic neurons and that of vesicular acetyl choline transporter (VAchT), and the fact that OCT2 can transport choline suggest that OCT2 could work as a low-affinity and high-capacity choline transporter at presynaptic terminals in cholinergic neurons in a firing-dependent manner. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

The Predominance of Electric Transport in Synaptic Transmission

OpenAIRE

Hamid Reza Noori

2008-01-01

The quantitative description of the motion of neurotransmitters in the synaptic cleft appears to be one of the most difficult problems in the modeling of synapses. Here we show in contradiction to the common view, that this process is merely governed by electric transport than diffusion forces.

Phasic dopamine release drives rapid activation of striatal D2-receptors

Science.gov (United States)

Marcott, Pamela F; Mamaligas, Aphroditi A; Ford, Christopher P

2014-01-01

Summary Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G-protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory post-synaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals. PMID:25242218

Synaptic Effects of Dopamine Breakdown and Their Relation to Schizophrenia-Linked Working Memory Deficits

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Andrew D. Bolton

2018-06-01

Full Text Available Working memory is the ability to hold information “online” over a time delay in order to perform a task. This kind of memory is encoded in the brain by persistent neural activity that outlasts the presentation of a stimulus. Patients with schizophrenia perform poorly in working memory tasks that require the brief memory of a target location in space. This deficit indicates that persistent neural activity related to spatial locations may be impaired in the disease. At the circuit level, many studies have shown that NMDA receptors and the dopamine system are involved in both schizophrenia pathology and working memory-related persistent activity. In this Hypothesis and Theory article, we examine the possible connection between NMDA receptors, the dopamine system, and schizophrenia-linked working memory deficits. In particular, we focus on the dopamine breakdown product homocysteine (HCY, which is consistently elevated in schizophrenia patients. Our previous studies have shown that HCY strongly reduces the desensitization of NMDA currents. Here, we show that HCY likely affects NMDA receptors in brain regions that support working memory; this is because these areas favor dopamine breakdown over transport to clear dopamine from synapses. Finally, within the context of two NMDA-based computational models of working memory, we suggest a mechanism by which HCY could give rise to the working memory deficits observed in schizophrenia patients.

Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

Science.gov (United States)

Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Lo Bianco, Luciana; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

2010-02-22

Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

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Alessandro Bertolino

2010-02-01

Full Text Available Variation of the gene coding for D2 receptors (DRD2 has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560 predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic and D2L (mainly post-synaptic. However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.Thirty-seven healthy subjects were genotyped for rs1076560 (G>T and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors, as well as BOLD fMRI during N-Back working memory.Subjects carrying the T allele (previously associated with reduced D2S expression had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT.Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport

DEFF Research Database (Denmark)

Fog, Jacob U; Khoshbouei, Habibeh; Holy, Marion

2006-01-01

Efflux of dopamine through the dopamine transporter (DAT) is critical for the psychostimulatory properties of amphetamines, but the underlying mechanism is unclear. Here we show that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) plays a key role in this efflux. CaMKIIalpha bound to the d...

Methamphetamine reduces LTP and increases baseline synaptic transmission in the CA1 region of mouse hippocampus.

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Jarod Swant

2010-06-01

Full Text Available Methamphetamine (METH is an addictive psychostimulant whose societal impact is on the rise. Emerging evidence suggests that psychostimulants alter synaptic plasticity in the brain--which may partly account for their adverse effects. While it is known that METH increases the extracellular concentration of monoamines dopamine, serotonin, and norepinephrine, it is not clear how METH alters glutamatergic transmission. Within this context, the aim of the present study was to investigate the effects of acute and systemic METH on basal synaptic transmission and long-term potentiation (LTP; an activity-induced increase in synaptic efficacy in CA1 sub-field in the hippocampus. Both the acute ex vivo application of METH to hippocampal slices and systemic administration of METH decreased LTP. Interestingly, the acute ex vivo application of METH at a concentration of 30 or 60 microM increased baseline synaptic transmission as well as decreased LTP. Pretreatment with eticlopride (D2-like receptor antagonist did not alter the effects of METH on synaptic transmission or LTP. In contrast, pretreatment with D1/D5 dopamine receptor antagonist SCH23390 or 5-HT1A receptor antagonist NAN-190 abrogated the effect of METH on synaptic transmission. Furthermore, METH did not increase baseline synaptic transmission in D1 dopamine receptor haploinsufficient mice. Our findings suggest that METH affects excitatory synaptic transmission via activation of dopamine and serotonin receptor systems in the hippocampus. This modulation may contribute to synaptic maladaption induced by METH addiction and/or METH-mediated cognitive dysfunction.

Clinical usefulness of dopamine transporter imaging

International Nuclear Information System (INIS)

Kim, Jong Min; Kim, Yu Kyeong; Kim, Sang Eun; Jeon, Beom S.

2007-01-01

Imaging of the dopamine transporter (DAT) provides a marker for the integrity of presynaptic nigrostriatal dopaminergic system. DAT density is reduced in Parkinson disease, multiple system atrophy, and progressive supranuclear palsy. In patients with suspicious parkinsonism, normal DAT imaging suggests an alternative diagnosis such as essential tremor, vascular parkinsonism, or drug-induced parkinsonism. DAT imaging is a useful tool to aid clinician's differential diagnosis in parkinsonism

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

DEFF Research Database (Denmark)

Hansen, Freja H; Skjørringe, Tina; Yasmeen, Saiqa

2014-01-01

experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine......Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we......-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake...

Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux

DEFF Research Database (Denmark)

Binda, Francesca; Dipace, Concetta; Bowton, Erica

2008-01-01

of the dopamine (DA) transporter (DAT) as the site of direct interaction with SYN1A. Amphetamine (AMPH) increases the association of SYN1A with human DAT (hDAT) in a heterologous expression system (hDAT cells) and with native DAT in murine striatal synaptosomes. Immunoprecipitation of DAT from the biotinylated...

Dopamine-transporter SPECT and Dopamine-D2-receptor SPECT in basal ganglia diseases

International Nuclear Information System (INIS)

Hesse, S.; Barthel, H.; Seese, A.; Sabri, O.

2007-01-01

The basal ganglia comprise a group of subcortical nuclei, which are essential for motor control. Dysfunction of these areas, especially in dopaminergic transmission, results in disordered movement and neurological diseases such as Parkinson's disease, Wilson's disease, or Huntington disease. Positron emission tomography and single photon emission computed tomography (SPECT) have enhanced the understanding of the underlying pathophysiology, but they much more contribute to the early differential diagnosis of patients suffering from Parkinsonian syndrome in routine care. The present article provides dopamine transporter and D 2 receptor SPECT findings in selected movement disorders. (orig.)

Evaluation of striatal dopamine transporter density using ({sup 123}I)-{beta}-CIT SPECT in schizophrenic patients treated with olanzapine: pilot study

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Kim, Chul Eung; Moon, Hey Won; Choe, Won Sick; Kim, Chang Ho; Chi, Dae Yoon [Inha Univ., Incheon (Korea, Republic of)

2002-08-01

This pilot study was performed to understand the pharmacological effect of olanzapine, an atypical antipsychotic agent, on dopamine transporter in schizophrenic patients. Six patients (3 male, 3 female) with schizophrenia, who had not taken any psychotropic drugs for at least four weeks, were studied. Nuclear imaging using ({sup 123}I)-{beta}-CIT SPECT was obtained before and after 4-week treatment with olanzapine. Analysis of ROI on the striatum, caudate nucleus, and putamen was performed. Post-treatment uptake was significantly increased in all the ROIs compared with pre-treatment uptake. This preliminary study with the small number of schizophrenic patients suggested an increase in uptake of dopamine transporter in the striatum, caudate nucleus, and putamen after 4-week treatment with olanzapine, which warrants a large-scaled controlled study to confirm the current findings.

Intranasal dopamine reduces in vivo [123I]FP-CIT binding to striatal dopamine transporter: correlation with behavioral changes and evidence for Pavlovian conditioned dopamine response

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Maria A de Souza Silva

2016-04-01

Full Text Available Purpose: Dopamine (DA, which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA, nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [123I]FP-CIT to the DAT should be decreased due to competition at the receptor.Methods: Rats were administered intranasal application of 3 mg/kg IN-DA and vehicle (VEH, with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming were assessed for 30 min in an open field prior to administration of [123I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT two hours following administration of the radioligand. Results: 1 After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered dopamine had central action and increased DA levels comparable to that found previously with L-DOPA administration. 2 DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant

The second sodium site in the dopamine transporter controls cation permeability and is regulated by chloride

DEFF Research Database (Denmark)

Borre, Lars; Andreassen, Thorvald F; Shi, Lei

2014-01-01

The dopamine transporter (DAT) belongs to the family of neurotransmitter:sodium symporters (NSSs) and controls dopamine (DA) homeostasis by mediating Na(+)- and Cl(-)-dependent reuptake of DA. Here we used two-electrode voltage clamp measurements in Xenopus oocytes together with targeted mutagene......The dopamine transporter (DAT) belongs to the family of neurotransmitter:sodium symporters (NSSs) and controls dopamine (DA) homeostasis by mediating Na(+)- and Cl(-)-dependent reuptake of DA. Here we used two-electrode voltage clamp measurements in Xenopus oocytes together with targeted...

Pyrethroid pesticide-induced alterations in dopamine transporter function

International Nuclear Information System (INIS)

Elwan, Mohamed A.; Richardson, Jason R.; Guillot, Thomas S.; Caudle, W. Michael; Miller, Gary W.

2006-01-01

Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies from our laboratory and others have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Here, we report that repeated exposure (3 injections over 2 weeks) of mice to two commonly used pyrethroid pesticides, deltamethrin (3 mg/kg) and permethrin (0.8 mg/kg), increases DAT-mediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, we determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 μM) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 μM) or 24 h (1, 5, and 10 μM) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD

Evidence for distinct sodium-, dopamine-, and cocaine-dependent conformational changes in transmembrane segments 7 and 8 of the dopamine transporter

DEFF Research Database (Denmark)

Norregaard, Lene; Loland, Claus Juul; Gether, Ulrik

2003-01-01

. Inhibitors such as cocaine did not alter the effect of MTSET in M371C. The protection of M371C inactivation by dopamine required Na+. Because dopamine binding is believed to be Na+-independent, this suggests that dopamine induces a transport-associated conformational change that decreases the reactivity of M......371C with MTSET. In contrast to M371C, cocaine decreased the reaction rate of A399C with MTSET, whereas dopamine had no effect. The protection by cocaine can either reflect that Ala-399 lines the cocaine binding crevice or that cocaine induces a conformational change that decreases the reactivity of A...

A role for accumbal glycine receptors in modulation of dopamine release by the glycine transporter-1 inhibitor Org25935

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Helga eHöifödt Lidö

2011-03-01

Full Text Available AbstractAccumbal glycine modulates basal and ethanol-induced dopamine levels in the nucleus accumbens (nAc as well as voluntary ethanol consumption. Also, systemic administration of the glycine transporter-1 inhibitor Org25935 elevates dopamine levels in nAc, prevents a further ethanol-induced dopamine elevation and robustly and dose-dependently decreases ethanol consumption in rats. Here we investigated whether Org25935 applied locally in nAc modulates dopamine release, and whether accumbal glycine receptors or NMDA receptors are involved in this tentative effect. We also addressed whether Org25935 and ethanol applied locally in nAc interact with dopamine levels, as seen after systemic administration. We used in vivo microdialysis coupled to HPLC-ED in freely moving male Wistar rats to monitor dopamine output in nAc after local perfusion of Org25935 alone, with ethanol, or Org25935-perfusion after pre-treatment with the glycine receptor antagonist strychnine or the NMDA receptor glycine site antagonist L-701.324. Local Org25935 increased extracellular dopamine levels in a subpopulation of rats. Local strychnine, but not systemic L-701.324, antagonized the dopamine-activating effect of Org25935. Ethanol failed to induce a dopamine overflow in the subpopulation responding to Org25935 with a dopamine elevation. The study supports a role for accumbal glycine receptors rather than NMDA receptor signaling in the dopamine-activating effect of Org25935. The results further indicate that the previously reported systemic Org25935-ethanol interaction with regard to accumbal dopamine is localized to the nAc. This adds to the growing evidence for the glycine receptor as an important player in the dopamine reward circuitry and in ethanol’s effects within this system.

Postendocytic sorting of constitutively internalized dopamine transporter in cell lines and dopaminergic neurons

DEFF Research Database (Denmark)

Eriksen, Jacob; Bjørn-Yoshimoto, Walden Emil; Jørgensen, Trine Nygaard

2010-01-01

The dopamine transporter (DAT) mediates reuptake of released dopamine and is the target for psychostimulants, such as cocaine and amphetamine. DAT undergoes marked constitutive endocytosis, but little is known about the fate and sorting of the endocytosed transporter. To study DAT sorting in cells...... lines, we fused the one-transmembrane segment protein Tac to DAT, thereby generating a transporter (TacDAT) with an extracellular antibody epitope suited for trafficking studies. TacDAT was functional and endocytosed constitutively in HEK293 cells. According to an ELISA-based assay, TacDAT intracellular...

Evaluating Dopamine Reward Pathway in ADHD; clinical implications

International Nuclear Information System (INIS)

Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Kollins, S.H.; Wigal, T.L.; Newcorn, J.H.; Telang, F.; Fowler, J.S.; Zhu, W.; Logan, J.; Ma, Y.; Pradhan, K.; Wong, C.T.; Swanson, J.M.

2009-01-01

Attention-deficit/hyperactivity disorder (ADHD) - characterized by symptoms of inattention and hyperactivity-impulsivity - is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). We used positron emission tomography to measure dopamine synaptic markers (transporters and D 2 /D 3 receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory. We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [ 11 C]cocaine and for D 2 /D 3 receptors using [ 11 C]raclopride, quantified as binding potential (distribution volume ratio -1). For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P 2 /D 3 receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02-0.17, P = .01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D 2 /D 3 for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10-0.56; P = .005) and differences in D 2 /D 3 in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02-0.12; P = .004). Ratings of attention correlated with D 2 /D 3 in the accumbens (r = 0.35; 95% CI, 0.15-0.52; P = .001), midbrain (r = 0.35; 95% CI, 0.14-0.52; P = .001), caudate (r = 0.32; 95% CI, 0.11-0.50; P = .003), and hypothalamic (r = 0.31; CI, 0.10-0.49; P = .003) regions and with DAT in the midbrain

Ascorbic acid and striatal transport of [3H]1-methyl-4-phenylpyridine (MPP+) and [3H]dopamine

International Nuclear Information System (INIS)

Debler, E.A.; Hashim, A.; Lajtha, A.; Sershen, H.

1988-01-01

The inhibition of uptake of [ 3 H]dopamine and [ 3 H]1-methyl-4-phenylpyridine (MPP + ) was examined in mouse striatal synaptosomal preparations. Kinetic analysis indicated that ascorbic acid is a noncompetitive inhibitor of [ 3 H]MPP + uptake. No inhibition of [ 3 H]dopamine uptake is observed. The dopamine uptake blockers, GBR-12909, cocaine, and mazindol strongly inhibit (IC 50 3 H]dopamine and [ 3 H]MPP + transport. Nicotine, its metabolites, and other tobacco alkaloids are weak inhibitors except 4-phenylpyridine and lobeline, which are moderate inhibitors of both [ 3 H]dopamine and [ 3 H]MPP + uptake. These similarities in potencies are in agreement with the suggestion that [ 3 H]MPP + and [ 3 H] are transported by the same carrier. The differences observed in the alteration of dopaminergic transport and mazindol binding by ascorbic acid suggest that ascorbic acid's effects on [ 3 H]MPP + transport are related to translocation and/or dissociation processes occurring subsequent to the initial binding event

[123I]Iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine - an in vivo imaging study with a dedicated small animal SPECT

International Nuclear Information System (INIS)

Nikolaus, Susanne; Larisch, Rolf; Wirrwar, Andreas; Jamdjeu-Noune, Marlyse; Antke, Christina; Beu, Markus; Mueller, Hans-Wilhelm; Schramm, Nils

2005-01-01

This study assessed [ 123 I]iodobenzamide binding to the rat dopamine D 2 receptor in competition with haloperidol and endogenous dopamine using a high-resolution small animal SPECT. Subsequent to baseline quantifications of D 2 receptor binding, imaging studies were performed on the same animals after pre-treatment with haloperidol and methylphenidate, which block D 2 receptors and dopamine transporters, respectively. Striatal baseline equilibrium ratios (V 3 '' ) of [ 123 I]iodobenzamide binding were 1.42±0.31 (mean±SD). After pre-treatment with haloperidol and methylphenidate, V 3 '' values decreased to 0.54±0.46 (p 123 I]iodobenzamide binding induced by pre-treatment with haloperidol reflects D 2 receptor blockade, whereas the decrease in receptor binding induced by pre-treatment with methylphenidate can be interpreted in terms of competition between [ 123 I]IBZM and endogenous dopamine. Findings show that multiple in vivo measurements of [ 123 I]iodobenzamide binding to D 2 receptors in competition with exogenous and endogenous ligands are feasible in the same animal. This may be of future relevance for the in vivo evaluation of novel radioligands as well as for studying the interrelations between pre- and/or postsynaptic radioligand binding and different levels of endogenous dopamine. (orig.)

In vivo neurochemical characterization of clothianidin induced striatal dopamine release.

Science.gov (United States)

Faro, L R F; Oliveira, I M; Durán, R; Alfonso, M

2012-12-16

Clothianidin (CLO) is a neonicotinoid insecticide with selective action on nicotinic acetylcholine receptors. The aim of this study was to determine the neurochemical basis for CLO-induced striatal dopamine release using the microdialysis technique in freely moving and conscious rats. Intrastriatal administration of CLO (3.5mM), produced an increase in both spontaneous (2462 ± 627% with respect to basal values) and KCl-evoked (4672 ± 706% with respect to basal values) dopamine release. This effect was attenuated in Ca(2+)-free medium, and was prevented in reserpine pre-treated animals or in presence of tetrodotoxin (TTX). To investigate the involvement of dopamine transporter (DAT), the effect of CLO was observed in presence of nomifensine. The coadministration of CLO and nomifensine produced an additive effect on striatal dopamine release. The results suggest that the effect of CLO on striatal dopamine release is predominantly mediated by an exocytotic mechanism, Ca(2+), vesicular and TTX-dependent and not by a mechanism mediated by dopamine transporter. Published by Elsevier Ireland Ltd.

Effect of co-transporter blockers on non-synaptic epileptiform activity—computational simulation

Science.gov (United States)

Rodrigues Lopes, Mariana; Canton Santos, Luiz Eduardo; Márcio Rodrigues, Antônio; Antônio Duarte, Mario; Catelli Infantosi, Antonio Fernando; Alexandre Scorza, Fulvio; Arida, Ricardo Mario; Madureira, Ana Paula; Amaral da Silveira, Gilcélio; dos Santos, Ivans Carlos; Abrão Cavalheiro, Esper; Guimarães de Almeida, Antônio-Carlos

2013-10-01

The important role of cation-chloride co-transporters in epilepsy is being supported by an increasing number of investigations. However, enormous complexity is involved since the action of these co-transporters has effects on the ionic homeostasis influencing directly the neuronal excitability and the tissue propensity to sustain seizure. To unravel the complex mechanisms involving the co-transporters action during seizure, this paper shows simulations of non-synaptic epileptiform activity and the effect of the blockage of the two different types of cation-chloride co-transporters present in the brain: Na, K and 2Cl co-transporter (NKCC) and K and Cl co-transporter (KCC). The simulations were performed with an electrochemical model representing the non-synaptic structure of the granule cell layer of the dentate gyrus (DG) of the rat hippocampus. The simulations suggest: (i) the potassium clearance is based on the systemic interplay between the Na/K pump and the NKCC co-transporters; (ii) the simultaneous blockage of the NKCC of the neurons and KCC of glial cells acts efficiently suppressing the epileptiform activities; and (iii) the simulations show that depending on the combined blockage of the co-transporters, the epileptiform activities may be suppressed or enhanced.

Regulation of dopamine transporter activity by carboxypeptidase E

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Zhang Heping

2009-05-01

Full Text Available Abstract Background The dopamine transporter (DAT plays a critical role in terminating the action of dopamine by rapid reuptake into the presynaptic neuron. Previous studies have revealed that the DAT carboxyl terminus (DAT-CT can directly interact with other cellular proteins and regulate DAT function and trafficking. Results Here, we have identified that carboxypeptidase E (CPE, a prohormone processing exopeptidase and sorting receptor for the regulated secretory pathway, interacts with the DAT-CT and affects DAT function. Mammalian cell lines coexpressing CPE and DAT exhibited increased DAT-mediated dopamine uptake activity compared to cells expressing DAT alone. Moreover, coexpression of an interfering DAT-CT minigene inhibited the effects of CPE on DAT. Functional changes caused by CPE could be attributed to enhanced DAT expression and subsequent increase in DAT cell surface localization, due to decreased DAT degradation. In addition, CPE association could reduce the phosphorylation state of DAT on serine residues, potentially leading to reduced internalization, thus stabilizing plasmalemmal DAT localization. Conclusion Taken together, our results reveal a novel role for CPE in the regulation of DAT trafficking and DAT-mediated DA uptake, which may provide a novel target in the treatment of dopamine-governed diseases such as drug addiction and obesity.

De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder

DEFF Research Database (Denmark)

Hamilton, P J; Campbell, N G; Sharma, S

2013-01-01

De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution...

Zn(2+) site engineering at the oligomeric interface of the dopamine transporter.

Science.gov (United States)

Norgaard-Nielsen, Kristine; Norregaard, Lene; Hastrup, Hanne; Javitch, Jonathan A; Gether, Ulrik

2002-07-31

Increasing evidence suggests that Na(+)/Cl(-)-dependent neurotransmitter transporters exist as homo-oligomeric proteins. However, the functional implication of this oligomerization remains unclear. Here we demonstrate the engineering of a Zn(2+) binding site at the predicted dimeric interface of the dopamine transporter (DAT) corresponding to the external end of transmembrane segment 6. Upon binding to this site, which involves a histidine inserted in position 310 (V310H) and the endogenous Cys306 within the same DAT molecule, Zn(2+) potently inhibits [(3)H]dopamine uptake. These data provide indirect evidence that conformational changes critical for the translocation process may occur at the interface between two transporter molecules in the oligomeric structure.

Central serotonin and dopamine transporters in overeating, obesity and insulin resistance

NARCIS (Netherlands)

Koopman, K.E.M.

2014-01-01

The objectives of this thesis were to study cerebral serotonin transporters (SERT) in the diencephalon and striatal dopamine transporters (DAT) in humans in different metabolic conditions (i.e. lean, obese and insulin resistant state) in relation to feeding behavior and to investigate the early

Preparation of a potential positron emission tomographic radioligand for the dopamine transporter

International Nuclear Information System (INIS)

Mueller, L.; Halldin, C.; Foged, C.; Karlsson, P.; Hall, H.; Swahn, C.G.; Suzdak, P.D.; Hohlweg, R.; Nielsen, E.B.; Frade, L.

1994-01-01

NNC 12-0722 (1-[2-(bis(4-fluorophenyl)-methoxy)ethyl]-4-methyl piperazine) is a new selective inhibitor of the dopamine transporter. [ 11 C]NNC 12-0722 was prepared by N-methylation of the desmethyl compound with [ 11 C]methyl iodide. The total radiochemical yield of [ 11 C]NNC 12-0722 was 40%-50% with an overall synthesis time of 30-35 min. The radiochemical purity was higher than 99% and the specific radioactivity about 1500 Ci/mmol (55 GBq/μmol). Autoradiographic examination of [ 11 C]NNC 12-0722 binding on whole hemisphere cryosections from human brain post mortem demonstrated specific binding in the caudate nucleus and putamen. In a positron emission tomographic examination of [ 11 C]NNC 12-0722 in a cynomolgus monkey there was a rapid uptake of radioactivity in the brain. In the striatum, a region with a high density of dopamine transporters, the radioactivity was two times higher than in the cerebellum. These results indicate that [ 11 C]NNC 12-0722 may be a useful radioligand for labelling of the dopamine transporter in man. (orig.)

[Study of dopamine transporter imaging on the brain of children with autism].

Science.gov (United States)

Sun, Xiaomian; Yue, Jing; Zheng, Chongxun

2008-04-01

This study was conducted to evaluate the applicability of 99mTc-2beta-[ N, N'-bis (2-mercaptoethyl) ethylenediamino]methyl,3beta(4-chlorophenyl)tropane(TRODAT-1) dopamine transporter(DAT) SPECT imaging in children with autism, and thus to provide an academic basis for the etiology, mechanism and clinical therapy of autism. Ten autistic children and ten healthy controls were examined with 99mTc-TRODAT-1 DAT SPECT imaging. Striatal specific uptake of 99mTc-TRODAT-1 was calculated with region of interest analysis according to the ratics between striatum and cerebellum [(STR-BKG)/BKG]. There was no statistically significant difference in semiquantitative dopamine transporter between the bilateral striata of autistic children (P=0.562), and between those of normal controls (p=0.573); Dopamine transporter in the brain of patients with autism increased significantly as compared with that in the brain of normal controls (P=0.017). Dopaminergic nervous system is dysfunctioning in the brain of children with autism, and DAT 99mTc-TRODAT-1 SPECT imaging on the brain will help the imaging diagnosis of childhcod autism.

Effect of age and gender on dopamine transporter imaging with [123I]FP-CIT SPET in healthy volunteers

International Nuclear Information System (INIS)

Lavalaye, J.; Booij, J.; Reneman, L.; Habraken, J.B.A.; Royen, E.A. van

2000-01-01

Dopamine transporter imaging is a valuable tool to investigate the integrity of the dopaminergic neurons. To date, several reports have shown an age-associated decline in dopamine transporters in healthy volunteers. Although animal studies suggest an effect of gender on dopamine transporter density, this gender effect has not yet been confirmed in human studies. To study the influence of age and gender on dopamine transporter imaging in healthy volunteers, we performed single-photon emission tomography imaging with [ 123 I]FP-CIT to quantify dopamine transporters. Forty-five healthy volunteers (23 males and 22 females) were included, ranging in age from 18 to 83 years. SPET imaging was performed 3 h after injection of ±110 MBq [ 123 I]FP-CIT. An operator-independent volume of interest analysis was used for quantification of [ 123 I]FP-CIT binding in the striatum. The ratio of specific striatal to non-specific [ 123 I]FP-CIT binding was found to decrease significantly with age. Moreover, we found a high variance in [ 123 I]FP-CIT binding in young adults. Finally, females were found to have significantly higher [ 123 I]FP-CIT binding ratios than males. This effect of gender on [ 123 I]FP-CIT binding ratios was not related to age. The results of this study are consistent with findings from previous studies, which showed that dopamine transporter density declines with age. The intriguing finding of a higher dopamine transporter density in females than in males is in line with findings from animal studies. (orig.)

Regulator of G protein signaling-12 modulates the dopamine transporter in ventral striatum and locomotor responses to psychostimulants.

Science.gov (United States)

Gross, Joshua D; Kaski, Shane W; Schroer, Adam B; Wix, Kimberley A; Siderovski, David P; Setola, Vincent

2018-02-01

Regulators of G protein signaling are proteins that accelerate the termination of effector stimulation after G protein-coupled receptor activation. Many regulators of G protein signaling proteins are highly expressed in the brain and therefore considered potential drug discovery targets for central nervous system pathologies; for example, here we show that RGS12 is highly expressed in microdissected mouse ventral striatum. Given a role for the ventral striatum in psychostimulant-induced locomotor activity, we tested whether Rgs12 genetic ablation affected behavioral responses to amphetamine and cocaine. RGS12 loss significantly decreased hyperlocomotion to lower doses of both amphetamine and cocaine; however, other outcomes of administration (sensitization and conditioned place preference) were unaffected, suggesting that RGS12 does not function in support of the rewarding properties of these psychostimulants. To test whether observed response changes upon RGS12 loss were caused by changes to dopamine transporter expression and/or function, we prepared crude membranes from the brains of wild-type and RGS12-null mice and measured dopamine transporter-selective [ 3 H]WIN 35428 binding, revealing an increase in dopamine transporter levels in the ventral-but not dorsal-striatum of RGS12-null mice. To address dopamine transporter function, we prepared striatal synaptosomes and measured [ 3 H]dopamine uptake. Consistent with increased [ 3 H]WIN 35428 binding, dopamine transporter-specific [ 3 H]dopamine uptake in RGS12-null ventral striatal synaptosomes was found to be increased. Decreased amphetamine-induced locomotor activity and increased [ 3 H]WIN 35428 binding were recapitulated with an independent RGS12-null mouse strain. Thus, we propose that RGS12 regulates dopamine transporter expression and function in the ventral striatum, affecting amphetamine- and cocaine-induced increases in dopamine levels that specifically elicit acute hyperlocomotor responses.

A combination of dopamine genes predicts success by professional Wall Street traders.

Science.gov (United States)

Sapra, Steve; Beavin, Laura E; Zak, Paul J

2012-01-01

What determines success on Wall Street? This study examined if genes affecting dopamine levels of professional traders were associated with their career tenure. Sixty professional Wall Street traders were genotyped and compared to a control group who did not trade stocks. We found that distinct alleles of the dopamine receptor 4 promoter (DRD4P) and catecholamine-O-methyltransferase (COMT) that affect synaptic dopamine were predominant in traders. These alleles are associated with moderate, rather than very high or very low, levels of synaptic dopamine. The activity of these alleles correlated positively with years spent trading stocks on Wall Street. Differences in personality and trading behavior were also correlated with allelic variants. This evidence suggests there may be a genetic basis for the traits that make one a successful trader.

CA2+/CALMODULIN-DEPENDENT KINASE II- ASSOCIATES WITH THE C TERMINUS OF THE DOPAMINE TRANSPORTER AND INCREASES AMPHETAMINE-INDUCED DOPAMINE EFFLUX VIA PHOSPHORYLATION OF N-TERMINAL SERINES

DEFF Research Database (Denmark)

Fog, Jacob; Khoshbouei, H; Holy, M

The dopamine transporter(DAT) plays a key role in clearing extracellular dopamine(DA) from the synapse. Moreover DAT is a target for the action of widely abused psychostimulants such as cocaine and amphetamine(AMPH). AMPH is a substrate for the DAT and promotes the reversal of transport and thus...

Flipped Phenyl Ring Orientations of Dopamine Binding with Human and Drosophila Dopamine Transporters: Remarkable Role of Three Nonconserved Residues.

Science.gov (United States)

Yuan, Yaxia; Zhu, Jun; Zhan, Chang-Guo

2018-03-09

Molecular modeling and molecular dynamics simulations were performed in the present study to examine the modes of dopamine binding with human and Drosophila dopamine transporters (hDAT and dDAT). The computational data revealed flipped binding orientations of dopamine in hDAT and dDAT due to the major differences in three key residues (S149, G153, and A423 of hDAT vs A117, D121, and S422 of dDAT) in the binding pocket. These three residues dictate the binding orientation of dopamine in the binding pocket, as the aromatic ring of dopamine tends to take an orientation with both the para- and meta-hydroxyl groups being close to polar residues and away from nonpolar residues of the protein. The flipped binding orientations of dopamine in hDAT and dDAT clearly demonstrate a generally valuable insight concerning how the species difference could drastically affect the protein-ligand binding modes, demonstrating that the species difference, which is a factor rarely considered in early drug design stage, must be accounted for throughout the ligand/drug design and discovery processes in general.

Cocaine Promotes Coincidence Detection and Lowers Induction Threshold during Hebbian Associative Synaptic Potentiation in Prefrontal Cortex.

Science.gov (United States)

Ruan, Hongyu; Yao, Wei-Dong

2017-01-25

Addictive drugs usurp neural plasticity mechanisms that normally serve reward-related learning and memory, primarily by evoking changes in glutamatergic synaptic strength in the mesocorticolimbic dopamine circuitry. Here, we show that repeated cocaine exposure in vivo does not alter synaptic strength in the mouse prefrontal cortex during an early period of withdrawal, but instead modifies a Hebbian quantitative synaptic learning rule by broadening the temporal window and lowers the induction threshold for spike-timing-dependent LTP (t-LTP). After repeated, but not single, daily cocaine injections, t-LTP in layer V pyramidal neurons is induced at +30 ms, a normally ineffective timing interval for t-LTP induction in saline-exposed mice. This cocaine-induced, extended-timing t-LTP lasts for ∼1 week after terminating cocaine and is accompanied by an increased susceptibility to potentiation by fewer pre-post spike pairs, indicating a reduced t-LTP induction threshold. Basal synaptic strength and the maximal attainable t-LTP magnitude remain unchanged after cocaine exposure. We further show that the cocaine facilitation of t-LTP induction is caused by sensitized D1-cAMP/protein kinase A dopamine signaling in pyramidal neurons, which then pathologically recruits voltage-gated l-type Ca 2+ channels that synergize with GluN2A-containing NMDA receptors to drive t-LTP at extended timing. Our results illustrate a mechanism by which cocaine, acting on a key neuromodulation pathway, modifies the coincidence detection window during Hebbian plasticity to facilitate associative synaptic potentiation in prefrontal excitatory circuits. By modifying rules that govern activity-dependent synaptic plasticity, addictive drugs can derail the experience-driven neural circuit remodeling process important for executive control of reward and addiction. It is believed that addictive drugs often render an addict's brain reward system hypersensitive, leaving the individual more susceptible to

Dopamine transporter; solubilization and characterization of [3H] GBR-12935 binding in canine caudate

International Nuclear Information System (INIS)

Sallee, F.R.

1988-01-01

The dopamine (DA) transporter protein, as indexed by [ 3 H]GBR-12935 binding, was solubilized from canine striatal membranes with the detergent digitonin. This solubilized protein retained the same pharmacological characteristics as membrane attached uptake sites. The binding of [ 3 H]GBR-12935 to solubilized preparations was specific, saturable and reversible with an equilibrium dissociation constant of approximately 3 nM and a maximum ligand binding (B max ) of 3.4 pmol/mg protein. [ 3 H]GBR-12935 also bound to solubilized sites in a sodium-independent manner with a K D of approximately 6 nM and a B max of 1.2 ± 0.2 pmol/mg protein. Dopamine uptake inhibitors and substrates of DA uptake inhibited [ 3 H]GBR-12935 binding in a stereoselective and concentration dependent manner. For these compounds rank order of potency for inhibition of [ 3 H]GBR-12935 binding correlated with their potency for inhibition of dopamine uptake. K D values for DA uptake inhibitors in solubilized preparations correlated with those obtained on [ 3 H]GBR-12935 binding in the native state. The dopamine transporter appears to be a transmembrane glycoprotein by virtue of its absorption and specific elution from wheat germ agglutinin (WGA)-lectin column. Solubilization of the putative dopamine transporter with full retention of binding activity now allows for the purification and biochemical characterization of this important membrane protein

Diet-induced obesity: dopamine transporter function, impulsivity and motivation.

Science.gov (United States)

Narayanaswami, V; Thompson, A C; Cassis, L A; Bardo, M T; Dwoskin, L P

2013-08-01

A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. Striatal D2-receptor density was determined by in vitro kinetic analysis of [(3)H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [(3)H]dopamine uptake, methamphetamine-evoked [(3)H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [(3)H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that

Altered neurocircuitry in the dopamine transporter knockout mouse brain.

Directory of Open Access Journals (Sweden)

Xiaowei Zhang

2010-07-01

Full Text Available The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI. Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn(2+ into the prefrontal cortex indicated that DAT KO mice have a truncated Mn(2+ distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn(2+ transport into more posterior midbrain nuclei and contralateral

Generation of an activating Zn(2+) switch in the dopamine transporter

DEFF Research Database (Denmark)

Loland, Claus Juul; Norregaard, Lene; Litman, Thomas

2002-01-01

Binding of Zn(2+) to the endogenous Zn(2+) binding site in the human dopamine transporter leads to potent inhibition of [(3)H]dopamine uptake. Here we show that mutation of an intracellular tyrosine to alanine (Y335A) converts this inhibitory Zn(2+) switch into an activating Zn(2+) switch, allowing...... Zn(2+)-dependent activation of the transporter. The tyrosine is part of a conserved YXX Phi trafficking motif (X is any residue and Phi is a residue with a bulky hydrophobic group), but Y335A did not show alterations in surface targeting or protein kinase C-mediated internalization. Despite wild...... for several substrates was increased. However, the presence of Zn(2+) in micromolar concentrations increased the V(max) up to 24-fold and partially restored the apparent affinities. The capability of Zn(2+) to restore transport is consistent with a reversible, constitutive shift in the distribution...

Imaging of dopamine transporters in rats using high-resolution pinhole single-photon emission tomography

Energy Technology Data Exchange (ETDEWEB)

Booij, Jan; Bruin, Kora de; Habraken, Jan B.A. [Department of Nuclear Medicine, F2N, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam (Netherlands); Voorn, Pieter [Department of Anatomy, Vrije Universiteit Medical Center, Amsterdam (Netherlands)

2002-09-01

To date, the vast majority of investigations on the dopaminergic system in small animals have been in vitro studies. In comparison with in vitro studies, single-photon emission tomography (SPET) or positron emission tomography (PET) imaging of the dopaminergic system in small animals has the advantage of permitting repeated studies within the same group of animals. Dopamine transporter imaging is a valuable non-invasive tool with which to investigate the integrity of dopaminergic neurons. The purpose of this study was to investigate the feasibility of assessing dopamine transporter density semi-quantitatively in rats using a recently developed high-resolution pinhole SPET system. This system was built exclusively for imaging of small animals. In this unique single-pinhole system, the animal rotates instead of the collimated detector. The system has proven to have a high spatial resolution. We performed SPET imaging with [{sup 123}I]FP-CIT to quantify striatal dopamine transporters in rat brain. In all seven studied control rats, symmetrical striatal binding to dopamine transporters was seen 2 h after injection of the radiotracer, with striatal-to-cerebellar binding ratios of approximately 3.5. In addition, test/retest variability of the striatal-to-cerebellar binding ratios was studied and found to be 14.5%. Finally, in unilaterally 6-hydroxydopamine-lesioned rats, striatal binding was only visible on the non-lesioned side. Quantitative analysis revealed that striatal-to-cerebellar SPET ratios were significantly lower on the lesioned (mean binding ratio 2.2{+-}0.2) than on the non-lesioned (mean ratio 3.1{+-}0.4) side. The preliminary results of this study indicate that semi-quantitative assessment of striatal dopamine transporter density using our recently developed high-resolution single-pinhole SPET system is feasible in living rat brain. (orig.)

Serotonin transporter and dopamine transporter imaging in the canine brain

International Nuclear Information System (INIS)

Peremans, Kathelijne; Goethals, Ingeborg; De Vos, Filip; Dobbeleir, A.; Ham, Hamphrey; Van Bree, Henri; Heeringen, Cees van; Audenaert, Kurt

2006-01-01

The serotonergic and dopaminergic systems are involved in a wide range of emotional and behavioral aspects of animals and humans and are involved in many neuropsychiatric disorders. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are designed to block the 5-HT transporter (SERT), thereby increasing the available 5-HT in the brain. Functional imaging with specific SERT and dopamine transporter (DAT) ligands contributes to the study of the SSRI-transporter interaction. First, we evaluated the feasibility of a canine model in the study of the SERT and DAT with the radioligands [ 123 I]-β-CIT and [ 123 I]-FP-CIT as well as single-photon emission computed tomography imaging. Second, we studied the effect of SSRIs (sertraline, citalopram and escitalopram) on the SERT and DAT in two dogs. The position of the canine model in the study of the SERT and DAT is discussed and compared with other animal models

Dopamine transporter density in the basal ganglia assessed with 123I-IPT SPECT in children with Tourette's deosoder

International Nuclear Information System (INIS)

Yoo, Y. H.; Cheon, K. A.; Yoon, M. J.; Kim, C. H.; Lee, J. D.; Kim, H. H.; Choi, T. H.

2002-01-01

Previous studies in patients with Tourette's disorder (TD) provided evidences of presynaptic dopaminergic dysfunction, demonstrating increased dopamine transporter densities. We investigated dopamine transporter densities using 123 I-IPT SPECT in drug-naive children with TD and postulated that dopamine transporter density reflected dopamine concentrations. 9 drug-naive children with ADHD and 8 normal children were included in the study. We performed brain SPECT 2 hours after administration of 123 I-IPT and made both quantitative and qualitative analyses for assessment of specific/nonspecific DAT binding ratio in the BG. We then investigated correlation between the severity of tics in children with TD assessed with the YGTSS and specific/nonspecific binding ratio on BG. Drug-naive children with TD showed a significantly increased specific/nonspecific DAT binding ratio in the BG compared with normal children. We found no significant correlation between severity of tics assessed with YGTSS in children with TD and specific/nonspecific DAT binding ratio in BG. These findings support the hypothesis of dopamine dysregulation in presynaptic dopamine function of BG being involved in pathophysiology of TD

Super-resolution microscopy reveals functional organization of dopamine transporters into cholesterol and neuronal activity-dependent nanodomains

DEFF Research Database (Denmark)

Rahbek-Clemmensen, Troels; Lycas, Matthew D.; Erlendsson, Simon

2017-01-01

is dynamically sequestrated into cholesterol-dependent nanodomains in the plasma membrane of presynaptic varicosities and neuronal projections of dopaminergic neurons. Stochastic optical reconstruction microscopy reveals irregular dopamine transporter nanodomains (∼70 nm mean diameter) that were highly sensitive...... to cholesterol depletion. Live photoactivated localization microscopy shows a similar dopamine transporter membrane organization in live heterologous cells. In neurons, dual-color dSTORM shows that tyrosine hydroxylase and vesicular monoamine transporter-2 are distinctively localized adjacent to...

Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion

Science.gov (United States)

Kouyoumdzian, Nicolás M.; Rukavina Mikusic, Natalia L.; Kravetz, María C.; Lee, Brenda M.; Carranza, Andrea; Del Mauro, Julieta S.; Pandolfo, Marcela; Gironacci, Mariela M.; Gorzalczany, Susana; Toblli, Jorge E.; Fernández, Belisario E.

2016-01-01

The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects. PMID:27392042

Identification of intracellular residues in the dopamine transporter critical for regulation of transporter conformation and cocaine binding

DEFF Research Database (Denmark)

Loland, Claus Juul; Grånäs, Charlotta; Javitch, Jonathan A

2004-01-01

Recently we showed evidence that mutation of Tyr-335 to Ala (Y335A) in the human dopamine transporter (hDAT) alters the conformational equilibrium of the transport cycle. Here, by substituting, one at a time, 16 different bulky or charged intracellular residues, we identify three residues, Lys-26...

Serotonin transporter and dopamine transporter imaging in the canine brain

Energy Technology Data Exchange (ETDEWEB)

Peremans, Kathelijne [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Goethals, Ingeborg [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); De Vos, Filip [Laboratory of Radiopharmacy, Pharmaceutical Sciences, Ghent University, B-9000 Ghent (Belgium); Dobbeleir, A. [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Ham, Hamphrey [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium); Van Bree, Henri [Department of Medical Imaging, Faculty of Veterinary Sciences, Ghent University, B-9000 Ghent (Belgium); Heeringen, Cees van [Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium); Audenaert, Kurt [Division of Nuclear Medicine, University Hospital Ghent, B-9000 Ghent (Belgium) and Department of Psychiatry and Medical Psychology, Faculty of Medical and Health Sciences, Ghent University, B-9000, Ghent (Belgium)]. E-mail: kurt.audenaert@ugent.be

2006-10-15

The serotonergic and dopaminergic systems are involved in a wide range of emotional and behavioral aspects of animals and humans and are involved in many neuropsychiatric disorders. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are designed to block the 5-HT transporter (SERT), thereby increasing the available 5-HT in the brain. Functional imaging with specific SERT and dopamine transporter (DAT) ligands contributes to the study of the SSRI-transporter interaction. First, we evaluated the feasibility of a canine model in the study of the SERT and DAT with the radioligands [{sup 123}I]-{beta}-CIT and [{sup 123}I]-FP-CIT as well as single-photon emission computed tomography imaging. Second, we studied the effect of SSRIs (sertraline, citalopram and escitalopram) on the SERT and DAT in two dogs. The position of the canine model in the study of the SERT and DAT is discussed and compared with other animal models.

[11]Cocaine: PET studies of cocaine pharmacokinetics, dopamine transporter availability and dopamine transporter occupancy

International Nuclear Information System (INIS)

Fowler, Joanna S.; Volkow, Nora D.; Wang, Gene-Jack; Gatley, S. John; Logan, Jean

2001-01-01

Cocaine was initially labeled with carbon-11 in order to track the distribution and pharmacokinetics of this powerful stimulant and drug of abuse in the human brain and body. It was soon discovered that [ 11 C]cocaine was not only useful for measuring cocaine pharmacokinetics and its relationship to behavior but that it is also a sensitive radiotracer for dopamine transporter (DAT) availability. Measures of DAT availability were facilitated by the development of a graphical analysis method (Logan Plot) for reversible systems which streamlined kinetic analysis. This expanded the applications of [ 11 C]cocaine to studies of DAT availability in the human brain and allowed the first comparative measures of the degree of DAT occupancy by cocaine and another stimulant drug methylphenidate. This article will summarize preclinical and clinical research with [ 11 C]cocaine

Dopamine Transporters in Striatum Correlate with Deactivation in the Default Mode Network during Visuospatial Attention

International Nuclear Information System (INIS)

Tomasi, D.; Fowler, J.; Tomasi, D.; Volkow, N.D.; Wang, R.L.; Telang, F.; Wang, Chang L.; Ernst, T.; Fowler, J.S.

2009-01-01

Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [ 11 C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN.

DELINEATING THE MOLECULAR BASIS FOR CONSTITUTIVE INTERNALIZATION AND DEGRADATION OF THE DOPAMINE TRANSPORTER

DEFF Research Database (Denmark)

Fog, Jacob; (Vægter), Christian Bjerggaard; Gether, Ulrik

The human dopamine transporter (hDAT) was transiently expressed in N2A neuroblastoma cells. Confocal fluorescence microscopy revealed efficient surface targeting of the transporter in undifferentiated cells as well as in differentiated cells. In the differentiated cells the hDAT displayed...

Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

OpenAIRE

Hayashizaki, Seiji; Hirai, Shinobu; Ito, Yumi; Honda, Yoshiko; Arime, Yosefu; Sora, Ichiro; Okado, Haruo; Kodama, Tohru; Takada, Masahiko

2013-01-01

Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behaviora...

Synaptic transmission modulates while non-synaptic processes govern the transition from pre-ictal to seizure activity in vitro

OpenAIRE

Jefferys, John; Fox, John; Jiruska, Premysl; Kronberg, Greg; Miranda, Dolores; Ruiz-Nuño, Ana; Bikson, Marom

2018-01-01

It is well established that non-synaptic mechanisms can generate electrographic seizures after blockade of synaptic function. We investigated the interaction of intact synaptic activity with non-synaptic mechanisms in the isolated CA1 region of rat hippocampal slices using the 'elevated-K+' model of epilepsy. Elevated K+ ictal bursts share waveform features with other models of electrographic seizures, including non-synaptic models where chemical synaptic transmission is suppressed, such as t...

Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction.

NARCIS (Netherlands)

van Huijstee, A.N.; Mansvelder, H.D.

2015-01-01

Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review

Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

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Siciliano, Cody A.; Fordahl, Steve C.

2016-01-01

Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Here we determined that cocaine self-administration in rats produced tolerance to the dopamine transporter-inhibiting effects of cocaine in the nucleus accumbens core, which was normalized following a 14 or 60 d abstinence period; however, although these rats appeared to be similar to controls, a single self-administered infusion of cocaine at the end of abstinence, even after 60 d, fully reinstated tolerance to cocaine's effects. A single cocaine infusion in a naive rat had no effect on cocaine potency, demonstrating that cocaine self-administration leaves the dopamine transporter in a “primed” state, which allows for cocaine-induced plasticity to be reinstated by a subthreshold cocaine exposure. Further, reinstatement of cocaine tolerance was accompanied by decreased cocaine-induced locomotion and escalated cocaine intake despite extended abstinence from cocaine. These data demonstrate that cocaine leaves a long-lasting imprint on the dopamine system that is activated by re-exposure to cocaine. Further, these results provide a potential mechanism for severe cocaine binge episodes, which occur even after sustained abstinence from cocaine, and suggest that treatments aimed at transporter sites may be efficacious in promoting binge termination following relapse. SIGNIFICANCE STATEMENT Tolerance is a DSM-V criterion for substance abuse disorders. Abusers consistently show reduced subjective effects of cocaine concomitant with reduced effects of cocaine at its main site of action

Does human presynaptic striatal dopamine function predict social conformity?

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Stokes, Paul R A; Benecke, Aaf; Puraite, Julita; Bloomfield, Michael A P; Shotbolt, Paul; Reeves, Suzanne J; Lingford-Hughes, Anne R; Howes, Oliver; Egerton, Alice

2014-03-01

Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹⁸F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹⁸F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹⁸F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D₂/₃ receptor expression rather than with synaptic dopamine levels.

Reversible Dopamine Transporter Modifications in Response to Methylphenidate Treatment of ADHD

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J Gordon Millichap

2005-09-01

Full Text Available Single-photon emission computed tomography (SPECT was used to monitor the dopamine transporter activity in 5 males, ages 8 to 10, with ADHD, after cessation of methylphenidate (MPH treatment, in a study at the University Hospital Maastricht, The Netherlands.

Evaluating Dopamine Reward Pathway in ADHD; clinical implications

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Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Kollins, S.H., Wigal, t.L.; Newcorn, J.H.; Telang, F.; Fowler, J.S.; Zhu, W.; Logan, J.; Ma, Y.; Pradhan, K.; Wong, C.T.; Swanson, J.M.

2009-09-09

Attention-deficit/hyperactivity disorder (ADHD) - characterized by symptoms of inattention and hyperactivity-impulsivity - is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). We used positron emission tomography to measure dopamine synaptic markers (transporters and D{sub 2}/D{sub 3} receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory. We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [{sup 11}C]cocaine and for D{sub 2}/D{sub 3} receptors using [{sup 11}C]raclopride, quantified as binding potential (distribution volume ratio -1). For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P < .005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03-0.13, P = .004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03-0.12; P {le} .001); for D{sub 2}/D{sub 3} receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02-0.17, P = .01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D{sub 2}/D{sub 3} for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0

Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis.

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Glimcher, Paul W

2011-09-13

A number of recent advances have been achieved in the study of midbrain dopaminergic neurons. Understanding these advances and how they relate to one another requires a deep understanding of the computational models that serve as an explanatory framework and guide ongoing experimental inquiry. This intertwining of theory and experiment now suggests very clearly that the phasic activity of the midbrain dopamine neurons provides a global mechanism for synaptic modification. These synaptic modifications, in turn, provide the mechanistic underpinning for a specific class of reinforcement learning mechanisms that now seem to underlie much of human and animal behavior. This review describes both the critical empirical findings that are at the root of this conclusion and the fantastic theoretical advances from which this conclusion is drawn.

Pre-synaptic control of remote fear extinction in the neocortex

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Gisella eVetere

2012-06-01

Full Text Available Consolidation of remote memory enhances immediate early genes induction (IEGs, augments the expression of the presynaptic growth associated protein 43 (GAP-43, and increases the density and size of dendritic spines in anterior cingulate (aCC and infra-limbic (ILC cortices. Remote memory extinction, however, does not uniformly alter consolidation-induced structural changes. In the aCC, the density, but not the size, of spines is reset to pseudo-conditioning levels while novel thin spines are formed in the ILC. Whether IEGs and GAP-43 also undergo region-specific changes upon remote memory extinction is undetermined. Here we confirm in the same batch of mice that c-Fos induction and GAP-43 expression are increased in both the aCC and the ILC 36 days after contextual fear conditioning. We then show that, in both regions, remote memory extinction is associated with decrease of c-Fos induction but no change in GAP-43 expression thus revealing similar, although protein-specific, pre-synaptic adaptations in aCC and ILC neurons. These observations, in addition to our previous report of region-specific post-synaptic structural changes, disclose a complex pattern of extinction-driven neocortical alterations suitable to support erasure or reinstatement of fear according to the environment demand.

Pre- and post-synaptic sympathetic function in human hibernating myocardium

International Nuclear Information System (INIS)

John, Anna S.; Pepper, John R.; Dreyfus, Gilles D.; Pennell, Dudley J.; Mongillo, Marco; Khan, Muhammad T.; Depre, Christophe; Rimoldi, Ornella E.; Camici, Paolo G.

2007-01-01

Impaired pre-synaptic noradrenaline uptake-1 mechanism has been reported in a swine model of hibernating myocardium (HM). To ascertain whether adrenergic neuroeffector abnormalities are present in human HM, we combined functional measurements in vivo using cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) to assess pre- and post-synaptic sympathetic function. Twelve patients with coronary artery disease and chronic left ventricular (LV) dysfunction underwent CMR at baseline and 6 months after bypass for assessment of regional and global LV function and identification of segments with reversible dysfunction. Before surgery, myocardial noradrenaline uptake-1 ([ 11 C]meta-hydroxy-ephedrine; HED) and β-adrenoceptor (β-AR) density ([ 11 C]CGP-12177) were measured with PET. Patient PET data were compared with those in 18 healthy controls. The volume of distribution (V d ) of HED in HM (47.95±28.05 ml/g) and infarcted myocardium (42.69±25.76 ml/g) was significantly reduced compared with controls (66.09±14.48 ml/g). The V d of HED in normal myocardium (49.93±20.48 ml/g) of patients was also lower than that in controls and the difference was close to statistical significance (p=0.06). Myocardial β-AR density was significantly lower in HM (5.49±2.35 pmol/g), infarcted (4.82±2.61 pmol/g) and normal (5.86±1.81 pmol/g) segments of patients compared with healthy controls (8.61±1.32 pmol/g). Noradrenaline uptake-1 mechanism and β-AR density are reduced in the myocardium of patients with chronic LV dysfunction and evidence of HM. The increased sympathetic activity to the heart in these patients is a generalised rather than regional phenomenon which is likely to contribute to the remodelling process of the whole LV rather than playing a causative role in HM. (orig.)

Pre- and post-synaptic sympathetic function in human hibernating myocardium

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John, Anna S.; Pepper, John R.; Dreyfus, Gilles D.; Pennell, Dudley J. [Imperial College, Hammersmith Hospital, National Heart and Lung Institute, London (United Kingdom); Mongillo, Marco; Khan, Muhammad T. [Imperial College, Hammersmith Hospital, Medical Research Council Clinical Sciences Centre, London (United Kingdom); Depre, Christophe [University of Medicine and Dentistry New Jersey, Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, New Jersey, NJ (United States); University of Medicine and Dentistry New Jersey, Cardiovascular Research Institute, Department of Medicine, New Jersey, NJ (United States); Rimoldi, Ornella E. [Imperial College, Hammersmith Hospital, National Heart and Lung Institute, London (United Kingdom); Imperial College, Hammersmith Hospital, Medical Research Council Clinical Sciences Centre, London (United Kingdom); New York Medical College, Cardiovascular Research Institute, Department of Medicine, Valhalla, NY (United States); Camici, Paolo G. [Imperial College, Hammersmith Hospital, National Heart and Lung Institute, London (United Kingdom); Imperial College, Hammersmith Hospital, Medical Research Council Clinical Sciences Centre, London (United Kingdom)

2007-12-15

Impaired pre-synaptic noradrenaline uptake-1 mechanism has been reported in a swine model of hibernating myocardium (HM). To ascertain whether adrenergic neuroeffector abnormalities are present in human HM, we combined functional measurements in vivo using cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) to assess pre- and post-synaptic sympathetic function. Twelve patients with coronary artery disease and chronic left ventricular (LV) dysfunction underwent CMR at baseline and 6 months after bypass for assessment of regional and global LV function and identification of segments with reversible dysfunction. Before surgery, myocardial noradrenaline uptake-1 ([{sup 11}C]meta-hydroxy-ephedrine; HED) and {beta}-adrenoceptor ({beta}-AR) density ([{sup 11}C]CGP-12177) were measured with PET. Patient PET data were compared with those in 18 healthy controls. The volume of distribution (V{sub d}) of HED in HM (47.95{+-}28.05 ml/g) and infarcted myocardium (42.69{+-}25.76 ml/g) was significantly reduced compared with controls (66.09{+-}14.48 ml/g). The V{sub d} of HED in normal myocardium (49.93{+-}20.48 ml/g) of patients was also lower than that in controls and the difference was close to statistical significance (p=0.06). Myocardial {beta}-AR density was significantly lower in HM (5.49{+-}2.35 pmol/g), infarcted (4.82{+-}2.61 pmol/g) and normal (5.86{+-}1.81 pmol/g) segments of patients compared with healthy controls (8.61{+-}1.32 pmol/g). Noradrenaline uptake-1 mechanism and {beta}-AR density are reduced in the myocardium of patients with chronic LV dysfunction and evidence of HM. The increased sympathetic activity to the heart in these patients is a generalised rather than regional phenomenon which is likely to contribute to the remodelling process of the whole LV rather than playing a causative role in HM. (orig.)

Raman Spectroscopic Signature Markers of Dopamine-Human Dopamine Transporter Interaction in Living Cells.

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Silwal, Achut P; Yadav, Rajeev; Sprague, Jon E; Lu, H Peter

2017-07-19

Dopamine (DA) controls many psychological and behavioral activities in the central nervous system (CNS) through interactions with the human dopamine transporter (hDAT) and dopamine receptors. The roles of DA in the function of the CNS are affected by the targeted binding of drugs to hDAT; thus, hDAT plays a critical role in neurophysiology and neuropathophysiology. An effective experimental method is necessary to study the DA-hDAT interaction and effects of variety of drugs like psychostimulants and antidepressants that are dependent on this interaction. In searching for obtaining and identifying the Raman spectral signatures, we have used surface enhanced Raman scattering (SERS) spectroscopy to record SERS spectra from DA, human embryonic kidney 293 cells (HEK293), hDAT-HEK293, DA-HEK293, and DA-hDAT-HEK293. We have demonstrated a specific 2D-distribution SERS spectral analytical approach to analyze DA-hDAT interaction. Our study shows that the Raman modes at 807, 839, 1076, 1090, 1538, and 1665 cm -1 are related to DA-hDAT interaction, where Raman shifts at 807 and 1076 cm -1 are the signature markers for the bound state of DA to probe DA-hDAT interaction. On the basis of density function theory (DFT) calculation, Raman shift of the bound state of DA at 807 cm -1 is related to combination of bending modes α(C3-O10-H21), α(C2-O11-H22), α(C7-C8-H18), α(C6-C4-H13), α(C7-C8-H19), and α(C7-C8-N9), and Raman shift at 1076 cm -1 is related to combination of bending modes α(H19-N9-C8), γ(N9-H19), γ(C8-H19), γ(N9-H20), γ(C8-H18), and α(C7-C8-H18). These findings demonstrate that protein-ligand interactions can be confirmed by probing change in Raman shift of ligand molecules, which could be crucial to understanding molecular interactions between neurotransmitters and their receptors or transporters.

BDNF-induced local protein synthesis and synaptic plasticity.

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Leal, Graciano; Comprido, Diogo; Duarte, Carlos B

2014-01-01

Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and long-term potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-γ (PLC-γ) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre- and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short- and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dopamine transporter polymorphism modulates oculomotor function and DAT1 mRNA expression in schizophrenia.

Science.gov (United States)

Wonodi, Ikwunga; Hong, L Elliot; Stine, O Colin; Mitchell, Braxton D; Elliott, Amie; Roberts, Rosalinda C; Conley, Robert R; McMahon, Robert P; Thaker, Gunvant K

2009-03-05

Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMT gene) and SPEM. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized that DAT1 10/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects of DAT1 genotype on: Clinical diagnosis in the study sample (n = 418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n = 200; 87 schizophrenia), and DAT1 gene expression in FEF tissue obtained from postmortem brain samples (n = 32; 16 schizophrenia). DAT1 genotype was not associated with schizophrenia. DAT1 10/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first-degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study, DAT1 10/10 genotype was associated with significantly reduced DAT1 mRNA transcript in FEF tissue from healthy control donors (P < 0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulate DAT1 gene function. 2008 Wiley-Liss, Inc.

Quantitative autoradiography of ligands for dopamine receptors and transporters in brain of Göttingen minipig

DEFF Research Database (Denmark)

Minuzzi, Luciano; Olsen, Aage Kristian; Bender, Dirk

2006-01-01

The pig has been used as animal model for positron emission tomography (PET) studies of dopamine (DA) receptors and pharmacological perturbations of DA neurotransmission. However, the binding properties of DA receptors and transporters in pig brain have not been characterized in vitro. Therefore...... in young and old pigs, and were close to those reported for rat and human brain. Furthermore, gradients in the concentrations of D1 and D2/3 sites in striatum measured in vitro agreed with earlier findings in PET studies. However, the dopamine transporter (DAT) ligand [3H]GBR12935 did not bind in pig brain...

R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity.

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Bharanidharan Shanmugasundaram

Full Text Available 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. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes.

Dopamine transporter density in the basal ganglia assessed with {sup 123}I-IPT SPECT in children with Tourette's deosoder

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Yoo, Y. H.; Cheon, K. A.; Yoon, M. J.; Kim, C. H.; Lee, J. D. [Yonsei University College of Medicine, Seoul (Korea, Republic of); Kim, H. H.; Choi, T. H. [Gachon Medical School, Incheon (Korea, Republic of)

2002-07-01

Previous studies in patients with Tourette's disorder (TD) provided evidences of presynaptic dopaminergic dysfunction, demonstrating increased dopamine transporter densities. We investigated dopamine transporter densities using {sup 123}I-IPT SPECT in drug-naive children with TD and postulated that dopamine transporter density reflected dopamine concentrations. 9 drug-naive children with ADHD and 8 normal children were included in the study. We performed brain SPECT 2 hours after administration of {sup 123}I-IPT and made both quantitative and qualitative analyses for assessment of specific/nonspecific DAT binding ratio in the BG. We then investigated correlation between the severity of tics in children with TD assessed with the YGTSS and specific/nonspecific binding ratio on BG. Drug-naive children with TD showed a significantly increased specific/nonspecific DAT binding ratio in the BG compared with normal children. We found no significant correlation between severity of tics assessed with YGTSS in children with TD and specific/nonspecific DAT binding ratio in BG. These findings support the hypothesis of dopamine dysregulation in presynaptic dopamine function of BG being involved in pathophysiology of TD.

Equipment-independent reference values for dopamine transporter imaging with 123I-FP-CIT

International Nuclear Information System (INIS)

Koch, W.; Hornung, J.; Poepperl, G.; Tatsch, K.; Hamann, C.

2007-01-01

Aim: Reliable reference values are helpful to interpret and compare the results of dopamine transporter imaging with SPECT. Since semi-quantitative reference values cannot be easily transferred between imaging equipments, this study aimed to establish equipment independent normal values for the true striatal binding of 123 I-FP-CIT. Patients, methods: Specific striatal FP-CIT binding of 6 healthy volunteers and 26 patients with essential tremor were used to generate a reference range by applying an equipment specific resolution dependent factor to compensate for recovery effects. This factor has been determined previously by a series of standardized phantom measurements of an anthropomorphic basal ganglia phantom. Herewith, the resulting DAT binding values represent the expected true specific binding in the striatum. Results: On average, true specific striatal binding was 5.83 ± 0.96 in healthy controls, 5.25 ± 0.67 in patients with essential tremor and 5.36 ± 0.75 in the entire study cohort. Conclusion: These preliminary results may serve as a basis for the generation of a generally accepted equipment independent reference range for dopamine transporter imaging with 123 I-FP-CIT. By a simple phantom measurement that can be accomplished within one day factors related to specific imaging equipment and processing can be corrected for, resulting in specific binding values which may enable a more standardized interpretation of dopamine transporter scans. (orig.)

A receptor-based model for dopamine-induced fMRI signal

Science.gov (United States)

Mandeville, Joseph. B.; Sander, Christin Y. M.; Jenkins, Bruce G.; Hooker, Jacob M.; Catana, Ciprian; Vanduffel, Wim; Alpert, Nathaniel M.; Rosen, Bruce R.; Normandin, Marc D.

2013-01-01

This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine’s effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET 11C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations. PMID:23466936

Altered effect of dopamine transporter 3'UTR VNTR genotype on prefrontal and striatal function in schizophrenia.

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Prata, Diana P; Mechelli, Andrea; Picchioni, Marco M; Fu, Cynthia H Y; Toulopoulou, Timothea; Bramon, Elvira; Walshe, Muriel; Murray, Robin M; Collier, David A; McGuire, Philip

2009-11-01

The dopamine transporter plays a key role in the regulation of central dopaminergic transmission, which modulates cognitive processing. Disrupted dopamine function and impaired executive processing are robust features of schizophrenia. To examine the effect of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3' untranslated region) on brain function during executive processing in healthy volunteers and patients with schizophrenia. We hypothesized that this variation would have a different effect on prefrontal and striatal activation in schizophrenia, reflecting altered dopamine function. Case-control study. Psychiatric research center. Eighty-five subjects, comprising 44 healthy volunteers (18 who were 9-repeat carriers and 26 who were 10-repeat homozygotes) and 41 patients with DSM-IV schizophrenia (18 who were 9-repeat carriers and 23 who were 10-repeat homozygotes). Regional brain activation during word generation relative to repetition in an overt verbal fluency task measured by functional magnetic resonance imaging. Main effects of genotype and diagnosis on activation and their interaction were estimated with analysis of variance in SPM5. Irrespective of diagnosis, the 10-repeat allele was associated with greater activation than the 9-repeat allele in the left anterior insula and right caudate nucleus. Trends for the same effect in the right insula and for greater deactivation in the rostral anterior cingulate cortex were also detected. There were diagnosis x genotype interactions in the left middle frontal gyrus and left nucleus accumbens, where the 9-repeat allele was associated with greater activation than the 10-repeat allele in patients but not controls. Insular, cingulate, and striatal function during an executive task is normally modulated by variation in the dopamine transporter gene. Its effect on activation in the dorsolateral prefrontal cortex and ventral striatum is altered in patients with schizophrenia

Acute administration of haloperidol does not influence 123I-FP-CIT binding to the dopamine transporter

NARCIS (Netherlands)

Booij, Jan; van Loon, Guus; de Bruin, Kora; Voorn, Pieter

2014-01-01

A recent (123)I-FP-CIT ((123)-I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) SPECT study on rats suggested that a single 1 mg/kg dose of the antipsychotic haloperidol induces enough dopamine release to compete with (123)I-FP-CIT for binding to the dopamine transporter. Taking into

Involvement of dopamine D2 receptors in addictive-like behaviour for acetaldehyde.

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Brancato, Anna; Plescia, Fulvio; Marino, Rosa Anna Maria; Maniaci, Giuseppe; Navarra, Michele; Cannizzaro, Carla

2014-01-01

Acetaldehyde, the first metabolite of ethanol, is active in the central nervous system, where it exerts motivational properties. Acetaldehyde is able to induce drinking behaviour in operant-conflict paradigms that resemble the core features of the addictive phenotype: drug-intake acquisition and maintenance, drug-seeking, relapse and drug use despite negative consequences. Since acetaldehyde directly stimulates dopamine neuronal firing in the mesolimbic system, the aim of this study was the investigation of dopamine D2-receptors' role in the onset of the operant drinking behaviour for acetaldehyde in different functional stages, by the administration of two different D2-receptor agonists, quinpirole and ropinirole. Our results show that acetaldehyde was able to induce and maintain a drug-taking behaviour, displaying an escalation during training, and a reinstatement behaviour after 1-week forced abstinence. Acetaldehyde operant drinking behaviour involved D2-receptor signalling: in particular, quinpirole administration at 0.03 mg/kg, induced a significant decrease in the number of lever presses both in extinction and in relapse. Ropinirole, administered at 0.03 mg/kg during extinction, did not produce any modification but, when administered during abstinence, induced a strong decrease in acetaldehyde intake in the following relapse session. Taken together, our data suggest that acetaldehyde exerts its own motivational properties, involving the dopaminergic transmission: indeed, activation of pre-synaptic D2-receptors by quinpirole, during extinction and relapse, negatively affects operant behaviour for acetaldehyde, likely decreasing acetaldehyde-induced dopamine release. The activation of post-synaptic D2-receptors by ropinirole, during abstinence, decreases the motivation to the consecutive reinstatement of acetaldehyde drinking behaviour, likely counteracting the reduction in the dopaminergic tone typical of withdrawal. These data further strengthen the evidence

Involvement of dopamine D2 receptors in addictive-like behaviour for acetaldehyde.

Directory of Open Access Journals (Sweden)

Anna Brancato

Full Text Available Acetaldehyde, the first metabolite of ethanol, is active in the central nervous system, where it exerts motivational properties. Acetaldehyde is able to induce drinking behaviour in operant-conflict paradigms that resemble the core features of the addictive phenotype: drug-intake acquisition and maintenance, drug-seeking, relapse and drug use despite negative consequences. Since acetaldehyde directly stimulates dopamine neuronal firing in the mesolimbic system, the aim of this study was the investigation of dopamine D2-receptors' role in the onset of the operant drinking behaviour for acetaldehyde in different functional stages, by the administration of two different D2-receptor agonists, quinpirole and ropinirole. Our results show that acetaldehyde was able to induce and maintain a drug-taking behaviour, displaying an escalation during training, and a reinstatement behaviour after 1-week forced abstinence. Acetaldehyde operant drinking behaviour involved D2-receptor signalling: in particular, quinpirole administration at 0.03 mg/kg, induced a significant decrease in the number of lever presses both in extinction and in relapse. Ropinirole, administered at 0.03 mg/kg during extinction, did not produce any modification but, when administered during abstinence, induced a strong decrease in acetaldehyde intake in the following relapse session. Taken together, our data suggest that acetaldehyde exerts its own motivational properties, involving the dopaminergic transmission: indeed, activation of pre-synaptic D2-receptors by quinpirole, during extinction and relapse, negatively affects operant behaviour for acetaldehyde, likely decreasing acetaldehyde-induced dopamine release. The activation of post-synaptic D2-receptors by ropinirole, during abstinence, decreases the motivation to the consecutive reinstatement of acetaldehyde drinking behaviour, likely counteracting the reduction in the dopaminergic tone typical of withdrawal. These data further

Insertion of tetracysteine motifs into dopamine transporter extracellular domains.

Directory of Open Access Journals (Sweden)

Deanna M Navaroli

Full Text Available The neuronal dopamine transporter (DAT is a major determinant of extracellular dopamine (DA levels and is the primary target for a variety of addictive and therapeutic psychoactive drugs. DAT is acutely regulated by protein kinase C (PKC activation and amphetamine exposure, both of which modulate DAT surface expression by endocytic trafficking. In order to use live imaging approaches to study DAT endocytosis, methods are needed to exclusively label the DAT surface pool. The use of membrane impermeant, sulfonated biarsenic dyes holds potential as one such approach, and requires introduction of an extracellular tetracysteine motif (tetraCys; CCPGCC to facilitate dye binding. In the current study, we took advantage of intrinsic proline-glycine (Pro-Gly dipeptides encoded in predicted DAT extracellular domains to introduce tetraCys motifs into DAT extracellular loops 2, 3, and 4. [(3H]DA uptake studies, surface biotinylation and fluorescence microscopy in PC12 cells indicate that tetraCys insertion into the DAT second extracellular loop results in a functional transporter that maintains PKC-mediated downregulation. Introduction of tetraCys into extracellular loops 3 and 4 yielded DATs with severely compromised function that failed to mature and traffic to the cell surface. This is the first demonstration of successful introduction of a tetracysteine motif into a DAT extracellular domain, and may hold promise for use of biarsenic dyes in live DAT imaging studies.

Learning and retrieval behavior in recurrent neural networks with pre-synaptic dependent homeostatic plasticity

Science.gov (United States)

Mizusaki, Beatriz E. P.; Agnes, Everton J.; Erichsen, Rubem; Brunnet, Leonardo G.

2017-08-01

The plastic character of brain synapses is considered to be one of the foundations for the formation of memories. There are numerous kinds of such phenomenon currently described in the literature, but their role in the development of information pathways in neural networks with recurrent architectures is still not completely clear. In this paper we study the role of an activity-based process, called pre-synaptic dependent homeostatic scaling, in the organization of networks that yield precise-timed spiking patterns. It encodes spatio-temporal information in the synaptic weights as it associates a learned input with a specific response. We introduce a correlation measure to evaluate the precision of the spiking patterns and explore the effects of different inhibitory interactions and learning parameters. We find that large learning periods are important in order to improve the network learning capacity and discuss this ability in the presence of distinct inhibitory currents.

Brain dopamine-serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder.

Science.gov (United States)

Jacobsen, Jessie C; Wilson, Callum; Cunningham, Vicki; Glamuzina, Emma; Prosser, Debra O; Love, Donald R; Burgess, Trent; Taylor, Juliet; Swan, Brendan; Hill, Rosamund; Robertson, Stephen P; Snell, Russell G; Lehnert, Klaus

2016-03-01

Two male siblings from a consanguineous union presented in early infancy with marked truncal hypotonia, a general paucity of movement, extrapyramidal signs and cognitive delay. By mid-childhood they had made little developmental progress and remained severely hypotonic and bradykinetic. They developed epilepsy and had problems with autonomic dysfunction and oculogyric crises. They had a number of orthopaedic problems secondary to their hypotonia. Cerebrospinal fluid (CSF) neurotransmitters were initially normal, apart from mildly elevated 5-hydroxyindolacetic acid, and the children did not respond favourably to a trial of levodopa-carbidopa. The youngest died from respiratory complications at 10 years of age. Repeat CSF neurotransmitters in the older sibling at eight years of age showed slightly low homovanillic acid and 5-hydroxyindoleacetic acid levels. Whole-exome sequencing revealed a novel mutation homozygous in both children in the monoamine transporter gene SLC18A2 (p.Pro237His), resulting in brain dopamine-serotonin vesicular transport disease. This is the second family to be described with a mutation in this gene. Treatment with the dopamine agonist pramipexole in the surviving child resulted in mild improvements in alertness, communication, and eye movements. This case supports the identification of the causal mutation in the original case, expands the clinical phenotype of brain dopamine-serotonin vesicular transport disease and confirms that pramipexole treatment may lead to symptomatic improvement in affected individuals.

Isolation of Synaptosomes, Synaptic Plasma Membranes, and Synaptic Junctional Complexes.

Science.gov (United States)

Michaelis, Mary L; Jiang, Lei; Michaelis, Elias K

2017-01-01

Isolation of synaptic nerve terminals or synaptosomes provides an opportunity to study the process of neurotransmission at many levels and with a variety of approaches. For example, structural features of the synaptic terminals and the organelles within them, such as synaptic vesicles and mitochondria, have been elucidated with electron microscopy. The postsynaptic membranes are joined to the presynaptic "active zone" of transmitter release through cell adhesion molecules and remain attached throughout the isolation of synaptosomes. These "post synaptic densities" or "PSDs" contain the receptors for the transmitters released from the nerve terminals and can easily be seen with electron microscopy. Biochemical and cell biological studies with synaptosomes have revealed which proteins and lipids are most actively involved in synaptic release of neurotransmitters. The functional properties of the nerve terminals, such as responses to depolarization and the uptake or release of signaling molecules, have also been characterized through the use of fluorescent dyes, tagged transmitters, and transporter substrates. In addition, isolated synaptosomes can serve as the starting material for the isolation of relatively pure synaptic plasma membranes (SPMs) that are devoid of organelles from the internal environment of the nerve terminal, such as mitochondria and synaptic vesicles. The isolated SPMs can reseal and form vesicular structures in which transport of ions such as sodium and calcium, as well as solutes such as neurotransmitters can be studied. The PSDs also remain associated with the presynaptic membranes during isolation of SPM fractions, making it possible to isolate the synaptic junctional complexes (SJCs) devoid of the rest of the plasma membranes of the nerve terminals and postsynaptic membrane components. Isolated SJCs can be used to identify the proteins that constitute this highly specialized region of neurons. In this chapter, we describe the steps involved

Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

Directory of Open Access Journals (Sweden)

Aile evan Huijstee

2015-01-01

Full Text Available Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behaviour, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA. This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc and the prefrontal cortex (PFC, with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioural symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drug-associated cues. Remodelling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction.

Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

Science.gov (United States)

van Huijstee, Aile N.; Mansvelder, Huibert D.

2015-01-01

Addictive drugs remodel the brain’s reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behavior, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA). This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC), with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioral symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drug-associated cues. Remodeling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction. PMID:25653591

Dopamine transporter down-regulation following repeated cocaine: implications for 3,4-methylenedioxymethamphetamine-induced acute effects and long-term neurotoxicity in mice.

Science.gov (United States)

Peraile, I; Torres, E; Mayado, A; Izco, M; Lopez-Jimenez, A; Lopez-Moreno, J A; Colado, M I; O'Shea, E

2010-01-01

3,4-Methylenedioxymethamphetamine (MDMA) and cocaine are two widely abused psychostimulant drugs targeting the dopamine transporter (DAT). DAT availability regulates dopamine neurotransmission and uptake of MDMA-derived neurotoxic metabolites. We aimed to determine the effect of cocaine pre-exposure on the acute and long-term effects of MDMA in mice. Mice received a course of cocaine (20 mg*kg(-1), x2 for 3 days) followed by MDMA (20 mg*kg(-1), x2, 3 h apart). Locomotor activity, extracellular dopamine levels and dopaminergic neurotoxicity were determined. Furthermore, following the course of cocaine, DAT density in striatal plasma membrane and endosome fractions was measured. Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline. Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA.

Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes.

Science.gov (United States)

Jean, Bernandie; Surratt, Christopher K; Madura, Jeffry D

2017-09-01

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. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design. Copyright © 2017 Elsevier Inc. All rights reserved.

Dopamine Signaling in reward-related behaviors

OpenAIRE

Baik, Ja-Hyun

2013-01-01

Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specifi...

Atypical dopamine efflux caused by 3,4-methylenedioxypyrovalerone (MDPV) via the human dopamine transporter.

Science.gov (United States)

Shekar, Aparna; Aguilar, Jenny I; Galli, Greta; Cozzi, Nicholas V; Brandt, Simon D; Ruoho, Arnold E; Baumann, Michael H; Matthies, Heinrich J G; Galli, Aurelio

2017-10-01

Synthetic cathinones are similar in chemical structure to amphetamines, and their behavioral effects are associated with enhanced dopaminergic signaling. The past ten years of research on the common constituent of bath salts, MDPV (the synthetic cathinone 3,4-methylenedioxypyrovalerone), has aided the understanding of how synthetic cathinones act at the dopamine (DA) transporter (DAT). Several groups have described the ability of MDPV to block the DAT with high-affinity. In this study, we demonstrate for the first time a new mode of action of MDPV, namely its ability to promote DAT-mediated DA efflux. Using single cell amperometric assays, we determined that low concentrations of MDPV (1nM) can cause reverse transport of DA via DAT. Notably, administration of MDPV leads to hyperlocomotion in Drosophila melanogaster. These data describe further how MDPV acts at the DAT, possibly paving the way for novel treatment strategies for individuals who abuse bath salts. Copyright © 2017 Elsevier B.V. All rights reserved.

Electrical coupling and excitatory synaptic transmission between rhythmogenic respiratory neurons in the preBötzinger complex

DEFF Research Database (Denmark)

Rekling, J C; Shao, X M; Feldman, J L

2000-01-01

Breathing pattern is postulated to be generated by brainstem neurons. However, determination of the underlying cellular mechanisms, and in particular the synaptic interactions between respiratory neurons, has been difficult. Here we used dual recordings from two distinct populations of brainstem...... respiratory neurons, hypoglossal (XII) motoneurons, and rhythmogenic (type-1) neurons in the preBötzinger complex (preBötC), the hypothesized site for respiratory rhythm generation, to determine whether electrical and chemical transmission is present. Using an in vitro brainstem slice preparation from newborn...... mice, we found that intracellularly recorded pairs of XII motoneurons and pairs of preBötC inspiratory type-1 neurons showed bidirectional electrical coupling. Coupling strength was low (neurons was heavily filtered (corner frequency,

Dopamine transporter density of the basal ganglia assessed with I-123 IPT SPECT in methamphetamine abusers

International Nuclear Information System (INIS)

Lee, Joo Ryung; Ahn, Byeong Cheol; Kewm, Do Hun

2005-01-01

Functional imaging of dopamine transporter (DAT) defines integrity of the dopaminergic system, and DAT is the target site of drugs of abuse such as cocaine and methamphetamine. Functional imaging the DAT may be a sensitive and selective indicator of neurotoxic change by the drug. The aim of the present study is to evaluate the clinical implications of qualitative/quantitative analyses of dopamine transporter imaging in methamphetamine abusers. Six detoxified methamphetamine abusers (abuser group) and 4 volunteers (control group) were enrolled in this study. Brain MRI was performed in all of abuser group. Abuser group underwent psychiatric and depression assessment using brief psychiatric rating scale (BPRS) and Hamilton depression rating scale (HAMD), respectively. All of the subjects underwent I-123 IPT SPECT (IPT SPECT). IPT SPECT image was analysed with visual qualitative method and quantitative method using basal ganglia dopamine transporter (DAT) specific/non-specific binding ratio (SBR). Comparison of DAT SBR between abuser and control groups was performed. We also performed correlation tests between psychiatric and depression assessment results and DAT SBR in abuser group. All of abuser group showed normal MRI finding, but had residual psychiatric and depressive symptoms, and psychiatric and depressive symptom scores were exactly correlated (r=1.0, ρ =0.005) each other. Five of them showed abnormal finding on qualitative visual I-123 IPT SPECT. Abuser group had lower basal ganglia DAT SBR than that of control (2.38 ± 0.20 vs 3.04 ± 0.27, ρ =0.000). Psychiatric and depressive symptoms were negatively well correlated with basal ganglia DAT SBR (r=-0.908, ρ =0.012, r=-0.924, ρ =0.009) This results suggest that dopamine transporter imaging using I-123 IPT SPECT may be used to evaluate dopaminergic system of the basal ganglia and the clinical status in methamphetamine abusers

Dopamine transporter density of the basal ganglia assessed with I-123 IPT SPECT in methamphetamine abusers

Energy Technology Data Exchange (ETDEWEB)

Lee, Joo Ryung; Ahn, Byeong Cheol [Kyungpook National University Medical School, Daegu (Korea, Republic of); Kewm, Do Hun [National Bugok Mental Hospital, Changryung (Korea, Republic of)] (and others)

2005-10-15

Functional imaging of dopamine transporter (DAT) defines integrity of the dopaminergic system, and DAT is the target site of drugs of abuse such as cocaine and methamphetamine. Functional imaging the DAT may be a sensitive and selective indicator of neurotoxic change by the drug. The aim of the present study is to evaluate the clinical implications of qualitative/quantitative analyses of dopamine transporter imaging in methamphetamine abusers. Six detoxified methamphetamine abusers (abuser group) and 4 volunteers (control group) were enrolled in this study. Brain MRI was performed in all of abuser group. Abuser group underwent psychiatric and depression assessment using brief psychiatric rating scale (BPRS) and Hamilton depression rating scale (HAMD), respectively. All of the subjects underwent I-123 IPT SPECT (IPT SPECT). IPT SPECT image was analysed with visual qualitative method and quantitative method using basal ganglia dopamine transporter (DAT) specific/non-specific binding ratio (SBR). Comparison of DAT SBR between abuser and control groups was performed. We also performed correlation tests between psychiatric and depression assessment results and DAT SBR in abuser group. All of abuser group showed normal MRI finding, but had residual psychiatric and depressive symptoms, and psychiatric and depressive symptom scores were exactly correlated (r=1.0, {rho} =0.005) each other. Five of them showed abnormal finding on qualitative visual I-123 IPT SPECT. Abuser group had lower basal ganglia DAT SBR than that of control (2.38 {+-} 0.20 vs 3.04 {+-} 0.27, {rho} =0.000). Psychiatric and depressive symptoms were negatively well correlated with basal ganglia DAT SBR (r=-0.908, {rho} =0.012, r=-0.924, {rho} =0.009) This results suggest that dopamine transporter imaging using I-123 IPT SPECT may be used to evaluate dopaminergic system of the basal ganglia and the clinical status in methamphetamine abusers.

Measuring dopamine release in the human brain with PET

Energy Technology Data Exchange (ETDEWEB)

Volkow, N.D. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York at Stony Brook, Stony Brook, NY (United States). Dept. of Psychiatry; Fowler, J.S.; Logan, J.; Wang, G.J. [Brookhaven National Lab., Upton, NY (United States)

1995-12-01

The dopamine system is involved in the regulation of brain regions that subserve motor, cognitive and motivational behaviors. Disruptions of dopamine (DA) function have ben implicated in neurological and psychiatric illnesses including substance abuse as well as on some of the deficits associated with aging of the human brain. This has made the DA system an important topic in research in the neurosciences and neuroimaging as well as an important molecular target for drug development. Positron Emission Tomography (PET), was the first technology that enabled direct measurement of components of the DA system in the living human brain. Imaging studies of DA in the living brain have been indirect, relying on the development of radiotracers to label DA receptors, DA transporters, compounds which have specificity for the enzymes which degrade synaptic DA. Additionally, through the use of tracers that provide information on regional brain activity (ie brain glucose metabolism and cerebral blood flow) and of appropriate pharmacological interventions, it has been possible to assess the functional consequences of changes in brain DA activity. DA specific ligands have been useful in the evaluation of patients with neuropsychiatric illnesses as well as to investigate receptor blockade by antipsychotic drugs. A limitation of strategies that rely on the use of DA specific ligands is that the measures do not necessarily reflect the functional state of the dopaminergic system and that there use to study the effects of drugs is limited to the investigation of receptor or transporter occupancy. Newer strategies have been developed in an attempt to provide with information on dopamine release and on the functional responsivity of the DA system in the human brain. This in turn allows to investigate the effects of pharmacological agent in an analogous way to what is done with microdialysis techniques.

Structural plasticity in mesencephalic dopaminergic neurons produced by drugs of abuse: critical role of BDNF and dopamine.

Directory of Open Access Journals (Sweden)

Ginetta eCollo

2014-11-01

Full Text Available Mesencephalic dopaminergic neurons were suggested to be a critical physiopathology substrate for addiction disorders. Among neuroadaptive processes to addictive drugs, structural plasticity has attracted attention. While structural plasticity occurs at both pre- and post-synaptic levels in the mesolimbic dopaminergic system, the present review focuses only on dopaminergic neurons. Exposures to addictive drugs determine two opposite structural responses, hypothrophic plasticity produced by opioids and cannabinoids (in particular during the early withdrawal phase and hypertrophic plasticity, mostly driven by psychostimulants and nicotine. In vitro and in vivo studies indentified BDNF and extracellular dopamine as two critical factors in determining structural plasticity, the two molecules sharing similar intracellular pathways involved in cell soma and dendrite growth, the MEK-ERK1/2 and the PI3K-Akt-mTOR, via preferential activation of TrkB and dopamine D3 receptors, respectively. At present information regarding specific structural changes associated to the various stages of the addiction cycle is incomplete. Encouraging neuroimaging data in humans indirectly support the preclinical evidence of hypotrophic and hypertrophic effects, suggesting a possible differential engagement of dopamine neurons in parallel and partially converging circuits controlling motivation, stress and emotions.

Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses.

Science.gov (United States)

Doly, Stéphane; Quentin, Emily; Eddine, Raphaël; Tolu, Stefania; Fernandez, Sebastian P; Bertran-Gonzalez, Jesus; Valjent, Emmanuel; Belmer, Arnauld; Viñals, Xavier; Callebert, Jacques; Faure, Philippe; Meye, Frank J; Hervé, Denis; Robledo, Patricia; Mameli, Manuel; Launay, Jean-Marie; Maldonado, Rafael; Maroteaux, Luc

2017-10-25

Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT 2B receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT 2B receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT 2B receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT 2B receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT 2B receptors are expressed by mesolimbic dopamine neurons. In vivo and ex vivo electrophysiological recordings showed that 5-HT 2B -receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT 2B receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse. SIGNIFICANCE STATEMENT Here we report that mice lacking 5-HT 2B receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT 2B receptors in a subpopulation of

Dopamine transporter and vesicular monoamine transporter knockout mice : implications for Parkinson's disease.

Science.gov (United States)

Miller, G W; Wang, Y M; Gainetdinov, R R; Caron, M G

2001-01-01

One of the most valuable methods for understanding the function of a particular protein is the generation of animals that have had the gene encoding for the protein of interest disrupted, commonly known as a "quo;knockout"quo; or null mutant. By incorporating a sequence of DNA (typically encoding antibiotic resistance to aid in the selection of the mutant gene) into embryonic stem cells by homologous recombination, the normal transcription of the gene is effectively blocked (Fig. 1). Since a particular protein is encoded by two copies of a gene, it is necessary to have the gene on both alleles "quo;knocked out."quo; This is performed by cross-breeding animals with one affected allele (heterozygote) to generate offspring that have inherited two mutant alleles (homozygote). This procedure has been used to generate animals lacking either the plasma membrane dopamine transporter (DAT; Fig. 2) or the vesicular monoamine transporter (VMAT2; Fig. 3). Both DAT and VMAT2 are essential for dopamine homeostasis and are thought to participate in the pathogenesis of Parkinson's disease (1-5). Fig. 1. Maps of the targeting vector and the mock construct. The mouse genomic fragment (clone 11) was isolated from a Stratagene 129 SvJ library by standard colony hybridization using a PCR probe from the 5' end of rat cDNA. The restriction site abbreviations are as follows: H, HindIII; N, NotI; Sc, SacI; Sn, SnaI; X, XbaI; and Xh, XhoI. The region between HindIII and SnaI on clone 11 containing the coding sequence from transmembrane domains 3 and 4 of VMAT2 was deleted and replaced with PGK-neo. The 3' fragment of clone 11 was reserved as an external probe for Southern analysis. To facilitate PCR screening of embryonic stem cell clones, a mock construct containing the SnaI/XbaI fragment and part of the Neo cassette was generated as a positive control. pPNT and pGEM4Z were used to construct knockout and mock vectors, respectively. (Reproduced with permission from ref. 1). Fig. 2. DAT and

A Ca2+-based computational model for NDMA receptor-dependent synaptic plasticity at individual post-synaptic spines in the hippocampus

Directory of Open Access Journals (Sweden)

Owen Rackham

2010-07-01

Full Text Available Associative synaptic plasticity is synapse specific and requires coincident activity in presynaptic and postsynaptic neurons to activate NMDA receptors (NMDARs. The resultant Ca2+ influx is the critical trigger for the induction of synaptic plasticity. Given its centrality for the induction of synaptic plasticity, a model for NMDAR activation incorporating the timing of presynaptic glutamate release and postsynaptic depolarization by back-propagating action potentials could potentially predict the pre- and post-synaptic spike patterns required to induce synaptic plasticity. We have developed such a model by incorporating currently available data on the timecourse and amplitude of the postsynaptic membrane potential within individual spines. We couple this with data on the kinetics of synaptic NMDARs and then use the model to predict the continuous spine [Ca2+] in response to regular or irregular pre- and post-synaptic spike patterns. We then incorporate experimental data from synaptic plasticity induction protocols by regular activity patterns to couple the predicted local peak [Ca2+] to changes in synaptic strength. We find that our model accurately describes [Ca2+] in dendritic spines resulting from NMDAR activation during presynaptic and postsynaptic activity when compared to previous experimental observations. The model also replicates the experimentally determined plasticity outcome of regular and irregular spike patterns when applied to a single synapse. This model could therefore be used to predict the induction of synaptic plasticity under a variety of experimental conditions and spike patterns.

Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

Science.gov (United States)

Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF

2013-01-01

Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

FDG PET, Dopamine Transporter SPECT, and Olfaction: Combining Biomarkers in REM Sleep Behavior Disorder

NARCIS (Netherlands)

Meles, Sanne K.; Vadasz, David; Renken, Remco J.; Sittig-Wiegand, Elisabeth; Mayer, Geert; Depboylu, Candan; Reetz, Kathrin; Overeem, Sebastiaan; Pijpers, Angelique; Reesink, Fransje E.; van Laar, Teus; Heinen, Lisette; Teune, Laura K.; Höffken, Helmut; Luster, Marcus; Kesper, Karl; Adriaanse, Sofie M.; Booij, Jan; Leenders, Klaus L.; Oertel, Wolfgang H.

2017-01-01

Background: Idiopathic REM sleep behavior disorder is a prodromal stage of Parkinson's disease and dementia with Lewy bodies. Hyposmia, reduced dopamine transporter binding, and expression of the brain metabolic PD-related pattern were each associated with increased risk of conversion to PD. The

A new model for separation between brain dopamine and serotonin transporters in {sup 123}I-{beta}-CIT SPECT measurements: normal values and sex and age dependence

Energy Technology Data Exchange (ETDEWEB)

Ryding, Erik; Rosen, Ingmar [Department of Clinical Neurophysiology, University Hospital, Lund (Sweden); Lindstroem, Mats; Bosson, Peter; Traeskman-Bendz, Lil [Department of Psychiatry, University Hospital, Lund (Sweden); Braadvik, Bjoern; Grabowski, Martin [Department of Neurology, University Hospital, Lund (Sweden)

2004-08-01

{sup 123}I-{beta}-CIT is a radioactive ligand for single-photon emission computed tomography (SPECT) imaging of the pre-synaptic (transporter) re-uptake sites for dopamine (DAT) and serotonin (5HTT), and it is widely used to visualize monoamine turnover. Since {sup 123}I-{beta}-CIT uptake occurs at 5HTT and DAT sites in conjunction with the presence of freely soluble {sup 123}I-{beta}-CIT in brain tissue, adequate separation of these three components is necessary. However, only partial separation is possible with current methods. Two main strategies have previously been used for {sup 123}I-{beta}-CIT component separation, based on the following considerations: (1) the faster uptake rate for 5HTT compared with DAT enables temporal separation by performing 5HTT imaging at 1-2 h and DAT imaging at 20-24 h; (2) blocking the 5HTT re-uptake with citalopram renders {sup 123}I-{beta}-CIT imaging DAT (non-5HTT) specific. In a new analytical model, we combined these two approaches with methods to isolate the passively dissolved {sup 123}I-{beta}-CIT in brain tissue from the monoamine transporter uptake, and to correct the 5HTT and DAT values for concomitant uptake. The new analytical model was used to study brain 5HTT and DAT in 23 normal subjects, with the aim of clarifying the effect of age and sex. A significant correlation between 5HTT and DAT values was found only in the thalamus, indicating successful component separation. Negative correlations between age and DAT were found for basal ganglia, thalami, brain stem and temporal lobes, but not for the frontal, parietal or occipital regions. No correlation with age was found for 5HTT. We found no sex difference for 5HTT or DAT. (orig.)

Tyrosine hydroxylase immunoreactivity and [3H]WIN 35,428 binding to the dopamine transporter in a hamster model of idiopathic paroxysmal dystonia

International Nuclear Information System (INIS)

Nobrega, J.N.; Gernert, M.; Loescher, W.; Raymond, R.; Belej, T.; Richter, A.

1999-01-01

Recent pharmacological studies and receptor analyses have suggested that dopamine neurotransmission is enhanced in mutant dystonic hamsters (dt sz ), a model of idiopathic paroxysmal dystonia which displays attacks of generalized dystonia in response to mild stress. In order to further characterize the nature of dopamine alterations, the present study investigated possible changes in the number of dopaminergic neurons, as defined by tyrosine hydroxylase immunohistochemistry, as well as binding to the dopamine transporter labelled with [ 3 H]WIN 35,428 in dystonic hamsters. No differences in the number of tyrosine hydroxylase-immunoreactive neurons were found within the substantia nigra and ventral tegmental area of mutant hamsters compared to non-dystonic control hamsters. Similarly, under basal conditions, i.e. in the absence of a dystonic episode, no significant changes in [ 3 H]WIN 35,428 binding were detected in dystonic brains. However, in animals killed during the expression of severe dystonia, significant decreases in dopamine transporter binding became evident in the nucleus accumbens and ventral tegmental area in comparison to controls exposed to the same external stimulation. Since stimulation tended to increase [ 3 H]WIN 35,428 binding in control brains, the observed decrease in the ventral tegmental area appeared to be due primarily to the fact that binding was increased less in dystonic brains than in similarly stimulated control animals.This finding could reflect a diminished ability of the dopamine transporter to undergo adaptive changes in response to external stressful stimulation in mutant hamsters. The selective dopamine uptake inhibitor GBR 12909 (20 mg/kg) aggravated dystonia in mutant hamsters, further suggesting that acute alterations in dopamine transporter function during stimulation may be an important component of dystonia in this model. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

Ctr9, a Protein in the Transcription Complex Paf1, Regulates Dopamine Transporter Activity at the Plasma Membrane.

Science.gov (United States)

De Gois, Stéphanie; Slama, Patrick; Pietrancosta, Nicolas; Erdozain, Amaia M; Louis, Franck; Bouvrais-Veret, Caroline; Daviet, Laurent; Giros, Bruno

2015-07-17

Dopamine (DA) is a major regulator of sensorimotor and cognitive functions. The DA transporter (DAT) is the key protein that regulates the spatial and temporal activity of DA release into the synaptic cleft via the rapid reuptake of DA into presynaptic termini. Several lines of evidence have suggested that transporter-interacting proteins may play a role in DAT function and regulation. Here, we identified the tetratricopeptide repeat domain-containing protein Ctr9 as a novel DAT binding partner using a yeast two-hybrid system. We showed that Ctr9 is expressed in dopaminergic neurons and forms a stable complex with DAT in vivo via GST pulldown and co-immunoprecipitation assays. In mammalian cells co-expressing both proteins, Ctr9 partially colocalizes with DAT at the plasma membrane. This interaction between DAT and Ctr9 results in a dramatic enhancement of DAT-mediated DA uptake due to an increased number of DAT transporters at the plasma membrane. We determined that the binding of Ctr9 to DAT requires residues YKF in the first half of the DAT C terminus. In addition, we characterized Ctr9, providing new insight into this protein. Using three-dimensional modeling, we identified three novel tetratricopeptide repeat domains in the Ctr9 sequence, and based on deletion mutation experiments, we demonstrated the role of the SH2 domain of Ctr9 in nuclear localization. Our results demonstrate that Ctr9 localization is not restricted to the nucleus, as previously described for the transcription complex Paf1. Taken together, our data provide evidence that Ctr9 modulates DAT function by regulating its trafficking. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Predictive value of dopamine transporter SPECT imaging with [123I]PE2I in patients with subtle parkinsonian symptoms

International Nuclear Information System (INIS)

Ziebell, Morten; Thomsen, Gerda; Knudsen, Gitte M.; Andersen, Birgitte B.; Pinborg, Lars H.; Karlsborg, Merete; Hasselbalch, Steen G.

2012-01-01

To examine the diagnostic sensitivity and specificity of dopamine transporter SPECT imaging with a highly dopamine transporter selective radioligand. The study included consecutively enrolled, drug-naive patients with an average short history of parkinsonian motor symptoms, referred for diagnostic scanning. The study group comprised 288 patients naive to antiparkinson treatment who were enrolled as they were admitted for a diagnostic SPECT scan with the radioligand [ 123 I]-N-(3-iodoprop-2E-enyl)-2-β-carbomethoxy-3β-(4-methylphenyl)n ortropane ( 123 I-PE2I). After the diagnostic scanning, patients were followed clinically with an average follow-up of 19.7 ± 12.5 months. A diagnosis could be clinically settled in 189 patients and among these patients, a dopamine transporter scan had a sensitivity of 88% and a specificity of 91% for discrimination between patients with and without striatal neurodegeneration. In cognitively impaired patients (Mini Mental State Examination 2 differentiated between idiopathic Parkinson's disease and atypical parkinsonian syndromes with a specificity of 84% and a sensitivity of 63%. In drug-naive patients with subtle clinical parkinsonian motor symptoms, dopamine transporter scan using 123 I-PE21 has a high sensitivity and specificity in distinguishing between patients with and without striatal neurodegeneration. The specificity is lower in patients who are also cognitively impaired. Calculation of the striatal APR can assist in differentiating between idiopathic Parkinson's disease and atypical parkinsonian syndromes. (orig.)

Synaptic consolidation across multiple timescales

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Lorric Ziegler

2014-03-01

transition from e-LTP to l-LTP. Interestingly, experimental work has linked the production of PRP and the maintenance of memory to the presence of neuromodulators such as dopamine, that can be caused by behavioral and environmental cues such as novelty, reward prediction error, aversive events or attention. We also show that our model of synaptic plasticity and consolidation when simulated and implemented in a network of thousands of model neurons can account for in vivo behavioral data that links memory maintenance to novelty. This supports the hypothesis that behavioral tagging and synaptic tagging could be based on the same mechanistic process.

Short- and long-term modulation of synaptic inputs to brain reward areas by nicotine

NARCIS (Netherlands)

Fagen, Z.M.; Mansvelder, H.D.; Keath, R.; McGehee, D.S.

2003-01-01

Dopamine signaling in brain reward areas is a key element in the development of drug abuse and dependence. Recent anatomical and electrophysiological research has begun to elucidate both complexity and specificity In synaptic connections between ventral tegmental neurons and their inputs.

Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex

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Joshua G.A Pinto

2015-02-01

Full Text Available Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin and found that synaptic development in human primary visual cortex continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the 4 proteins and include a stage during early development (<1 year when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the first year or two of life. A multidimensional analysis (principle component analysis showed that most of the variance was captured by the sum of the 4 synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors

DEFF Research Database (Denmark)

Cao, Jianjing; Slack, Rachel D.; Bakare, Oluyomi M.

2016-01-01

The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacolog...

Presynaptic mechanisms of L-DOPA-induced dyskinesia: the findings, the debate, the therapeutic implications.

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M Angela eCenci

2014-12-01

Full Text Available The dopamine precursor L-DOPA has been the most effective treatment for Parkinson´s disease (PD for over 40 years. However, the response to this treatment changes during the progression of PD, and most patients develop dyskinesias (abnormal involuntary movements and motor fluctuations within a few years of L-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal dopamine transmission. Several presynaptic mechanisms converge to generate large dopamine swings in the brain concomitant with the peaks-and-troughs of plasma L-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in dopamine transmission depend on deficiency/dysfunction of the dopamine transporter, aberrant release of dopamine from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from dopamine play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of L-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

The effects of benzofury (5-APB) on the dopamine transporter and 5-HT2-dependent vasoconstriction in the rat.

Science.gov (United States)

Dawson, Patrick; Opacka-Juffry, Jolanta; Moffatt, James D; Daniju, Yusuf; Dutta, Neelakshi; Ramsey, John; Davidson, Colin

2014-01-03

5-APB, commonly marketed as 'benzofury' is a new psychoactive substance and erstwhile 'legal high' which has been implicated in 10 recent drug-related deaths in the UK. This drug was available on the internet and in 'head shops' and was one of the most commonly sold legal highs up until its recent UK temporary ban (UK Home Office). Despite its prominence, very little is known about its pharmacology. This study was undertaken to examine the pharmacology of 5-APB in vitro. We hypothesised that 5-APB would activate the dopamine and 5-HT systems which may underlie its putative stimulant and hallucinogenic effects. Autoradiographic studies showed that 5-APB displaced both [(125)I] RTI-121 and [(3)H] ketanserin from rat brain tissue suggesting affinity at the dopamine transporter and 5-HT2 receptor sites respectively. Voltammetric studies in rat accumbens brain slices revealed that 5-APB slowed dopamine reuptake, and at high concentrations caused reverse transport of dopamine. 5-APB also caused vasoconstriction of rat aorta, an effect antagonised by the 5-HT2A receptor antagonist ketanserin, and caused contraction of rat stomach fundus, which was reversed by the 5-HT2B receptor antagonist RS-127445. These data show that 5-APB interacts with the dopamine transporter and is an agonist at the 5-HT2A and 5-HT2B receptors in the rat. Thus 5-APB's pharmacology is consistent with it having both stimulant and hallucinogenic properties. In addition, 5-APB's activity at the 5-HT2B receptor may cause cardiotoxicity. © 2013.

Age-related decline in dopamine transporter in human brain using PET with a new radioligand [18F]FE-PE2I

International Nuclear Information System (INIS)

Shingai, Yoshitoshi; Tateno, Amane; Arakawa, Ryosuke; Sakayori, Takeshi; Kim, WooChan; Okubo, Yoshiro; Suzuki, Hidenori

2014-01-01

Dopamine transporter (DAT) density is considered as a marker of pre-synaptic function. Numerous neuroimaging studies have consistently demonstrated an age-related decrease in DAT density in normal human brain. However, the precise degree of the regional decline is not yet clear. The purpose of this study was to evaluate the effect of the normal aging process on DAT densities in human-specific brain regions including the substantia nigra and thalamus using positron emission tomography (PET) with [ 18 F]FE-PE2I, a new PET radioligand with high affinity and selectivity for DAT. Thirty-six healthy volunteers ranging in age from 22 to 80 years were scanned with PET employing [ 18 F]FE-PE2I for measuring DAT densities. Region of interest (ROI)-based analysis was used, and ROIs were manually defined for the caudate, putamen, substantia nigra, thalamus, and cerebellar cortex. DAT binding was quantified using a simplified reference tissue model, and the cerebellum was used as reference region. Estimations of binding potential in the caudate, putamen, substantia nigra, and thalamus were individually regressed according to age using simple regression analysis. Estimates of DAT loss per decade were obtained using the values from the regression slopes. There were 7.6, 7.7, and 3.4% per-decade declines in DAT in the caudate, putamen, and substantia nigra, respectively. By contrast, there was no age-related decline of DAT in the thalamus. [ 18 F]FE-PE2I allowed reliable quantification of DAT, not only in the caudate and putamen but also in the substantia nigra. From the results, we demonstrated the age-related decline in the caudate and putamen as reported in previous studies, and additionally for those in the substantia nigra for the first time. (author)

Serotonin and Dopamine Transporter Binding in Children with Autism Determined by SPECT

Science.gov (United States)

Makkonen, Ismo; Riikonen, Raili; Kokki, Hannu; Airaksinen, Mauno M.; Kuikka, Jyrki T.

2008-01-01

Disturbances in the serotonergic system have been recognized in autism. To investigate the association between serotonin and dopamine transporters and autism, we studied 15 children (14 males, one female; mean age 8y 8mo [SD 3y 10mo]) with autism and 10 non-autistic comparison children (five males, five females; mean age 9y 10mo [SD 2y 8mo]) using…

Regulation of dopamine transporter function by protein-protein interactions: new discoveries and methodological challenges

DEFF Research Database (Denmark)

Eriksen, Jacob; Jørgensen, Trine Nygaard; Gether, Ulrik

2010-01-01

-synaptic neurons. This has led to the identification of a plethora of different kinases, receptors and scaffolding proteins that interact with DAT and hereby either modulate the catalytic activity of the transporter or regulate its trafficking and degradation. Several new tools for studying DAT regulation in live...

Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

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Laurent Ladepeche

Full Text Available Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

Reproducibility of [123I]PE2I binding to dopamine transporters with SPECT

DEFF Research Database (Denmark)

Ziebell, Morten; Thomsen, Gerda; Knudsen, Gitte M

2007-01-01

The iodinated cocaine derivative [(123)I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with SPECT. Recently, a bolus/infusion (B/I) protocol for [(123)I]PE2I measurements of DAT density was established [Pinborg LH et al. J Nucl Med 2005;46:1119-271]. The aims...

DIRECT VISUALIZATION OF THE DOPAMINE TRANSPORTER IN CULTURED NEWBORN RAT MIDBRAIN NEURONS USING THE FLUORESCENT COCAINE ANALOGUE JHC 1-64

DEFF Research Database (Denmark)

Rasmussen, Søren; Vægter, Christian Bjerggaard; Cha, J

In this study we have established methods for visualization and tracking of the dopamine transporter (DAT) in cultured dopaminergic neurons in real time using a fluorescent cocaine analogue JHC 1-64 and confocal fluorescence microscopy. The initial binding experiments in HEK 293 cells stably...... 1-64 was prevented by excess concentrations of dopamine, cocaine, mazindol, or RTI-55, whereas the norepinephrine and/or serotonin transporter specific inhibitors desmethylimipramine and citalopram did not affect fluorescent labeling of the neurons. This strongly supports that JHC 1-64 specifically...

Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance

Science.gov (United States)

Cohen, Laurie D.; Zuchman, Rina; Sorokina, Oksana; Müller, Anke; Dieterich, Daniela C.; Armstrong, J. Douglas; Ziv, Tamar; Ziv, Noam E.

2013-01-01

Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non–Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2–5 days. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. The relatively low turnover rates measured here (∼0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load

Akinetic Crisis in Parkinson's Disease Is Associated with a Severe Loss of Striatal Dopamine Transporter Function: A Report of Two Cases

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Valtteri Kaasinen

2014-11-01

Full Text Available Akinetic crisis or acute akinesia is a life-threatening complication of Parkinson's disease (PD with unknown pathophysiological mechanisms. Clinically, it resembles the neuroleptic malignant syndrome, and dopaminergic drugs are transiently ineffective in the acute phase of the condition. There are no published dopaminergic functional imaging studies on PD patients with akinetic crisis. Here we report 2 advanced PD patients with akinetic crisis who were scanned with SPECT using brain dopamine transporter ligand [123I]FP-CIT. The first patient was additionally scanned before the condition developed, and the second patient was scanned after recovery. Striatal dopamine transporter binding was lower during than before the crisis, and both patients showed a nearly complete loss of dopamine transporter binding during the crisis. Serial imaging showed that the uptake remained negligible despite an improvement in motor function after recovery. Akinetic crisis in PD appears to be associated with a particularly severe loss of presynaptic striatal dopamine function that does not improve after recovery. Apart from presynaptic dopaminergic function, other dopaminergic or nondopaminergic mechanisms are involved in the clinical improvement of motor functions after akinetic crisis in PD.

Tyrosine hydroxylase immunoreactivity and [{sup 3}H]WIN 35,428 binding to the dopamine transporter in a hamster model of idiopathic paroxysmal dystonia

Energy Technology Data Exchange (ETDEWEB)

Nobrega, J.N. [Neuroimaging Research Section, Clarke Institute of Psychiatry, Toronto (Canada); Gernert, M.; Loescher, W. [Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Buenteweg 17, D-30559 Hannover (Germany); Raymond, R.; Belej, T. [Neuroimaging Research Section, Clarke Institute of Psychiatry, Toronto (Canada); Richter, A. [Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Buenteweg 17, D-30559 Hannover (Germany)

1999-08-01

Recent pharmacological studies and receptor analyses have suggested that dopamine neurotransmission is enhanced in mutant dystonic hamsters (dt{sup sz}), a model of idiopathic paroxysmal dystonia which displays attacks of generalized dystonia in response to mild stress. In order to further characterize the nature of dopamine alterations, the present study investigated possible changes in the number of dopaminergic neurons, as defined by tyrosine hydroxylase immunohistochemistry, as well as binding to the dopamine transporter labelled with [{sup 3}H]WIN 35,428 in dystonic hamsters. No differences in the number of tyrosine hydroxylase-immunoreactive neurons were found within the substantia nigra and ventral tegmental area of mutant hamsters compared to non-dystonic control hamsters. Similarly, under basal conditions, i.e. in the absence of a dystonic episode, no significant changes in [{sup 3}H]WIN 35,428 binding were detected in dystonic brains. However, in animals killed during the expression of severe dystonia, significant decreases in dopamine transporter binding became evident in the nucleus accumbens and ventral tegmental area in comparison to controls exposed to the same external stimulation. Since stimulation tended to increase [{sup 3}H]WIN 35,428 binding in control brains, the observed decrease in the ventral tegmental area appeared to be due primarily to the fact that binding was increased less in dystonic brains than in similarly stimulated control animals.This finding could reflect a diminished ability of the dopamine transporter to undergo adaptive changes in response to external stressful stimulation in mutant hamsters. The selective dopamine uptake inhibitor GBR 12909 (20 mg/kg) aggravated dystonia in mutant hamsters, further suggesting that acute alterations in dopamine transporter function during stimulation may be an important component of dystonia in this model. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved000.

Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

NARCIS (Netherlands)

Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

2009-01-01

Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular

Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors

DEFF Research Database (Denmark)

Løland, Claus Juul; Desai, Rajeev I; Zou, Mu-Fa

2007-01-01

Cocaine exerts its stimulatory effect by inhibiting the dopamine transporter (DAT). However, novel benztropine- and rimcazole-based inhibitors show reduced stimulant effects compared with cocaine, despite higher affinity and selectivity for DAT. To investigate possible mechanisms, we compared...... the extracellular transporter gate is open but inaccessible when it is closed. The data indicated that cocaine analogs bind an open conformation, whereas benztropine and rimcazole analogs bind a closed conformation. Next, we investigated the changes in inhibition potency of [(3)H]dopamine uptake of the compounds...... at a mutant DAT (Y335A) characterized by a global change in the conformational equilibrium. We observed a close relationship between the decrease in potencies of inhibitors at this mutant and cocaine-like responding in rats trained to discriminate cocaine from saline injections. Our data suggest...

An intracellular interaction network regulates conformational transitions in the dopamine transporter

DEFF Research Database (Denmark)

Kniazeff, Julie; Shi, Lei; Løland, Claus Juul

2008-01-01

Neurotransmitter:sodium symporters (NSS)(1) mediate sodium-dependent reuptake of neurotransmitters from the synaptic cleft and are targets for many psychoactive drugs. The crystal structure of the prokaryotic NSS protein, LeuT, was recently solved at high resolution; however, the mechanistic...... and the intracellular milieu. The mechanism that emerges from these findings may be unique to the NSS family, where the local disruption of ionic interactions modulates the transition of the transporter between the outward- and inward-facing conformations....

Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease

International Nuclear Information System (INIS)

Kaasinen, Valtteri; Kinos, Maija; Joutsa, Juho; Seppaenen, Marko; Noponen, Tommi

2014-01-01

Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor. [ 123 I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates. Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen. The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor. (orig.)

Diacylglycerol kinases in the coordination of synaptic plasticity

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Dongwon Lee

2016-08-01

Full Text Available Synaptic plasticity is activity-dependent modification of the efficacy of synaptic transmission. Although detailed mechanisms underlying synaptic plasticity are diverse and vary at different types of synapses, diacylglycerol (DAG-associated signaling has been considered as an important regulator of many forms of synaptic plasticity, including long-term potentiation (LTP and long-term depression (LTD. Recent evidence indicate that DAG kinases (DGKs, which phosphorylate DAG to phosphatidic acid to terminate DAG signaling, are important regulators of LTP and LTD, as supported by the results from mice lacking specific DGK isoforms. This review will summarize these studies and discuss how specific DGK isoforms distinctly regulate different forms of synaptic plasticity at pre- and postsynaptic sites. In addition, we propose a general role of DGKs as coordinators of synaptic plasticity that make local synaptic environments more permissive for synaptic plasticity by regulating DAG concentration and interacting with other synaptic proteins.

Alteration of synaptic activity-regulating genes underlying functional improvement by long-term exposure to an enriched environment in the adult brain.

Science.gov (United States)

Lee, Min-Young; Yu, Ji Hea; Kim, Ji Yeon; Seo, Jung Hwa; Park, Eun Sook; Kim, Chul Hoon; Kim, Hyongbum; Cho, Sung-Rae

2013-01-01

Housing animals in an enriched environment (EE) enhances behavioral function. However, the mechanism underlying this EE-mediated functional improvement and the resultant changes in gene expression have yet to be elucidated. We attempted to investigate the underlying mechanisms associated with long-term exposure to an EE by evaluating gene expression patterns. We housed 6-week-old CD-1 (ICR) mice in standard cages or an EE comprising a running wheel, novel objects, and social interaction for 2 months. Motor and cognitive performances were evaluated using the rotarod test and passive avoidance test, and gene expression profile was investigated in the cerebral hemispheres using microarray and gene set enrichment analysis (GSEA). In behavioral assessment, an EE significantly enhanced rotarod performance and short-term working memory. Microarray analysis revealed that genes associated with neuronal activity were significantly altered by an EE. GSEA showed that genes involved in synaptic transmission and postsynaptic signal transduction were globally upregulated, whereas those associated with reuptake by presynaptic neurotransmitter transporters were downregulated. In particular, both microarray and GSEA demonstrated that EE exposure increased opioid signaling, acetylcholine release cycle, and postsynaptic neurotransmitter receptors but decreased Na+ / Cl- -dependent neurotransmitter transporters, including dopamine transporter Slc6a3 in the brain. Western blotting confirmed that SLC6A3, DARPP32 (PPP1R1B), and P2RY12 were largely altered in a region-specific manner. An EE enhanced motor and cognitive function through the alteration of synaptic activity-regulating genes, improving the efficient use of neurotransmitters and synaptic plasticity by the upregulation of genes associated with postsynaptic receptor activity and downregulation of presynaptic reuptake by neurotransmitter transporters.

Loss of synaptic zinc transport in progranulin deficient mice may contribute to progranulin-associated psychopathology and chronic pain.

Science.gov (United States)

Hardt, Stefanie; Heidler, Juliana; Albuquerque, Boris; Valek, Lucie; Altmann, Christine; Wilken-Schmitz, Annett; Schäfer, Michael K E; Wittig, Ilka; Tegeder, Irmgard

2017-11-01

Affective and cognitive processing of nociception contributes to the development of chronic pain and vice versa, pain may precipitate psychopathologic symptoms. We hypothesized a higher risk for the latter with immanent neurologic diseases and studied this potential interrelationship in progranulin-deficient mice, which are a model for frontotemporal dementia, a disease dominated by behavioral abnormalities in humans. Young naïve progranulin deficient mice behaved normal in tests of short-term memory, anxiety, depression and nociception, but after peripheral nerve injury, they showed attention-deficit and depression-like behavior, over-activity, loss of shelter-seeking, reduced impulse control and compulsive feeding behavior, which did not occur in equally injured controls. Hence, only the interaction of 'pain x progranulin deficiency' resulted in the complex phenotype at young age, but neither pain nor progranulin deficiency alone. A deep proteome analysis of the prefrontal cortex and olfactory bulb revealed progranulin-dependent alterations of proteins involved in synaptic transport, including neurotransmitter transporters of the solute carrier superfamily. In particular, progranulin deficiency was associated with a deficiency of nuclear and synaptic zinc transporters (ZnT9/Slc30a9; ZnT3/Slc30a3) with low plasma zinc. Dietary zinc supplementation partly normalized the attention deficit of progranulin-deficient mice, which was in part reminiscent of autism-like and compulsive behavior of synaptic zinc transporter Znt3-knockout mice. Hence, the molecular studies point to defective zinc transport possibly contributing to progranulin-deficiency-associated psychopathology. Translated to humans, our data suggest that neuropathic pain may precipitate cognitive and psychopathological symptoms of an inherent, still silent neurodegenerative disease. Copyright © 2017. Published by Elsevier B.V.

Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation.

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Matthew T C Brown

2010-12-01

Full Text Available Addictive drugs have in common that they cause surges in dopamine (DA concentration in the mesolimbic reward system and elicit synaptic plasticity in DA neurons of the ventral tegmental area (VTA. Cocaine for example drives insertion of GluA2-lacking AMPA receptors (AMPARs at glutamatergic synapes in DA neurons. However it remains elusive which molecular target of cocaine drives such AMPAR redistribution and whether other addictive drugs (morphine and nicotine cause similar changes through their effects on the mesolimbic DA system.We used in vitro electrophysiological techniques in wild-type and transgenic mice to observe the modulation of excitatory inputs onto DA neurons by addictive drugs. To observe AMPAR redistribution, post-embedding immunohistochemistry for GluA2 AMPAR subunit was combined with electron microscopy. We also used a double-floxed AAV virus expressing channelrhodopsin together with a DAT Cre mouse line to selectively express ChR2 in VTA DA neurons. We find that in mice where the effect of cocaine on the dopamine transporter (DAT is specifically blocked, AMPAR redistribution was absent following administration of the drug. Furthermore, addictive drugs known to increase dopamine levels cause a similar AMPAR redistribution. Finally, activating DA VTA neurons optogenetically is sufficient to drive insertion of GluA2-lacking AMPARs, mimicking the changes observed after a single injection of morphine, nicotine or cocaine.We propose the mesolimbic dopamine system as a point of convergence at which addictive drugs can alter neural circuits. We also show that direct activation of DA neurons is sufficient to drive AMPAR redistribution, which may be a mechanism associated with early steps of non-substance related addictions.

Evaluation of the Dopamine Hypothesis of ADHD with PET Brain Imaging

International Nuclear Information System (INIS)

Swanson, James

2010-01-01

The Dopamine (DA) Hypothesis of ADHD (Wender, 1971; Levy, 1990) suggests that abnormalities in the synaptic mechanisms of DA transmission may be disrupted, and specific abnormalities in DA receptors and DA transporters (DAT) have been proposed (see Swanson et al, 1998). Early studies with small samples (e.g., n = 6, Dougherty et al, 1999) used single photon emission tomography (SPECT) and the radioligand (123I Altropane) to test a theory that ADHD may be caused by an over expression of DAT and reported 'a 70% increase in age-corrected dopamine transporter density in patients with attention deficit hyperactivity disorder compared with healthy controls' and suggested that treatment with stimulant medication decreased DAT density in ADHD patients and corrected an underlying abnormality (Krause et al, 2000). The potential importance of these findings was noted by Swanson (1999): 'If true, this is a major finding and points the way for new investigations of the primary pharmacological treatment for ADHD (with the stimulant drugs - e.g., methylphenidate), for which the dopamine transporter is the primary site of action. The potential importance of this finding demands special scrutiny'. This has been provided over the past decade using Positron Emission Tomography (PET). Brain imaging studies were conducted at Brookhaven National Laboratory (BNL) in a relatively large sample of stimulant-naive adults assessed for DAT (11C cocaine) density and DA receptors (11C raclopride) availability. These studies (Volkow et al, 2007; Volkow et al, 2009) do not confirm the hypothesis of increased DAT density and suggest the opposite (i.e., decreased rather than increased DAT density), and follow-up after treatment (Wang et al, 2010) does not confirm the hypothesis that therapeutic doses of methylphenidate decrease DAT density and suggests the opposite (i.e., increased rather than decreased DAT density). The brain regions implicated by these PET imaging studies also suggest that a

Agrin and synaptic laminin are required to maintain adult neuromuscular junctions.

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Melanie A Samuel

Full Text Available As synapses form and mature the synaptic partners produce organizing molecules that regulate each other's differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ, these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-α4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.

Quantitation of dopamine transporter blockade by methylphenidate: first in vivo investigation using [123I]FP-CIT and a dedicated small animal SPECT

International Nuclear Information System (INIS)

Nikolaus, Susanne; Wirrwar, Andreas; Antke, Christina; Arkian, Shahram; Mueller, Hans-Wilhelm; Larisch, Rolf; Schramm, Nils

2005-01-01

The aim of this study was to investigate the feasibility of assessing dopamine transporter binding after treatment with methylphenidate in the rat using a recently developed high-resolution small animal single-photon emission computed tomograph (TierSPECT) and [ 123 I]FP-CIT. [ 123 I]FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (10 mg/kg) or vehicle. Animals underwent scanning 2 h after radioligand administration. The striatum was identified by superimposition of [ 123 I]FP-CIT scans with bone metabolism and perfusion scans obtained with 99m Tc-DPD and 99m Tc-tetrofosmin, respectively. As these tracers do not pass the blood-brain barrier, their distribution permits the identification of extracerebral anatomical landmarks such as the orbitae and the harderian glands. The cerebellum was identified by superimposing [ 123 I]FP-CIT scans with images of brain perfusion obtained with 99m Tc-HMPAO. Methylphenidate-treated animals and vehicle-treated animals yielded striatal equilibrium ratios (V '' 3 ) of 0.24±0.26 (mean ± SD) and 1.09±0.42, respectively (ttest, two-tailed, p '' 3 values amounted to 0.05±0.28 (methylphenidate) and 0.3±0.39 (saline, p=0.176). This first in vivo study of rat dopamine transporter binding after pre-treatment with methylphenidate showed a mean reduction of 78% in striatal [ 123 I]FP-CIT accumulation. The results can be interpreted in terms of a pharmacological blockade in the rat striatum and show that in vivo quantitation of dopamine transporter binding is feasible with [ 123 I]FP-CIT and the TierSPECT. This may be of future relevance for in vivo investigations on rat models of attention deficit/hyperactivity disorder. Furthermore, our findings suggest that investigations in other animal models, e.g. of Parkinson's and Huntington's disease, may be feasible using SPECT radioligands and small animal imaging systems. (orig.)

The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain.

Science.gov (United States)

Burchett, Scott A; Hicks, T Philip

2006-08-01

The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic "amphetamine-like" effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as beta-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N

Myocardial pre-synaptic sympathetic function correlates with glucose uptake in the failing human heart

International Nuclear Information System (INIS)

Mongillo, Marco; Leccisotti, Lucia; John, Anna S.; Pennell, Dudley J.; Camici, Paolo G.

2007-01-01

We have previously shown that the myocardium of patients with heart failure (HF) is insulin resistant. Chronic β-adrenergic stimulation has been implicated in insulin resistance in cultured cardiomyocytes in vitro, where sustained noradrenaline stimulation inhibited insulin-modulated glucose uptake. As the failing heart is characterized by increased sympathetic drive, we hypothesized that there is a correlation between pre-synaptic sympathetic function and insulin sensitivity in the myocardium of patients with HF. Eight patients (aged 67 ± 7 years) with coronary artery disease and left ventricular dysfunction (ejection fraction 44 ± 10%) underwent function and viability assessment with cardiovascular magnetic resonance. Myocardial glucose utilization (MGU) was measured using positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG). Pre-synaptic noradrenaline re-uptake was measured by calculating [ 11 C]meta-hydroxy-ephedrine (HED) volume of distribution (V d ) with PET. Two groups of healthy volunteers served as controls for the FDG (n = 8, aged 52 ± 4 years, p -1 .g -1 ) and dysfunctional (0.49 ± 0.14 μmol.min -1 .g -1 ) segments compared with controls (0.61 ± 0.7 μmol.min -1 .g -1 ; p d was reduced in dysfunctional segments of patients (38.9 ± 21.2 ml.g -1 ) compared with normal segments (52.2 ± 19.6 ml.g -1 ) and compared with controls (62.7 ± 11.3 ml.g -1 ). In patients, regional MGU was correlated with HED V d . The results of this study provide novel evidence of a correlation between cardiac sympathetic function and insulin sensitivity, which may represent one of the mechanisms contributing to insulin resistance in failing human hearts. (orig.)

Synaptic control of motoneuronal excitability

DEFF Research Database (Denmark)

Rekling, J C; Funk, G D; Bayliss, D A

2000-01-01

important in understanding the transformation of neural activity to motor behavior. Here, we review recent studies on the control of motoneuronal excitability, focusing on synaptic and cellular properties. We first present a background description of motoneurons: their development, anatomical organization......, and membrane properties, both passive and active. We then describe the general anatomical organization of synaptic input to motoneurons, followed by a description of the major transmitter systems that affect motoneuronal excitability, including ligands, receptor distribution, pre- and postsynaptic actions...... and norepinephrine, and neuropeptides, as well as the glutamate and GABA acting at metabotropic receptors, modulate motoneuronal excitability through pre- and postsynaptic actions. Acting principally via second messenger systems, their actions converge on common effectors, e.g., leak K(+) current, cationic inward...

A rapid method for the determination of dopamine in porcine muscle by pre-column derivatization and HPLC with fluorescence detection

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Hong-Xia Zhao

2011-08-01

Full Text Available A rapid method has been developed based on the sample preparation procedure named as QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe, combined with reversed-phase high performance liquid chromatography with fluorescence detector and C18 column after pre-column derivatization using o-phthalaldehyde and 2-mercaptoethanol to determine dopamine in porcine muscle. Methanol and deionized water (0.1% acetic acid, v/v with a ratio of 60:40 was used as mobile phase. The flow rate was 0.8 mL/min and dopamine was eluted within 15 min. The linearity range was 0.003–8 μg/mL with r=0.9992. The detection limit for dopamine was 4 μg/kg and the quantification limit was 9 μg/kg. Recovery studies were carried out at 0.1, 0.5 and 1.0 mg/kg fortification levels and the average recoveries obtained ranged from 90.4% to 98.2% with relative standard deviations between 3.5% and 8.1%. The method was found to be suitable for detection of dopamine in animal product tissues at the maximum residue level. Keywords: Liquid chromatography, Dopamine, o-phthalaldehyde, QuEChERS

TFH-derived dopamine accelerates productive synapses in germinal centres.

Science.gov (United States)

Papa, Ilenia; Saliba, David; Ponzoni, Maurilio; Bustamante, Sonia; Canete, Pablo F; Gonzalez-Figueroa, Paula; McNamara, Hayley A; Valvo, Salvatore; Grimbaldeston, Michele; Sweet, Rebecca A; Vohra, Harpreet; Cockburn, Ian A; Meyer-Hermann, Michael; Dustin, Michael L; Doglioni, Claudio; Vinuesa, Carola G

2017-07-20

Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (T FH ) cells in germinal centres. The rapid T-B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we show that a proportion of human T FH cells contain dense-core granules marked by chromogranin B, which are normally found in neuronal presynaptic terminals storing catecholamines such as dopamine. T FH cells produce high amounts of dopamine and release it upon cognate interaction with B cells. Dopamine causes rapid translocation of intracellular ICOSL (inducible T-cell co-stimulator ligand, also known as ICOSLG) to the B-cell surface, which enhances accumulation of CD40L and chromogranin B granules at the human T FH cell synapse and increases the synapse area. Mathematical modelling suggests that faster dopamine-induced T-B-cell interactions increase total germinal centre output and accelerate it by days. Delivery of neurotransmitters across the T-B-cell synapse may be advantageous in the face of infection.

Imaging of dopamine release induced by pharmacologic and nonpharmacologic stimulations

Energy Technology Data Exchange (ETDEWEB)

Cho, Sang Soo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

2007-04-15

Technological advances in molecular imaging made it possible to image synaptic neurotransmitter concentration in living human brain. The dopaminergic system has been most intensively studied because of its importance in neurological as well as psychiatric disorders. This paper provides a brief overview of recent progress in imaging studies of dopamine release induced by pharmacologic and nonpharmacologic stimulations.

Self-Limited Kleptomania Symptoms as a Side Effect of Duloxetine

OpenAIRE

Miller, Christopher W. T.; Gallagher, Keith E.

2016-01-01

Introduction. Impulse control disorders (ICDs) have been described as a side effect of dopamine agonists, frequently used in neurodegenerative conditions affecting the nigrostriatal pathway. Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine) have dose-dependent differential affinity for monoaminergic transporters, inhibiting the dopamine transporter at higher doses, thus increasing availability of synaptic dopamine, with the potential for similar impulse control side effects. Cas...

Pre-existing differences and diet-induced alterations in striatal dopamine systems of obesity-prone rats.

Science.gov (United States)

Vollbrecht, Peter J; Mabrouk, Omar S; Nelson, Andrew D; Kennedy, Robert T; Ferrario, Carrie R

2016-03-01

Interactions between pre-existing differences in mesolimbic function and neuroadaptations induced by consumption of fatty, sugary foods are thought to contribute to human obesity. This study examined basal and cocaine-induced changes in striatal neurotransmitter levels without diet manipulation and D2 /D3 dopamine receptor-mediated transmission prior to and after consumption of "junk-foods" in obesity-prone and obesity-resistant rats. Microdialysis and liquid chromatography-mass spectrometry were used to determine basal and cocaine-induced changes in neurotransmitter levels in real time with cocaine-induced locomotor activity. Sensitivity to the D2 /D3 dopamine receptor agonist quinpirole was examined before and after restricted junk-food exposure. Selectively bred obesity-prone and obesity-resistant rats were used. Cocaine-induced locomotion was greater in obesity-prone rats versus obesity-resistant rats prior to diet manipulation. Basal and cocaine-induced increases in dopamine and serotonin levels did not differ. Obesity-prone rats were more sensitive to the D2 receptor-mediated effects of quinpirole, and junk-food produced modest alterations in quinpirole sensitivity in obesity-resistant rats. These data show that mesolimbic systems differ prior to diet manipulation in susceptible versus resistant rats, and that consumption of fatty, sugary foods produce different neuroadaptations in these populations. These differences may contribute to enhanced food craving and an inability to limit food intake in susceptible individuals. © 2016 The Obesity Society.

Nature of rate-limiting steps in a compartmentalized enzyme system. Quantitation of dopamine transport and hydroxylation rates in resealed chromaffin granule ghosts

International Nuclear Information System (INIS)

Ahn, N.G.; Klinman, J.P.

1989-01-01

Using isolated chromaffin granule ghosts from bovine adrenal medullae, we have studied the kinetics of dopamine beta-monooxygenase (D beta M) activity as it is linked to dopamine transport. Measurements of the initial rates of transport and of transport-linked norepinephrine formation suggested that enzyme activity may be partially rate-limiting in the coupled carrier/enzyme system. This was confirmed by (i) measurements of initial rates of norepinephrine formation using deuterated substrate, which gave isotope effects greater than 2.0, and (ii) kinetic measurements using ghosts pulsed with varying concentrations of labeled dopamine, which indicated substantial substrate accumulation in the vesicle interior as a function of time. Initial rates of product formation, when combined with approximations of internal substrate concentrations, allowed estimates of Kcat and Km for intravesicular D beta M. Activation by external reductant was apparent in both initial rate parameters and the measurements of transients. Under conditions of optimal D beta M activity, the enzyme rate parameters (kcat = 0.31 nmol/s.mg and Km = 2 mM) indicated partial rate limitation compared to dopamine transport (kcat = 0.38 nmol/s.mg and Km = 32 microM). Compartmental analysis of the time curves, performed using numerical nonlinear least squares methods, gave least squares estimates of rate constants for a simple carrier mechanism and kcat values for D beta M which were consistent with estimates from initial rates

Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

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Dickenson Anthony H

2009-02-01

Full Text Available Abstract Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2δ1 has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2δ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2δ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2δ1 transgenic mice. Our data indicated that overexpression of Cavα2δ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2δ1-mediated spinal sensitization in which elevated Cavα2δ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal

Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity

Science.gov (United States)

Nguyen, David; Deng, Ping; Matthews, Elizabeth A; Kim, Doo-Sik; Feng, Guoping; Dickenson, Anthony H; Xu, Zao C; Luo, Z David

2009-01-01

Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2δ1) has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2δ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia) similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2δ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR) neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2δ1 transgenic mice. Our data indicated that overexpression of Cavα2δ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2δ1-mediated spinal sensitization in which elevated Cavα2δ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal horn neurons to innocuous

The effect of modafinil on the rat dopamine transporter and dopamine receptors D1-D3 paralleling cognitive enhancement in the radial arm maze

Directory of Open Access Journals (Sweden)

Yasemin eKarabacak

2015-08-01

Full Text Available A series of drugs have been reported to increase memory performance modulating the dopaminergic system and herein modafinil was tested for its working memory (WM enhancing properties. Reuptake inhibition of dopamine, serotonin (SERT and norepinephrine (NET by modafinil was tested. 60 male Sprague Dawley rats were divided into six groups (modafinil-treated 1-5-10 mg/kg body weight, trained and untrained and vehicle treated trained and untrained rats; daily injected intraperitoneally for a period of 10 days and tested in a radial arm maze (RAM, a paradigm for testing spatial WM. Hippocampi were taken six hours following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT-CC and pDAT-CC and complexes containing the D1-3 dopamine receptor subunits (D1-D3-CC were determined. Modafinil was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50=11.11; SERT 1547; NET 182. From day 8 (day 9 for 1 mg/kg body weight modafinil was decreasing WM errors in the RAM significantly and remarkably at all doses tested as compared to the vehicle controls. WMEs were linked to the D2R-CC and the pDAT-CC. pDAT and D1-D3-CC levels were modulated significantly and modafinil was shown to enhance spatial WM in the rat in a well-documented paradigm at all the three doses and dopamine reuptake inhibition with subsequent modulation of D1-3-CC is proposed as a possible mechanism of action.

Quantitation of dopamine transporter blockade by methylphenidate: first in vivo investigation using [{sup 123}I]FP-CIT and a dedicated small animal SPECT

Energy Technology Data Exchange (ETDEWEB)

Nikolaus, Susanne; Wirrwar, Andreas; Antke, Christina; Arkian, Shahram; Mueller, Hans-Wilhelm; Larisch, Rolf [Heinrich-Heine University, Clinic of Nuclear Medicine, Duesseldorf (Germany); Schramm, Nils [Research Center Juelich, Central Laboratory for Electronics, Juelich (Germany)

2005-03-01

The aim of this study was to investigate the feasibility of assessing dopamine transporter binding after treatment with methylphenidate in the rat using a recently developed high-resolution small animal single-photon emission computed tomograph (TierSPECT) and [{sup 123}I]FP-CIT. [{sup 123}I]FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (10 mg/kg) or vehicle. Animals underwent scanning 2 h after radioligand administration. The striatum was identified by superimposition of [{sup 123}I]FP-CIT scans with bone metabolism and perfusion scans obtained with {sup 99m}Tc-DPD and {sup 99m}Tc-tetrofosmin, respectively. As these tracers do not pass the blood-brain barrier, their distribution permits the identification of extracerebral anatomical landmarks such as the orbitae and the harderian glands. The cerebellum was identified by superimposing [{sup 123}I]FP-CIT scans with images of brain perfusion obtained with {sup 99m}Tc-HMPAO. Methylphenidate-treated animals and vehicle-treated animals yielded striatal equilibrium ratios (V''{sub 3}) of 0.24{+-}0.26 (mean {+-} SD) and 1.09{+-}0.42, respectively (ttest, two-tailed, p<0.0001). Cortical V''{sub 3} values amounted to 0.05{+-}0.28 (methylphenidate) and 0.3{+-}0.39 (saline, p=0.176). This first in vivo study of rat dopamine transporter binding after pre-treatment with methylphenidate showed a mean reduction of 78% in striatal [{sup 123}I]FP-CIT accumulation. The results can be interpreted in terms of a pharmacological blockade in the rat striatum and show that in vivo quantitation of dopamine transporter binding is feasible with [{sup 123}I]FP-CIT and the TierSPECT. This may be of future relevance for in vivo investigations on rat models of attention deficit/hyperactivity disorder. Furthermore, our findings suggest that investigations in other animal models, e.g. of Parkinson's and Huntington's disease, may be feasible using SPECT radioligands and

[{sup 18}F]L.B.T.-999, a new radioligand to study the dopamine transporter with PET: characterization in baboons

Energy Technology Data Exchange (ETDEWEB)

Saba, W.; Schollhorn, M.A.; Valette, H.; Dolle, F.; Bottlaender, M. [Service Hospitalier Frederic Joliot, DRM/DSV, 91 - Orsay (France); Chalon, S.; Garreau, L.; Emond, P.; Guilloteau, D. [Institut National de la Sante et de la Recherche Medicale (INSERM), U619, 37 - Tours (France); Deloye, J.B. [Cyclopharma, 63 - Clermont Ferrand (France)

2008-02-15

The dopamine transporter (D.A.T.) is the main regulator of the synaptic concentration of dopamine in the brain and plays a key role in many neurological and psychiatric diseases. The goal of the study was to characterize the properties of [{sup 18}F]L.B.T.-999 in baboons. Regional brain distribution was examined in vitro by autoradiographic studies on brain sections and in vivo by PET. Results of in vitro autoradiographic studies were in agreement with the localisation of the D.A.T. and revealed high level of [{sup 18}F]L.B.T.-999 binding in the putamen and caudate, moderate level in the midbrain, and low level in the cortex and cerebellum. In PET study, the time course of the concentration of [{sup 18}F]L.B.T.-999 in different regions of the brain showed that the highest accumulation of [{sup 18}F]L.B.T.-999 was observed in the striatum with a peak uptake at 50 min (maximum = 5.7 {+-} 1.7 and 4.7 {+-}1.0% I.D./100 ml in putamen and caudate nucleus respectively, n 5). The radioactivity uptake peaked at 8 min in the midbrain (2.3 {+-} 1.2% I.D./100 ml) and decreased rapidly as a function of time. The lowest uptake was observed in the cortex (0.62 {+-}0.1 % I.D./100 ml, at 50 min) and in the cerebellum (0.44 {+-} 0.08% I.D./100 ml, at 50 min). In the test retest studies (n = 3) the variability of the uptake was 5% in the putamen and 6% in the caudate. Following HPLC analysis of plasma samples, [{sup 18}F]L.B.T.-999 was rapidly metabolized. Unchanged [{sup 18}F]L.B.T.-999 accounted for around 21% and 7% of the radioactivity at 30 and 120 min post-injection respectively. The region to cerebellum radioactivity ratio was calculated. This ratio reached a maximum at 110 min post injection (22.1 {+-} 4.6 and 18.8 {+-} 2.1 in the putamen and the caudate respectively) and remained stable during the time of the PET scan (4 h). This ratio was 4.21 {+-} 0.92, 2.0 {+-} 0.3 and 1.6 {+-} 0.2 in the midbrain, thalamus, and cortical structure at 110 min post-injection. Binding

Linking unfounded beliefs to genetic dopamine availability

Science.gov (United States)

Schmack, Katharina; Rössler, Hannes; Sekutowicz, Maria; Brandl, Eva J.; Müller, Daniel J.; Petrovic, Predrag; Sterzer, Philipp

2015-01-01

Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity toward unfounded beliefs. One hundred two healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818, and rs4680, also known as val158met) that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioral experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity toward unfounded beliefs, and that this effect was statistically mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world. PMID:26483654

Linking unfounded beliefs to genetic dopamine availability

Directory of Open Access Journals (Sweden)

Katharina eSchmack

2015-09-01

Full Text Available Unfounded convictions involving beliefs in the paranormal, grandiosity ideas or suspicious thoughts are endorsed at varying degrees among the general population. Here, we investigated the neurobiopsychological basis of the observed inter-individual variability in the propensity towards unfounded beliefs. 109 healthy individuals were genotyped for four polymorphisms in the COMT gene (rs6269, rs4633, rs4818 and rs4680, also known as val158met that define common functional haplotypes with substantial impact on synaptic dopamine degradation, completed a questionnaire measuring unfounded beliefs, and took part in a behavioural experiment assessing perceptual inference. We found that greater dopamine availability was associated with a stronger propensity towards unfounded beliefs, and that this effect was mediated by an enhanced influence of expectations on perceptual inference. Our results indicate that genetic differences in dopaminergic neurotransmission account for inter-individual differences in perceptual inference linked to the formation and maintenance of unfounded beliefs. Thus, dopamine might be critically involved in the processes underlying one's interpretation of the relationship between the self and the world.

Synthesis of 3-[18F]fluoromethyl-BTCP and evaluation as a potential PET radioligand for the dopamine transporter in baboons

International Nuclear Information System (INIS)

Ponchant, M.; Crouzel, C.; Varastet, M.; Hantraye, P.;

1993-01-01

In an attempt to visualize in vivo the dopamine transporter and evaluate its potential as an imaging tool for monitoring dopamine fiber degeneration by positron emission tomography, the 18 F-positron-emitting analogue of 3-fluoromethyl-1-[2-benzothienyl)-cyclohexyl]-piperidine, [ 18 F]BTCP, was synthesized and tested in a primate model of hemiparkinsonism. When comparing binding ratios between the intact and the dopamine-denervated striatum, there was a modest loss of binding in denervated striatum, suggesting that degeneration of dopaminergic fibers could be detected using 3-[ 18 F]fluoromethyl-BTCP. However due to a high non-specific binding in vivo, the interest of 3-[ 18 F]fluoromethyl-BTCP to image the dopamine reuptake system in vivo appears limited. (author)

Interaction of Dopamine Transporter (DAT1) Genotype and Maltreatment for ADHD: A Latent Class Analysis

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Li, James J.; Lee, Steve S.

2012-01-01

Background: Although the association of the dopamine transporter (DAT1) gene and attention-deficit/hyperactivity disorder (ADHD) has been widely studied, far less is known about its potential interaction with environmental risk factors. Given that maltreatment is a replicated risk factor for ADHD, we explored the interaction between DAT1 and…

Functionally distinct dopamine signals in nucleus accumbens core and shell in the freely moving rat

DEFF Research Database (Denmark)

Dreyer, Jakob K.; Vander Weele, Caitlin M.; Lovic, Vedran

2016-01-01

Dynamic signaling of mesolimbic dopamine (DA) neurons has been implicated in reward learning, drug abuse, and motivation. However, this system is complex because firing patterns of these neurons are heterogeneous; subpopulations receive distinct synaptic inputs, and project to anatomically...

The roles of dopamine and serotonin in decision making: evidence from pharmacological experiments in humans.

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Rogers, Robert D

2011-01-01

Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre- vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive

Dopamine Transporter Gene Moderates Response to Behavioral Parent Training in Children With ADHD : A Pilot Study

NARCIS (Netherlands)

van den Hoofdakker, Barbara J.; Dijck-Brouwer, D. A. Janneke; Nauta, Maaike H.; van der Veen-Mulders, Lianne; Sytema, Sjoerd; Emmelkamp, Paul M. G.; Minderaa, Ruud B.; Hoekstra, Pieter J.

There is great variability in the degree to which children with attention deficit/hyperactivity disorder (ADHD) improve through behavioral treatments. This study investigates the influence of the dopamine transporter gene (SCL6A3/DAT1) on outcome of behavioral parent training (BPT). Study subjects

Dopamine transporter gene moderates response to behavioral parent training in children with ADHD: A pilot study

NARCIS (Netherlands)

van den Hoofdakker, B.J.; Nauta, M.H.; Dijck-Brouwer, D.A.J.; van der Veen-Mulders, L.; Sytema, S.; Emmelkamp, P.M.G.; Minderaa, R.B.; Hoekstra, P.J.

2012-01-01

There is great variability in the degree to which children with attention deficit/hyperactivity disorder (ADHD) improve through behavioral treatments. This study investigates the influence of the dopamine transporter gene (SCL6A3/DAT1) on outcome of behavioral parent training (BPT). Study subjects

Intranasal Dopamine Reduces In Vivo [(123)I]FP-CIT Binding to Striatal Dopamine Transporter: Correlation with Behavioral Changes and Evidence for Pavlovian Conditioned Dopamine Response.

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de Souza Silva, Maria A; Mattern, Claudia; Decheva, Cvetana; Huston, Joseph P; Sadile, Adolfo G; Beu, Markus; Müller, H-W; Nikolaus, Susanne

2016-01-01

Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [(123)I]FP-CIT to the DAT should be decreased due to competition at the receptor. Rats were administered 3 mg/kg IN-DA and vehicle (VEH), with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming) were assessed for 30 min in an open field prior to administration of [(123)I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT 2 h following administration of the radioligand. (1) After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered DA had central action and increased DA levels comparable to that found previously with L-DOPA administration; and (2) DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased) the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant drugs. (a) demonstrate a direct central action of intranasally

Clinical application of 99Tcm-TRODAT-1 SPECT imaging of dopamine transporter in monitoring the state of Parkinson's disease

International Nuclear Information System (INIS)

Deng Huaifu; Hu Ping

2005-01-01

To discuss the applicability of 99 Tc m -TRODAT-1 SPECT imaging of dopamine transporter in monitoring the state of Parkinson's disease (PD), 20 patients with PD and a control group of 14 healthy subjects were chosen to conduct dopamine transporter (DAT) imaging by SPECT with 99 Tc m -TRODAT-1. The radioactive ratio between bilateral striatum and cerebellum and the asymmetry index (Al) of bilateral striatum were computed by using the region of interest (ROI) technology. Meanwhile, the PD patients were classified by the improved Hoehn-Yahr Disability Score and then evaluated by Unified Parkinson's Disease Rating Scale (UPDRS). The findings show that there is a negative correlation between the bilateral ST/CB mean of the PD and the Hoehn-Yahr grading of the patients' state of illness, the UPDRS score, the patients' self-caring ability, the ability to move around. As for the asymmetry index AI PD , there was a positive correlation with the duration of disease, and a significant difference between the PD and the control group, with the former much higher than the latter. Therefore, the dopamine transporter imaging by SPECT with 99 Tc m -TRODAT-1 can monitor the state of Parkinson's disease, and show the symptom severity of Parkinson's disease. (authors)

Amphetamine activates Rho GTPase signaling to mediate dopamine transporter internalization and acute behavioral effects of amphetamine

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Wheeler, David S.; Underhill, Suzanne M.; Stolz, Donna B.; Murdoch, Geoffrey H.; Thiels, Edda; Romero, Guillermo; Amara, Susan G.

2015-01-01

Acute amphetamine (AMPH) exposure elevates extracellular dopamine through a variety of mechanisms that include inhibition of dopamine reuptake, depletion of vesicular stores, and facilitation of dopamine efflux across the plasma membrane. Recent work has shown that the DAT substrate AMPH, unlike cocaine and other nontransported blockers, can also stimulate endocytosis of the plasma membrane dopamine transporter (DAT). Here, we show that when AMPH enters the cytoplasm it rapidly stimulates DAT internalization through a dynamin-dependent, clathrin-independent process. This effect, which can be observed in transfected cells, cultured dopamine neurons, and midbrain slices, is mediated by activation of the small GTPase RhoA. Inhibition of RhoA activity with C3 exotoxin or a dominant-negative RhoA blocks AMPH-induced DAT internalization. These actions depend on AMPH entry into the cell and are blocked by the DAT inhibitor cocaine. AMPH also stimulates cAMP accumulation and PKA-dependent inactivation of RhoA, thus providing a mechanism whereby PKA- and RhoA-dependent signaling pathways can interact to regulate the timing and robustness of AMPH’s effects on DAT internalization. Consistent with this model, the activation of D1/D5 receptors that couple to PKA in dopamine neurons antagonizes RhoA activation, DAT internalization, and hyperlocomotion observed in mice after AMPH treatment. These observations support the existence of an unanticipated intracellular target that mediates the effects of AMPH on RhoA and cAMP signaling and suggest new pathways to target to disrupt AMPH action. PMID:26553986

Experimental Implementation of a Biometric Laser Synaptic Sensor

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Alexander N. Pisarchik

2013-12-01

Full Text Available We fabricate a biometric laser fiber synaptic sensor to transmit information from one neuron cell to the other by an optical way. The optical synapse is constructed on the base of an erbium-doped fiber laser, whose pumped diode current is driven by a pre-synaptic FitzHugh–Nagumo electronic neuron, and the laser output controls a post-synaptic FitzHugh–Nagumo electronic neuron. The implemented laser synapse displays very rich dynamics, including fixed points, periodic orbits with different frequency-locking ratios and chaos. These regimes can be beneficial for efficient biorobotics, where behavioral flexibility subserved by synaptic connectivity is a challenge.

Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini*

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Vuorenpää, Anne; Jørgensen, Trine N.; Newman, Amy H.; Madsen, Kenneth L.; Scheinin, Mika

2016-01-01

The norepinephrine transporter (NET) mediates reuptake of synaptically released norepinephrine in central and peripheral noradrenergic neurons. The molecular processes governing availability of NET in the plasma membrane are poorly understood. Here we use the fluorescent cocaine analogue JHC 1-64, as well as several other approaches, to investigate the trafficking itinerary of NET in live noradrenergic neurons. Confocal imaging revealed extensive constitutive internalization of JHC 1-64-labeled NET in the neuronal somata, proximal extensions and presynaptic boutons. Phorbol 12-myristate 13-acetate increased intracellular accumulation of JHC 1-64-labeled NET and caused a parallel reduction in uptake capacity. Internalized NET strongly colocalized with the “long loop” recycling marker Rab11, whereas less overlap was seen with the “short loop” recycling marker Rab4 and the late endosomal marker Rab7. Moreover, mitigating Rab11 function by overexpression of dominant negative Rab11 impaired NET function. Sorting of NET to the Rab11 recycling compartment was further supported by confocal imaging and reversible biotinylation experiments in transfected differentiated CATH.a cells. In contrast to NET, the dopamine transporter displayed markedly less constitutive internalization and limited sorting to the Rab11 recycling compartment in the differentiated CATH.a cells. Exchange of domains between the two homologous transporters revealed that this difference was determined by non-conserved structural elements in the intracellular N terminus. We conclude that NET displays a distinct trafficking itinerary characterized by continuous shuffling between the plasma membrane and the Rab11 recycling compartment and that the functional integrity of the Rab11 compartment is critical for maintaining proper presynaptic NET function. PMID:26786096

Pregnenolone rescues schizophrenia-like behavior in dopamine transporter knockout mice.

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Peiyan Wong

Full Text Available Pregnenolone belongs to a class of endogenous neurosteroids in the central nervous system (CNS, which has been suggested to enhance cognitive functions through GABA(A receptor signaling by its metabolites. It has been shown that the level of pregnenolone is altered in certain brain areas of schizophrenic patients, and clozapine enhances pregnenolone in the CNS in rats, suggesting that pregnenolone could be used to treat certain symptoms of schizophrenia. In addition, early phase proof-of-concept clinical trials have indicated that pregnenolone is effective in reducing the negative symptoms and cognitive deficits of schizophrenia patients. Here, we evaluate the actions of pregnenolone on a mouse model for schizophrenia, the dopamine transporter knockout mouse (DAT KO. DAT KO mice mirror certain symptoms evident in patients with schizophrenia, such as the psychomotor agitation, stereotypy, deficits of prepulse inhibition and cognitive impairments. Following acute treatment, pregnenolone was found to reduce the hyperlocomotion, stereotypic bouts and pre-pulse inhibition (PPI deficits in DAT KO mice in a dose-dependent manner. At 60 mg/kg of pregnenolone, there were no significant differences in locomotor activities and stereotypy between wild-type and DAT KO mice. Similarly, acute treatment of 60 mg/kg of pregnenolone fully rescued PPI deficits of DAT KO mice. Following chronic treatment with pregnenolone at 60 mg/kg, the cognitive deficits of DAT KO mice were rescued in the paradigms of novel object recognition test and social transmission of food preference test. Pregnenolone thus holds promise as a therapeutic candidate in schizophrenia.

pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract

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McCrimmon, Donald R.; Martina, Marco

2013-01-01

The nucleus of the solitary tract (NTS) is the major site for termination of visceral sensory afferents contributing to homeostatic regulation of, for example, arterial pressure, gastric motility, and breathing. Whereas much is known about how different neuronal populations influence these functions, information about the role of glia remains scant. In this article, we propose that glia may contribute to NTS functions by modulating excitatory neurotransmission. We found that acidification (pH 7.0) depolarizes NTS glia by inhibiting K+-selective membrane currents. NTS glia also showed functional expression of voltage-sensitive glutamate transporters, suggesting that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake. To test this hypothesis, we evoked glutamatergic slow excitatory potentials (SEPs) in NTS neurons with repetitive stimulation (20 pulses at 10 Hz) of the solitary tract. This SEP depends on accumulation of glutamate following repetitive stimulation, since it was potentiated by blocking glutamate uptake with dl-threo-β-benzyloxyaspartic acid (TBOA) or a glia-specific glutamate transport blocker, dihydrokainate (DHK). Importantly, extracellular acidification (pH 7.0) also potentiated the SEP. This effect appeared to be mediated through a depolarization-induced inhibition of glial transporter activity, because it was occluded by TBOA and DHK. In agreement, pH 7.0 did not directly alter d-aspartate-induced responses in NTS glia or properties of presynaptic glutamate release. Thus acidification-dependent regulation of glial function affects synaptic transmission within the NTS. These results suggest that glia play a modulatory role in the NTS by integrating local tissue signals (such as pH) with synaptic inputs from peripheral afferents. PMID:23615553

Behavioral Phenotyping of Dopamine Transporter Knockout Rats: Compulsive Traits, Motor Stereotypies, and Anhedonia

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Stefano Cinque

2018-02-01

Full Text Available Alterations in dopamine neurotransmission are generally associated with diseases such as attention-deficit/hyperactivity disorder (ADHD and obsessive-compulsive disorder (OCD. Such diseases typically feature poor decision making and lack of control on executive functions and have been studied through the years using many animal models. Dopamine transporter (DAT knockout (KO and heterozygous (HET mice, in particular, have been widely used to study ADHD. Recently, a strain of DAT KO rats has been developed (1. Here, we provide a phenotypic characterization of reward sensitivity and compulsive choice by adult rats born from DAT–HET dams bred with DAT–HET males, in order to further validate DAT KO rats as an animal model for preclinical research. We first tested DAT KO rats’ sensitivity to rewarding stimuli, provided by highly appetitive food or sweet water; then, we tested their choice behavior with an Intolerance-to-Delay Task (IDT. During these tests, DAT KO rats appeared less sensitive to rewarding stimuli than wild-type (WT and HET rats: they also showed a prominent hyperactive behavior with a rigid choice pattern and a wide number of compulsive stereotypies. Moreover, during the IDT, we tested the effects of amphetamine (AMPH and RO-5203648, a trace amine-associated receptor 1 (TAAR1 partial agonist. AMPH accentuated impulsive behaviors in WT and HET rats, while it had no effect in DAT KO rats. Finally, we measured the levels of tyrosine hydroxylase, dopamine receptor 2 (D2, serotonin transporter, and TAAR1 mRNA transcripts in samples of ventral striatum, finding no significant differences between WT and KO genotypes. Throughout this study, DAT KO rats showed alterations in decision-making processes and in motivational states, as well as prominent motor and oral stereotypies: more studies are warranted to fully characterize and efficiently use them in preclinical research.

Factors Influencing Short-term Synaptic Plasticity in the Avian Cochlear Nucleus Magnocellularis

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Jason Tait Sanchez Quinones

2015-01-01

Full Text Available Defined as reduced neural responses during high rates of activity, synaptic depression is a form of short-term plasticity important for the temporal filtering of sound. In the avian cochlear nucleus magnocellularis (NM, an auditory brainstem structure, mechanisms regulating short-term synaptic depression include pre-, post-, and extrasynaptic factors. Using varied paired-pulse stimulus intervals, we found that the time course of synaptic depression lasts up to four seconds at late-developing NM synapses. Synaptic depression was largely reliant on exogenous Ca 2+ -dependent probability of presynaptic neurotransmitter release, and to a lesser extent, on the desensitization of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPA-R. Interestingly, although extrasynaptic glutamate clearance did not play a significant role in regulating synaptic depression, blocking glutamate clearance at early-developing synapses altered synaptic dynamics, changing responses from depression to facilitation. These results suggest a developmental shift in the relative reliance on pre-, post-, and extrasynaptic factors in regulating short-term synaptic plasticity in NM.

FMR1 gene expansion and scans without evidence of dopaminergic deficits in parkinsonism patients.

Science.gov (United States)

Hall, D A; Jennings, D; Seibyl, J; Tassone, F; Marek, K

2010-11-01

To determine if patients with parkinsonism and fragile X mental retardation 1 (FMR1) gene expansions have a striatal dopamine deficit similar to Parkinson disease (PD) patients. The authors studied three patients with parkinsonism carrying small expansions in the FMR1 gene (41-60 CGG) with [(123)I]β-CIT SPECT imaging. The patients responded to dopaminergic medications, but had preserved dopamine transporter density. These results suggest that parkinsonism associated with smaller FMR1 expansions may be related to mechanisms other than pre-synaptic dopaminergic changes and may represent a potential explanation for at least some parkinsonian cases with scans without evidence of dopaminergic deficits (SWEDD). Copyright © 2010 Elsevier Ltd. All rights reserved.

Pet's research at the SHFJ, Cea, one example: development and validation of a radioligand for the study of the cerebral dopaminergic system

International Nuclear Information System (INIS)

Ribeiro, M.J.

2005-01-01

The aim of this work is the evaluation of biodistribution and radiation dosimetry of a cocaine analog, the N-(3-iodo-prop-2E-enyl)-2beta-carbo-methoxy-3beta-(4-methyl-phenyl) nor-tropane (PE2I), labeled with carbon 11 ([ 11 C]PE2I). The [ 11 C]PE2I is a selective radioligand for imaging neuronal dopamine transporter (DAT) with positron emission tomography (PET). The DAT is a membrane-bound pre synaptically located protein that regulates the concentration of dopamine at nerve terminals. DAT radioligands are often used to evaluate the progression of Parkinson's disease or the efficiency of neuro-protective therapeutics and, typically, these studies required several successive PET scans. (author)

The dopamine hypothesis of drug addiction and its potential therapeutic value.

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Marco eDiana

2011-11-01

Full Text Available Dopamine (DA transmission is deeply affected by drugs of abuse, and alterations in DA function are involved in various phases of drug addiction and potentially exploitable therapeutically. In particular, basic studies have documented a reduction in the electrophysiological activity of DA neurons in alcohol, opiate, cannabinoid and other drug-dependent rats. Further, DA release in the Nacc is decreased in virtually all drug-dependent rodents. In parallel, these studies are supported by increments in intracranial self stimulation (ICSS thresholds during withdrawal from alcohol, nicotine, opiates, and other drugs of abuse, thereby suggesting a hypofunction of the neural substrate of ICSS. Accordingly, morphological evaluations fed into realistic computational analysis of the Medium Spiny Neuron (MSN of the Nucleus accumbens (Nacc, post-synaptic counterpart of DA terminals, show profound changes in structure and function of the entire mesolimbic system. In line with these findings, human imaging studies have shown a reduction of dopamine receptors accompanied by a lesser release of endogenous DA in the ventral striatum of cocaine, heroin and alcohol-dependent subjects, thereby offering visual proof of the ‘dopamine-impoverished’ addicted human brain.The reduction in physiological activity of the DA system leads to the idea that an increment in its activity, to restore pre-drug levels, may yield significant clinical improvements (reduction of craving, relapse and drug-seeking/taking. In theory, it may be achieved pharmacologically and/or with novel interventions such as Transcranial Magnetic Stimulation (TMS. Its anatomo-physiological rationale as a possible therapeutic aid in alcoholics and other addicts will be described and proposed as a theoretical framework to be subjected to experimental testing in human addicts.

Blockade of group II metabotropic glutamate receptors produces hyper-locomotion in cocaine pre-exposed rats by interactions with dopamine receptors.

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Yoon, Hyung Shin; Jang, Ju Kyong; Kim, Jeong-Hoon

2008-09-01

It was previously reported that blockade of group II metabotropic glutamate receptors (mGluRs) produces hyper-locomotion in rats previously exposed to amphetamine, indicating that group II mGluRs are well positioned to modulate the expression of behavioral sensitization by amphetamine. The present study further examined the locomotor activating effects of specific blockade of these receptors after cocaine pre-exposures. First, rats were pre-exposed to seven daily injections of cocaine (15mg/kg, IP). When challenged the next day with an injection of either saline or the group II mGluR antagonist LY341495 (0.5, 1.0 or 2.5mg/kg, IP), they produced hyper-locomotor activity, measured by infrared beam interruptions, to LY341495 compared to saline in a dose-dependent manner. Second, rats were pre-exposed to either saline or seven daily injections of cocaine (15mg/kg, IP). Three weeks later, when they were challenged with an injection of either saline or LY341495 (1.0mg/kg, IP), only rats pre-exposed to cocaine produced hyper-locomotor activity to LY341495 compared to saline. These effects, however, were not present when dopamine D1 (SCH23390; 5 or 10microg/kg), but not D2 (eticlopride; 10 or 50microg/kg), receptor antagonist was pre-injected, indicating that this cocaine-induced hyper-locomotor activity to LY341495 may be mediated in dopamine D1 receptor-dependent manner. These results suggest that group II mGluRs may be adapted to interact with dopaminergic neuronal signaling in mediating the sensitized locomotor activity produced by repeated cocaine pre-exposures.

Oxytocin receptor antagonist treatments alter levels of attachment to mothers and central dopamine activity in pre-weaning mandarin vole pups.

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He, Zhixiong; Hou, Wenjuan; Hao, Xin; Dong, Na; Du, Peirong; Yuan, Wei; Yang, Jinfeng; Jia, Rui; Tai, Fadao

2017-10-01

Oxytocin (OT) is known to be important in mother-infant bonding. Although the relationship between OT and filial attachment behavior has been studied in a few mammalian species, the effects on infant social behavior have received little attention in monogamous species. The present study examined the effects of OT receptor antagonist (OTA) treatment on attachment behavior and central dopamine (DA) activity in male and female pre-weaning mandarin voles (Microtus mandarinus). Our data showed that OTA treatments decreased the attachment behavior of pups to mothers, measured using preference tests at postnatal day 14, 16, 18 and 20. OTA treatments reduced serum OT concentration in pre-weaning pups and decreased tyrosine hydroxylase (TH) levels in the ventral tegmental area (VTA), indicating a decrease in central DA activity. In male and female pups, OTA reduced DA levels, DA 1-type receptor (D1R) and DA 2-type receptor (D2R) protein expression in the nucleus accumbens (NAcc). Our results indicate that OTA treatment inhibits the attachment of pre-weaning pups to mothers. This inhibition is possibly associated with central DA activity and levels of two types of dopamine receptor in the NAcc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease.

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2005-08-01

Full Text Available Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs.

Dopamine transporter imaging in rapid eye movement sleep behavior disorder

International Nuclear Information System (INIS)

Kim, Yu Kyeong; Yoon, In Young; Kim, Jong Min; Jeong, Seok Hoon; Kim, Ji Sun; Lee, Byung Chul; Lee, Won Woo; Kim, Sang Eun

2007-01-01

The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is still unknown. However, involvement of dopaminergic system in RBD has been hypothesized because of frequent association with degenerative movement disorders such as Parkinson's disease. The purpose of this study was to examine the extent and pattern of loss of dopamine transporter in RBD using FP-CIT SPECT. Fourteen patient with idiopathic RBD (mean age:665 yrs, M:F=10:3) participated in this study. Polysonmography confirmed loss of REM atonia and determined RBD severities by amount of tonic/phasic muscle activity during REM sleep in all cases. To compare with RBD, 14 early idiopathic Parkinson's disease rated as Hoehn and Yahr stage 1 (IPD) and 12 healthy controls were also selected. All participants performed single-photon emission computed tomography (SPECT) imaging 3 hours after injection of [123I]FP-CIT. Regions of interest were drawn on bilateral caudate and putamen, whole striatum and occipital cortex. Specific binding for dopamine transporters (DAT) were calculated using region to occipital uptake ratio based on the transient equilibrium method. Overall mean of DAT density in the striatum was lower in RBD group than controls, and higher than IPD group, However, DAT density in most individual RBD was still within normal range, and total striatal DAT density was not correlated with severity of RBD. Meanwhile, the caudate to putamen uptake ratio (C/P ratio) in RBD group was insignificantly higher than those in healthy controls. Nevertheless, C/P ratio within RBD group was reversely correlated with the RBD severity. Our study suggested that nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. Further longitudinal evaluation of presynaptic dopaminergic system in idiopathic RBD may guarantee the more understanding for RBD and associated neurodegenerative disease

Dopamine transporter imaging in rapid eye movement sleep behavior disorder

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Kim, Yu Kyeong; Yoon, In Young; Kim, Jong Min; Jeong, Seok Hoon; Kim, Ji Sun; Lee, Byung Chul; Lee, Won Woo; Kim, Sang Eun [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

2007-07-01

The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is still unknown. However, involvement of dopaminergic system in RBD has been hypothesized because of frequent association with degenerative movement disorders such as Parkinson's disease. The purpose of this study was to examine the extent and pattern of loss of dopamine transporter in RBD using FP-CIT SPECT. Fourteen patient with idiopathic RBD (mean age:665 yrs, M:F=10:3) participated in this study. Polysonmography confirmed loss of REM atonia and determined RBD severities by amount of tonic/phasic muscle activity during REM sleep in all cases. To compare with RBD, 14 early idiopathic Parkinson's disease rated as Hoehn and Yahr stage 1 (IPD) and 12 healthy controls were also selected. All participants performed single-photon emission computed tomography (SPECT) imaging 3 hours after injection of [123I]FP-CIT. Regions of interest were drawn on bilateral caudate and putamen, whole striatum and occipital cortex. Specific binding for dopamine transporters (DAT) were calculated using region to occipital uptake ratio based on the transient equilibrium method. Overall mean of DAT density in the striatum was lower in RBD group than controls, and higher than IPD group, However, DAT density in most individual RBD was still within normal range, and total striatal DAT density was not correlated with severity of RBD. Meanwhile, the caudate to putamen uptake ratio (C/P ratio) in RBD group was insignificantly higher than those in healthy controls. Nevertheless, C/P ratio within RBD group was reversely correlated with the RBD severity. Our study suggested that nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. Further longitudinal evaluation of presynaptic dopaminergic system in idiopathic RBD may guarantee the more understanding for RBD and associated neurodegenerative disease.

Differential Dopamine Regulation of Ca2+ Signaling and Its Timing Dependence in the Nucleus Accumbens

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Immani Swapna

2016-04-01

Full Text Available Dopamine action in the nucleus accumbens (NAc is thought to drive appetitive behavior and Pavlovian reward learning. However, it remains controversial how dopamine achieves these behavioral effects by regulating medium spiny projection neurons (MSNs of the NAc, especially on a behaviorally relevant timescale. Metabotropic glutamate receptor (mGluR-induced Ca2+ signaling dependent on the Ca2+- releasing messenger inositol 1,4,5-triphosphate (IP3 plays a critical role in controlling neuronal excitability and synaptic plasticity. Here, we show that transient dopamine application facilitates mGluR/IP3-induced Ca2+ signals within a time window of ∼2–10 s in a subpopulation of MSNs in the NAc core. Dopamine facilitation of IP3-induced Ca2+ signaling is mediated by D1 dopamine receptors. In dopamine-insensitive MSNs, activation of A2A adenosine receptors causes enhancement of IP3-evoked Ca2+ signals, which is reversed by D2 dopamine receptor activation. These results show that dopamine differentially regulates Ca2+ signaling on the order of seconds in two distinct MSN subpopulations.

Essential Oils from the Medicinal Herbs Upregulate Dopamine Transporter in Rat Pheochromocytoma Cells.

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Choi, Min Sun; Choi, Bang-sub; Kim, Sang Heon; Pak, Sok Cheon; Jang, Chul Ho; Chin, Young-Won; Kim, Young-Mi; Kim, Dong-il; Jeon, Songhee; Koo, Byung-Soo

2015-10-01

The dopamine transporter (DAT) protein, a component of the dopamine system, undergoes adaptive neurobiological changes from drug abuse. Prevention of relapse and reduction of withdrawal symptoms are still the major limitations in the current pharmacological treatments of drug addiction. The present study aimed to investigate the effects of essential oils extracted from Elsholtzia ciliata, Shinchim, Angelicae gigantis Radix, and Eugenia caryophyllata, well-known traditional Korean medicines for addiction, on the modulation of dopamine system in amphetamine-treated cells and to explore the possible mechanism underlying its therapeutic effect. The potential cytotoxic effect of essential oils was evaluated in PC12 rat pheochromocytoma cells using cell viability assays. Quantification of DAT, p-CREB, p-MAPK, and p-Akt was done by immunoblotting. DAT was significantly reduced in cells treated with 50 μM of amphetamine in a time-dependent manner. No significant toxicity of essential oils from Elsholtzia ciliata and Shinchim was observed at doses of 10, 25, and 50 μg/mL. However, essential oils from A. gigantis Radix at a dose of 100 μg/mL and E. caryophyllata at doses of 50 and 100 μg/mL showed cytotoxicity. Treatment with GBR 12909, a highly selective DAT inhibitor, significantly increased DAT expression compared with that of amphetamine only by enhancing phosphorylation of mitogen-activated protein kinases (MAPK) and Akt. In addition, essential oils effectively induced hyperphosphorylation of cyclic-AMP response element-binding protein (CREB), MAPK, and Akt, which resulted in DAT upregulation. Our study implies that the essential oils may rehabilitate brain dopamine function through increased DAT availability in abstinent former drug users.

Self-organised criticality via retro-synaptic signals

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Hernandez-Urbina, Victor; Herrmann, J. Michael

2016-12-01

The brain is a complex system par excellence. In the last decade the observation of neuronal avalanches in neocortical circuits suggested the presence of self-organised criticality in brain networks. The occurrence of this type of dynamics implies several benefits to neural computation. However, the mechanisms that give rise to critical behaviour in these systems, and how they interact with other neuronal processes such as synaptic plasticity are not fully understood. In this paper, we present a long-term plasticity rule based on retro-synaptic signals that allows the system to reach a critical state in which clusters of activity are distributed as a power-law, among other observables. Our synaptic plasticity rule coexists with other synaptic mechanisms such as spike-timing-dependent plasticity, which implies that the resulting synaptic modulation captures not only the temporal correlations between spiking times of pre- and post-synaptic units, which has been suggested as requirement for learning and memory in neural systems, but also drives the system to a state of optimal neural information processing.

The Design, Synthesis and Structure-Activity Relationship of Mixed Serotonin, Norepinephrine and Dopamine Uptake Inhibitors

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Chen, Zhengming; Yang, Ji; Skolnick, Phil

The evolution of antidepressants over the past four decades has involved the replacement of drugs with a multiplicity of effects (e.g., TCAs) by those with selective actions (i.e., SSRIs). This strategy was employed to reduce the adverse effects of TCAs, largely by eliminating interactions with certain neurotransmitters or receptors. Although these more selective compounds may be better tolerated by patients, selective drugs, specifically SSRIs, are not superior to older drugs in treating depressed patients as measured by response and remission rates. It may be an advantage to increase synaptic levels of both serotonin and norepinephrine, as in the case of dual uptake inhibitors like duloxetine and venlafaxine. An important recent development has been the emergence of the triple-uptake inhibitors (TUIs/SNDRIs), which inhibit the uptake of the three neurotransmitters most closely linked to depression: serotonin, norepinephrine, and dopamine. Preclinical studies and clinical trials indicate that a drug inhibiting the reuptake of all three of these neurotransmitters could produce more rapid onset of action and greater efficacy than traditional antidepressants. This review will detail the medicinal chemistry involved in the design, synthesis and discovery of mixed serotonin, norepinephrine and dopamine transporter uptake inhibitors.

Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies.

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Kaasinen, Valtteri; Vahlberg, Tero

2017-12-01

A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882. © 2017 American Neurological Association.

Systemic effects of low-dose dopamine during administration of cytarabine.

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Connelly, James; Benani, Dina J; Newman, Matthew; Burton, Bradley; Crow, Jessica; Levis, Mark

2017-09-01

Purpose Low-dose dopamine has been utilized to improve renal blood flow, urine output, and reduce drug-induced nephrotoxicity. The purpose of this study was to assess changes in renal function, cardiovascular adverse events, and neurologic toxicity in patients receiving cytarabine with or without low-dose dopamine. Methods A retrospective, single-center, cohort study of patients receiving cytarabine at 667 mg/m 2 /dose or greater, with or without dopamine at ≤5 mcg/kg/min. Cohorts were based upon initiation or absence of low-dose dopamine; cytarabine only, cytarabine + pre- and day of low-dose dopamine, and cytarabine + post-low-dose dopamine. Renal outcomes (urine output, serum creatinine, and creatinine clearance) were compared with baseline and between cohorts. Safety endpoints (arrhythmias, tachycardia, and neurotoxicity) were compared between cohorts based on low-dose dopamine exposure. Results There was no difference in urine output from baseline in all cohorts. Comparing cytarabine only and pre- and day of low-dose dopamine cohorts, there was no difference in urine output. In those receiving low-dose dopamine, there was no difference in serum creatinine and creatinine clearance from baseline. No arrhythmias were documented during the study period, and there was no difference in the incidence of tachycardia between groups (P = 0.66). Neurotoxicity was reported in three patients who were on low-dose dopamine. Conclusion Though variation existed in individual patients administered low-dose dopamine, the use of low-dose dopamine did not significantly impact renal function in this small sample at a single institution. In addition, low-dose dopamine did not negatively impact cardiovascular function.

Distinct Roles of Opioid and Dopamine Systems in Lateral Hypothalamic Intracranial Self-Stimulation.

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Ide, Soichiro; Takahashi, Takehiro; Takamatsu, Yukio; Uhl, George R; Niki, Hiroaki; Sora, Ichiro; Ikeda, Kazutaka

2017-05-01

Opioid and dopamine systems play crucial roles in reward. Similarities and differences in the neural mechanisms of reward that are mediated by these 2 systems have remained largely unknown. Thus, in the present study, we investigated the differences in reward function in both µ-opioid receptor knockout mice and dopamine transporter knockout mice, important molecules in the opioid and dopamine systems. Mice were implanted with electrodes into the right lateral hypothalamus (l hour). Mice were then trained to put their muzzle into the hole in the head-dipping chamber for intracranial electrical stimulation, and the influences of gene knockout were assessed. Significant differences are observed between opioid and dopamine systems in reward function. µ-Opioid receptor knockout mice exhibited enhanced intracranial electrical stimulation, which induced dopamine release. They also exhibited greater motility under conditions of "despair" in both the tail suspension test and water wheel test. In contrast, dopamine transporter knockout mice maintained intracranial electrical stimulation responding even when more active efforts were required to obtain the reward. The absence of µ-opioid receptor or dopamine transporter did not lead to the absence of intracranial electrical stimulation responsiveness but rather differentially altered it. The present results in µ-opioid receptor knockout mice are consistent with the suppressive involvement of µ-opioid receptors in both positive incentive motivation associated with intracranial electrical stimulation and negative incentive motivation associated with depressive states. In contrast, the results in dopamine transporter knockout mice are consistent with the involvement of dopamine transporters in positive incentive motivation, especially its persistence. Differences in intracranial electrical stimulation in µ-opioid receptor and dopamine transporter knockout mice underscore the multidimensional nature of reward. © The Author

Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease

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Kaasinen, Valtteri; Kinos, Maija; Joutsa, Juho [University of Turku and Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Seppaenen, Marko [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); University of Turku and Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku (Finland); Noponen, Tommi [University of Turku and Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku (Finland)

2014-10-15

Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor. [{sup 123}I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates. Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen. The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor. (orig.)

The sigma-1 receptor modulates dopamine transporter conformation and cocaine binding and may thereby potentiate cocaine self-administration in rats.

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Hong, Weimin Conrad; Yano, Hideaki; Hiranita, Takato; Chin, Frederick T; McCurdy, Christopher R; Su, Tsung-Ping; Amara, Susan G; Katz, Jonathan L

2017-07-07

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 (σ 1 R) is a molecular chaperone, and its ligands have been shown to modulate DA neuronal signaling, although their effects on DAT activity are unclear. Here, we report that the prototypical σ 1 R agonist (+)-pentazocine potentiated the dose response of cocaine self-administration in rats, consistent with the effects of the σR agonists PRE-084 and DTG (1,3-di- o -tolylguanidine) reported previously. These behavioral effects appeared to be correlated with functional changes of DAT. Preincubation with (+)-pentazocine or PRE-084 increased the B max values of [ 3 H]WIN35428 binding to DAT in rat striatal synaptosomes and transfected cells. A specific interaction between σ 1 R and DAT was detected by co-immunoprecipitation and bioluminescence resonance energy transfer assays. Mutational analyses indicated that the transmembrane domain of σ 1 R likely mediated this interaction. Furthermore, cysteine accessibility assays showed that σ 1 R agonist preincubation potentiated cocaine-induced changes in DAT conformation, which were blocked by the specific σ 1 R antagonist CM304. Moreover, σ 1 R ligands had distinct effects on σ 1 R multimerization. CM304 increased the proportion of multimeric σ 1 Rs, whereas (+)-pentazocine increased monomeric σ 1 Rs. Together these results support the hypothesis that σ 1 R agonists promote dissociation of σ 1 R multimers into monomers, which then interact with DAT to stabilize an outward-facing DAT conformation and enhance cocaine binding. We propose that this novel molecular mechanism underlies the behavioral potentiation of cocaine self-administration by σ 1 R agonists in animal models. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex

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Pinto, Joshua G. A.; Jones, David G.; Williams, C. Kate; Murphy, Kathryn M.

2015-01-01

Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin) and found that synaptic development in human primary visual cortex (V1) continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the four proteins and include a stage during early development (visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic. PMID:25729353

Antagonism of presynaptic dopamine receptors by phenothiazine drug metabolites

International Nuclear Information System (INIS)

Nowak, J.Z.; Arbilla, S.; Langer, S.Z.; Dahl, S.G.

1990-01-01

Electrically evoked release of dopamine from the caudate nucleus is reduced by the dopamine receptor agonists, apomorphine and bromocriptine, and facilitated by neuroleptic drugs, which act as dopamine autoreceptor antagonists. The potencies of chlorpromazine, fluphenazine, levomepromazine and their hydroxy-metabolites in modulating electrically evoked release of dopamine were examined by superfusion of rabbit caudate nucleus slices pre-incubated with 3 H-dopamine. O-Desmethyl levomepromazine, 3-hydroxy- and 7-hydroxy metabolites of chlorpromazine and levomepromazine facilitated electrically evoked release of 3 H-dopamine, having potencies similar to that of the parent compounds. 7-Hydroxy fluphenazine was less active than fluphenazine in this system. These results indicate that phenolic metabolites of chlorpromazine and levomepromazine, but not of fluphenazine, may contribute to effects of the drugs mediated by presynaptic dopamine receptors

Myocardial pre-synaptic sympathetic function correlates with glucose uptake in the failing human heart

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Mongillo, Marco; Leccisotti, Lucia [Hammersmith Hospital, Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, London (United Kingdom); John, Anna S. [Hammersmith Hospital, National Heart and Lung Institute, Imperial College, London (United Kingdom); Pennell, Dudley J. [Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London (United Kingdom); Camici, Paolo G. [Hammersmith Hospital, Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, London (United Kingdom); Hammersmith Hospital, National Heart and Lung Institute, Imperial College, London (United Kingdom)

2007-08-15

We have previously shown that the myocardium of patients with heart failure (HF) is insulin resistant. Chronic {beta}-adrenergic stimulation has been implicated in insulin resistance in cultured cardiomyocytes in vitro, where sustained noradrenaline stimulation inhibited insulin-modulated glucose uptake. As the failing heart is characterized by increased sympathetic drive, we hypothesized that there is a correlation between pre-synaptic sympathetic function and insulin sensitivity in the myocardium of patients with HF. Eight patients (aged 67 {+-} 7 years) with coronary artery disease and left ventricular dysfunction (ejection fraction 44 {+-} 10%) underwent function and viability assessment with cardiovascular magnetic resonance. Myocardial glucose utilization (MGU) was measured using positron emission tomography (PET) with {sup 18}F-fluorodeoxyglucose (FDG). Pre-synaptic noradrenaline re-uptake was measured by calculating [{sup 11}C]meta-hydroxy-ephedrine (HED) volume of distribution (V{sub d}) with PET. Two groups of healthy volunteers served as controls for the FDG (n = 8, aged 52 {+-} 4 years, p < 0.01 vs patients) and HED (n = 8, aged 40 {+-} 6 years, p < 0.01 vs patients) data. MGU in patients was reduced in both normal remote (0.44 {+-} 0.14 {mu}mol.min{sup -1}.g{sup -1}) and dysfunctional (0.49 {+-} 0.14 {mu}mol.min{sup -1}.g{sup -1}) segments compared with controls (0.61 {+-} 0.7 {mu}mol.min{sup -1}.g{sup -1}; p < 0.001 vs both). HED V{sub d} was reduced in dysfunctional segments of patients (38.9 {+-} 21.2 ml.g{sup -1}) compared with normal segments (52.2 {+-} 19.6 ml.g{sup -1}) and compared with controls (62.7 {+-} 11.3 ml.g{sup -1}). In patients, regional MGU was correlated with HED V{sub d}. The results of this study provide novel evidence of a correlation between cardiac sympathetic function and insulin sensitivity, which may represent one of the mechanisms contributing to insulin resistance in failing human hearts. (orig.)

Dopamine transporter SPECT in patients with Parkinson's disease

International Nuclear Information System (INIS)

Hamano, Tadanori; Tsuchida, Tatsuro; Hirayama, Mikio; Fujiyama, Jiro; Mutoh, Tatsuro; Yonekura, Yoshiharu; Kuriyama, Masaru

2000-01-01

The major neuropathological feature in Parkinson's disease (PD) is severe degeneration of the dopamine (DA) neurons in the substantia nigra. Dopamine transporter (DAT) is an important protein in the regulation of DA neurotransmission. It has been reported that PD patients show a loss of DAT in striatum. We report here the findings of single photon emission computed tomography (SPECT) of the DAT with 2β-carboxymethoxy-3β-(4[ 123 I]iodophenyl)tropane ([ 123 I]β-CIT) to investigate striatal DAT in 10 patients with PD, one patient with vascular parkinsonism (VP), and one patient with dystonia syndrome. Patients were evaluated using the Webster rating scale. Specific/nondisplaceable striatal binding ratio (V3'') was obtained in each case. In PD patients, the uptake of [ 123 I]β-CIT was reduced, especially in the tail of putamen compared with caudate nucleus. Even in the early stage of PD, the uptake of β-CIT was reduced not only in the severely affected side, but also in the mildly disturbed side of the brain. Putamen caudate ratio was generally low in PD patients. In VP patient, the uptake was reduced, but putamen caudate ratio was not decreased. V3'' values showed significant correlation with the severity of clinical symptoms such as self-care, facies, posture, gait, speech, and Hoehn-Yahr's stage. On the other hand, V3'' values were not significantly correlated with the degree of tremor, seborrhea, and duration of the illness. In conclusion, we found that SPECT of the [ 123 I]β-CIT is a useful method for the diagnosis in the patients presenting parkinsonism, and for the clinico-physiological estimation of parkinsonian symptoms such as self-care, facies, posture, gait, and speech. (author)

Homeostatic mechanisms in dopamine synthesis and release: a mathematical model

Directory of Open Access Journals (Sweden)

Nijhout H Frederik

2009-09-01

Full Text Available Abstract Background Dopamine is a catecholamine that is used as a neurotransmitter both in the periphery and in the central nervous system. Dysfunction in various dopaminergic systems is known to be associated with various disorders, including schizophrenia, Parkinson's disease, and Tourette's syndrome. Furthermore, microdialysis studies have shown that addictive drugs increase extracellular dopamine and brain imaging has shown a correlation between euphoria and psycho-stimulant-induced increases in extracellular dopamine 1. These consequences of dopamine dysfunction indicate the importance of maintaining dopamine functionality through homeostatic mechanisms that have been attributed to the delicate balance between synthesis, storage, release, metabolism, and reuptake. Methods We construct a mathematical model of dopamine synthesis, release, and reuptake and use it to study homeostasis in single dopaminergic neuron terminals. We investigate the substrate inhibition of tyrosine hydroxylase by tyrosine, the consequences of the rapid uptake of extracellular dopamine by the dopamine transporters, and the effects of the autoreceoptors on dopaminergic function. The main focus is to understand the regulation and control of synthesis and release and to explicate and interpret experimental findings. Results We show that the substrate inhibition of tyrosine hydroxylase by tyrosine stabilizes cytosolic and vesicular dopamine against changes in tyrosine availability due to meals. We find that the autoreceptors dampen the fluctuations in extracellular dopamine caused by changes in tyrosine hydroxylase expression and changes in the rate of firing. We show that short bursts of action potentials create significant dopamine signals against the background of tonic firing. We explain the observed time courses of extracellular dopamine responses to stimulation in wild type mice and mice that have genetically altered dopamine transporter densities and the observed

PRESYNAPTIC DOPAMINE MODULATION BY STIMULANT SELF ADMINISTRATION

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España, Rodrigo A.; Jones, Sara R.

2013-01-01

The mesolimbic dopamine system is an essential participant in the initiation and modulation of various forms of goal-directed behavior, including drug reinforcement and addiction processes. Dopamine neurotransmission is increased by acute administration of all drugs of abuse, including the stimulants cocaine and amphetamine. Chronic exposure to these drugs via voluntary self-administration provides a model of stimulant abuse that is useful in evaluating potential behavioral and neurochemical adaptations that occur during addiction. This review describes commonly used methodologies to measure dopamine and baseline parameters of presynaptic dopamine regulation, including exocytotic release and reuptake through the dopamine transporter in the nucleus accumbens core, as well as dramatic adaptations in dopamine neurotransmission and drug sensitivity that occur with acute non-contingent and chronic, contingent self-administration of cocaine and amphetamine. PMID:23277050

Evaluation of dopamine transporters and D2 receptors in hemiparkinsonian rat brains in vivo using consecutive PET scans of [18F]FPCIT and [18F]fallypride

International Nuclear Information System (INIS)

Choi, Jae Yong; Kim, Chul Hoon; Jeon, Tae Joo; Cho, Won Gil; Lee, Jin Suk; Lee, Soo Jin; Choi, Tae Hyun; Kim, Byoung Soo; Yi, Chi Hoon; Seo, Youngbeom; Yi, Dae Ik; Han, Sang Jin; Lee, Minkyung; Kim, Dong Goo; Lee, Jong Doo; An, Gwangil

2012-01-01

The aim of this study was to investigate dopaminergic function in unilaterally lesioned 6-OHDA rats by dual PET radioligands: [ 18 F]FPCIT (a dopamine transporter imaging radioligand) and [ 18 F]fallypride (a dopamine D2 receptors imaging radioligand). As a result, the brain uptake of [ 18 F]FPCIT was significantly reduced and that of [ 18 F]fallypride was increased in the ipsilateral striatum (lesion side) of the 6-OHDA rats. These findings implicated that dopamine transporter is down-regulated and dopamine D2 receptor is up-regulated in this hemiparkinsonian rat model. - Highlights: ► The dopaminergic integrity in unilateral 6-OHDA was evaluated by dual PET tracers. ► The brain uptake and BP ND of [ 18 F]FPCIT was greatly decreased. ► The brain uptake and BP ND [ 18 F]fallypride was slightly increased. ► DAT are down-regulated and D2R are up-regulated.

Myopic (HD-PTP, PTPN23) selectively regulates synaptic neuropeptide release.

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Bulgari, Dinara; Jha, Anupma; Deitcher, David L; Levitan, Edwin S

2018-02-13

Neurotransmission is mediated by synaptic exocytosis of neuropeptide-containing dense-core vesicles (DCVs) and small-molecule transmitter-containing small synaptic vesicles (SSVs). Exocytosis of both vesicle types depends on Ca 2+ and shared secretory proteins. Here, we show that increasing or decreasing expression of Myopic (mop, HD-PTP, PTPN23), a Bro1 domain-containing pseudophosphatase implicated in neuronal development and neuropeptide gene expression, increases synaptic neuropeptide stores at the Drosophila neuromuscular junction (NMJ). This occurs without altering DCV content or transport, but synaptic DCV number and age are increased. The effect on synaptic neuropeptide stores is accounted for by inhibition of activity-induced Ca 2+ -dependent neuropeptide release. cAMP-evoked Ca 2+ -independent synaptic neuropeptide release also requires optimal Myopic expression, showing that Myopic affects the DCV secretory machinery shared by cAMP and Ca 2+ pathways. Presynaptic Myopic is abundant at early endosomes, but interaction with the endosomal sorting complex required for transport III (ESCRT III) protein (CHMP4/Shrub) that mediates Myopic's effect on neuron pruning is not required for control of neuropeptide release. Remarkably, in contrast to the effect on DCVs, Myopic does not affect release from SSVs. Therefore, Myopic selectively regulates synaptic DCV exocytosis that mediates peptidergic transmission at the NMJ.

ILLICIT DOPAMINE TRANSIENTS: RECONCILING ACTIONS OF ABUSED DRUGS

OpenAIRE

Covey, Dan P.; Roitman, Mitchell F.; Garris, Paul A.

2014-01-01

Phasic increases in brain dopamine are required for cue-directed reward seeking. While compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyper-activating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyper-activation as a unifying hypothesis of abuse...

The Role of the Dopamine Transporter (DAT) in the Development of PTSD in Preschool Children

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Drury, Stacy S.; Theall, Katherine P.; Keats, Bronya J.B.; Scheeringa, Michael

2015-01-01

Population-based association studies have supported the heritability of posttraumatic stress disorder (PTSD). This study explored the influence of genetic variation in the dopamine transporter (DAT) 3′ untranslated region variable number tandem repeat on the development of PTSD in preschool children exposed to Hurricane Katrina, diagnosed using a developmentally appropriate semistructured interview. A diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association, 1994), total symptoms, and specifically Criterion D symptoms were significantly more likely to be found in children with the 9 allele. This study replicates a previous finding in adults with PTSD. The specificity of this finding to the increased arousal symptoms of Criterion D suggests that dopamine and the DAT allele may contribute to one heritable path in a multifinality model of the development of PTSD. PMID:19960520

Operant conditioning of synaptic and spiking activity patterns in single hippocampal neurons.

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Ishikawa, Daisuke; Matsumoto, Nobuyoshi; Sakaguchi, Tetsuya; Matsuki, Norio; Ikegaya, Yuji

2014-04-02

Learning is a process of plastic adaptation through which a neural circuit generates a more preferable outcome; however, at a microscopic level, little is known about how synaptic activity is patterned into a desired configuration. Here, we report that animals can generate a specific form of synaptic activity in a given neuron in the hippocampus. In awake, head-restricted mice, we applied electrical stimulation to the lateral hypothalamus, a reward-associated brain region, when whole-cell patch-clamped CA1 neurons exhibited spontaneous synaptic activity that met preset criteria. Within 15 min, the mice learned to generate frequently the excitatory synaptic input pattern that satisfied the criteria. This reinforcement learning of synaptic activity was not observed for inhibitory input patterns. When a burst unit activity pattern was conditioned in paired and nonpaired paradigms, the frequency of burst-spiking events increased and decreased, respectively. The burst reinforcement occurred in the conditioned neuron but not in other adjacent neurons; however, ripple field oscillations were concomitantly reinforced. Neural conditioning depended on activation of NMDA receptors and dopamine D1 receptors. Acutely stressed mice and depression model mice that were subjected to forced swimming failed to exhibit the neural conditioning. This learning deficit was rescued by repetitive treatment with fluoxetine, an antidepressant. Therefore, internally motivated animals are capable of routing an ongoing action potential series into a specific neural pathway of the hippocampal network.

Activity Induces Fmr1-Sensitive Synaptic Capture of Anterograde Circulating Neuropeptide Vesicles.

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Cavolo, Samantha L; Bulgari, Dinara; Deitcher, David L; Levitan, Edwin S

2016-11-16

Synaptic neuropeptide and neurotrophin stores are maintained by constitutive bidirectional capture of dense-core vesicles (DCVs) as they circulate in and out of the nerve terminal. Activity increases DCV capture to rapidly replenish synaptic neuropeptide stores following release. However, it is not known whether this is due to enhanced bidirectional capture. Here experiments at the Drosophila neuromuscular junction, where DCVs contain neuropeptides and a bone morphogenic protein, show that activity-dependent replenishment of synaptic neuropeptides following release is evident after inhibiting the retrograde transport with the dynactin disruptor mycalolide B or photobleaching DCVs entering a synaptic bouton by retrograde transport. In contrast, photobleaching anterograde transport vesicles entering a bouton inhibits neuropeptide replenishment after activity. Furthermore, tracking of individual DCVs moving through boutons shows that activity selectively increases capture of DCVs undergoing anterograde transport. Finally, upregulating fragile X mental retardation 1 protein (Fmr1, also called FMRP) acts independently of futsch/MAP-1B to abolish activity-dependent, but not constitutive, capture. Fmr1 also reduces presynaptic neuropeptide stores without affecting activity-independent delivery and evoked release. Therefore, presynaptic motoneuron neuropeptide storage is increased by a vesicle capture mechanism that is distinguished from constitutive bidirectional capture by activity dependence, anterograde selectivity, and Fmr1 sensitivity. These results show that activity recruits a separate mechanism than used at rest to stimulate additional synaptic capture of DCVs for future release of neuropeptides and neurotrophins. Synaptic release of neuropeptides and neurotrophins depends on presynaptic accumulation of dense-core vesicles (DCVs). At rest, DCVs are captured bidirectionally as they circulate through Drosophila motoneuron terminals by anterograde and retrograde

Validation of a method for accurate and highly reproducible quantification of brain dopamine transporter SPECT studies

DEFF Research Database (Denmark)

Jensen, Peter S; Ziebell, Morten; Skouboe, Glenna

2011-01-01

In nuclear medicine brain imaging, it is important to delineate regions of interest (ROIs) so that the outcome is both accurate and reproducible. The purpose of this study was to validate a new time-saving algorithm (DATquan) for accurate and reproducible quantification of the striatal dopamine t...... transporter (DAT) with appropriate radioligands and SPECT and without the need for structural brain scanning....

Decoding the dopamine signal in macaque prefrontal cortex: a simulation study using the Cx3Dp simulator.

Directory of Open Access Journals (Sweden)

Isabelle Ayumi Spühler

Full Text Available Dopamine transmission in the prefrontal cortex plays an important role in reward based learning, working memory and attention. Dopamine is thought to be released non-synaptically into the extracellular space and to reach distant receptors through diffusion. This simulation study examines how the dopamine signal might be decoded by the recipient neuron. The simulation was based on parameters from the literature and on our own quantified, structural data from macaque prefrontal area 10. The change in extracellular dopamine concentration was estimated at different distances from release sites and related to the affinity of the dopamine receptors. Due to the sparse and random distribution of release sites, a transient heterogeneous pattern of dopamine concentration emerges. Our simulation predicts, however, that at any point in the simulation volume there is sufficient dopamine to bind and activate high-affinity dopamine receptors. We propose that dopamine is broadcast to its distant receptors and any change from the local baseline concentration might be decoded by a transient change in the binding probability of dopamine receptors. Dopamine could thus provide a graduated 'teaching' signal to reinforce concurrently active synapses and cell assemblies. In conditions of highly reduced or highly elevated dopamine levels the simulations predict that relative changes in the dopamine signal can no longer be decoded, which might explain why cognitive deficits are observed in patients with Parkinson's disease, or induced through drugs blocking dopamine reuptake.

Decoding the Dopamine Signal in Macaque Prefrontal Cortex: A Simulation Study Using the Cx3Dp Simulator

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Spühler, Isabelle Ayumi; Hauri, Andreas

2013-01-01

Dopamine transmission in the prefrontal cortex plays an important role in reward based learning, working memory and attention. Dopamine is thought to be released non-synaptically into the extracellular space and to reach distant receptors through diffusion. This simulation study examines how the dopamine signal might be decoded by the recipient neuron. The simulation was based on parameters from the literature and on our own quantified, structural data from macaque prefrontal area 10. The change in extracellular dopamine concentration was estimated at different distances from release sites and related to the affinity of the dopamine receptors. Due to the sparse and random distribution of release sites, a transient heterogeneous pattern of dopamine concentration emerges. Our simulation predicts, however, that at any point in the simulation volume there is sufficient dopamine to bind and activate high-affinity dopamine receptors. We propose that dopamine is broadcast to its distant receptors and any change from the local baseline concentration might be decoded by a transient change in the binding probability of dopamine receptors. Dopamine could thus provide a graduated ‘teaching’ signal to reinforce concurrently active synapses and cell assemblies. In conditions of highly reduced or highly elevated dopamine levels the simulations predict that relative changes in the dopamine signal can no longer be decoded, which might explain why cognitive deficits are observed in patients with Parkinson’s disease, or induced through drugs blocking dopamine reuptake. PMID:23951205

Dual-isotope single-photon emission computed tomography for dopamine and serotonin transporters in normal and parkinsonian monkey brains

International Nuclear Information System (INIS)

Li, I-H.; Huang, W.-S.; Yeh, C.-B.; Liao, M.-H.; Chen, C.-C.; Shen, L.-H.; Liu, J.-C.; Ma, K.-H.

2009-01-01

Introduction: Parkinson's disease (PD) affects both dopaminergic and serotonergic systems. In this study, we simultaneously evaluated dopamine and serotonin transporters in primates using dual-isotope single-photon emission computed tomography (SPECT) imaging and compared the results with traditional single-isotope imaging. Methods: Four healthy and one 6-OHDA-induced PD monkeys were used for this study. SPECT was performed over 4 h after individual or simultaneous injection of [ 99m Tc]TRODAT-1 (a dopamine transporter imaging agent) and [ 123 I]ADAM (a serotonin transporter imaging agent). Results: The results showed that the image quality and uptake ratios in different brain regions were comparable between single- and dual-isotope studies. The striatal [ 99m Tc]TRODAT-1 uptake in the PD monkey was markedly lower than that in normal monkeys. The uptake of [ 123 I]ADAM in the midbrain of the PD monkey was comparable to that in the normal monkeys, but there were decreased uptakes in the thalamus and striatum of the PD monkey. Conclusions: Our results suggest that dual-isotope SPECT using [ 99m Tc]TRODAT-1 and [ 123 I]ADAM can simultaneously evaluate changes in dopaminergic and serotonergic systems in a PD model.

Dopamine

International Nuclear Information System (INIS)

Walters, L.

1983-01-01

Dopamine is an important neurotransmittor in the central nervous system. The physiological function of the peripheral dopamine receptors is unknown, but they are of therapeutic importance as dopamine is used to improve renal blood flow in shocked patients. There are 4 dopamine receptors. The classification of these dopamine receptors has been made possible by research with radiopharmaceuticals. Dopamine sensitive adenylate cyclase is an inherent part of the dopamine-1-receptor. Dopamine-1-receptors are stimulated by micromolar (physiological) concentrations of dopamine and inhibited by micromolar (supratherapeutic) concentrations of the antipsychotic drugs. The vascular effect of dopamine is mediated through the dopamine-1-receptors. Dopamine-2-receptors are responsible for the effect of dopamine at the mesolimbic, nigrostriatal and chemoreceptortrigger areas. It is activated by micromolar concentrations of dopamine and blocked by nanomolar (therapeutic) concentrations of the anti-psychotic drugs. Dopamine-3-receptors are activated by nanomolar concentrations of dopamine and inhibited by micromolar concentrations of the antipsychotic drugs. They occur on presynaptic nerve terminals and have a negative feedback effect on the liberation of dopamine, noradrenaline and serotonin. The dopamine-4-receptors are activated by nanomolar concentrations of dopamine. These are the only dopamine receptors that could be responsible for effects in the hypophysis as only nanomolar concentrations of dopamine occur there. These receptors are blocked by nanomolar concentrations of the antipsychotic drugs

Loss of Huntingtin stimulates capture of retrograde dense-core vesicles to increase synaptic neuropeptide stores.

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Bulgari, Dinara; Deitcher, David L; Levitan, Edwin S

2017-08-01

The Huntington's disease protein Huntingtin (Htt) regulates axonal transport of dense-core vesicles (DCVs) containing neurotrophins and neuropeptides. DCVs travel down axons to reach nerve terminals where they are either captured in synaptic boutons to support later release or reverse direction to reenter the axon as part of vesicle circulation. Currently, the impact of Htt on DCV dynamics in the terminal is unknown. Here we report that knockout of Drosophila Htt selectively reduces retrograde DCV flux at proximal boutons of motoneuron terminals. However, initiation of retrograde transport at the most distal bouton and transport velocity are unaffected suggesting that synaptic capture rate of these retrograde DCVs could be altered. In fact, tracking DCVs shows that retrograde synaptic capture efficiency is significantly elevated by Htt knockout or knockdown. Furthermore, synaptic boutons contain more neuropeptide in Htt knockout larvae even though bouton size, single DCV fluorescence intensity, neuropeptide release in response to electrical stimulation and subsequent activity-dependent capture are unaffected. Thus, loss of Htt increases synaptic capture as DCVs travel by retrograde transport through boutons resulting in reduced transport toward the axon and increased neuropeptide in the terminal. These results therefore identify native Htt as a regulator of synaptic capture and neuropeptide storage. Copyright © 2017 Elsevier GmbH. All rights reserved.

A Conserved Salt Bridge between Transmembrane Segment 1 and 10 Constitutes an Extracellular Gate in the Dopamine Transporter

DEFF Research Database (Denmark)

Pedersen, Anders Vingborg; Andreassen, Thorvald Faurschou; Løland, Claus Juul

2014-01-01

into the structural and dynamic requirements for substrate transport. These structures support the existence of gating domains controlling access to a central binding site. On the extracellular side, access is controlled by the "thin gate" formed by an interaction between Arg-30 and Asp-404. In the human dopamine...

Maternal separation affects dopamine transporter function in the Spontaneously Hypertensive Rat: An in vivo electrochemical study

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Womersley Jacqueline S

2011-12-01

Full Text Available Abstract Background Attention-deficit/hyperactivity disorder (ADHD is a developmental disorder characterised by symptoms of inattention, impulsivity and hyperactivity. The spontaneously hypertensive rat (SHR is a well-characterised model of this disorder and has been shown to exhibit dopamine dysregulation, one of the hypothesised causes of ADHD. Since stress experienced in the early stages of life can have long-lasting effects on behaviour, it was considered that early life stress may alter development of the dopaminergic system and thereby contribute to the behavioural characteristics of SHR. It was hypothesized that maternal separation would alter dopamine regulation by the transporter (DAT in ways that distinguish SHR from control rat strains. Methods SHR and control Wistar-Kyoto (WKY rats were subjected to maternal separation for 3 hours per day from postnatal day 2 to 14. Rats were tested for separation-induced anxiety-like behaviour followed by in vivo chronoamperometry to determine whether changes had occurred in striatal clearance of dopamine by DAT. The rate of disappearance of ejected dopamine was used as a measure of DAT function. Results Consistent with a model for ADHD, SHR were more active than WKY in the open field. SHR entered the inner zone more frequently and covered a significantly greater distance than WKY. Maternal separation increased the time that WKY spent in the closed arms and latency to enter the open arms of the elevated plus maze, consistent with other rat strains. Of note is that, maternal separation failed to produce anxiety-like behaviour in SHR. Analysis of the chronoamperometric data revealed that there was no difference in DAT function in the striatum of non-separated SHR and WKY. Maternal separation decreased the rate of dopamine clearance (k-1 in SHR striatum. Consistent with this observation, the dopamine clearance time (T100 was increased in SHR. These results suggest that the chronic mild stress of

Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole.

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MacDonald, Hayley J; Stinear, Cathy M; Ren, April; Coxon, James P; Kao, Justin; Macdonald, Lorraine; Snow, Barry; Cramer, Steven C; Byblow, Winston D

2016-07-01

Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision-making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists.

The Mechanistic Basis for Noncompetitive Ibogaine Inhibition of Serotonin and Dopamine Transporters*

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Bulling, Simon; Schicker, Klaus; Zhang, Yuan-Wei; Steinkellner, Thomas; Stockner, Thomas; Gruber, Christian W.; Boehm, Stefan; Freissmuth, Michael; Rudnick, Gary; Sitte, Harald H.; Sandtner, Walter

2012-01-01

Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study. PMID:22451652

The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters.

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Bulling, Simon; Schicker, Klaus; Zhang, Yuan-Wei; Steinkellner, Thomas; Stockner, Thomas; Gruber, Christian W; Boehm, Stefan; Freissmuth, Michael; Rudnick, Gary; Sitte, Harald H; Sandtner, Walter

2012-05-25

Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study.

[99mTc]/[123I] Simultaneous dual-isotope brain striatum phantom SPECT study: preparing for simultaneous [99mTc]TRODAT-1/[123I]-IBZM pre- and post-synaptic dopamine imaging

International Nuclear Information System (INIS)

Kao, PF; Hsu, HT; Tzen, KY; Wey, SP

2004-01-01

Introduction: The brain dopamine transporters (DAT) and dopamine D2 receptors are implicated in all kinds of movement disorders. Both sites are also targets for drug treatment, Therefore, brain dopamine system is important in both basic and clinical neurological researches. Kung HF et al. developed [ 99m Tc]TRODAT-l for DAT and [ 123 I]IBZM for D2 receptor SPECT imaging in living human brain. In this work, the possibility of doing [ 99m Tc]TRODAT-1/[ 123 I]IBZM simultaneous dual-isotope SPECT for both DAT/D2 receptor imaging was studied. The SPECT acquisition protocol, the percent of 99m Tc/ 123 I energy cross contamination, and the reproducibility of striatal /background ratios were studied with a striatal phantom to confirm the accuracy of 99m Tc/ 123 I dual-isotope simultaneous SPECT technique. Materials and Methods: In each set of experiment, the 4 striatum (target) chambers and the rest of the brain (background) were filled with solutions containing 99m Tc only, 123 I only, and both isotopes. Several sets of experiment with different target/background ratios were tested. For SPECT image acquisition, a triple-head gamma camera equipp with high resolution fan-beam collimators (Siemens Multi-SPECT3). Energy window settings of a 15% centered window at 140KeV for 99m Tc and a 10% asymmetric window with a lower bound at 159KeV for 123 I were used. After filtered backprojection and Chang's attenuation correction, regions of interest were defined at the bilateral basal ganglia and occipital areas. The reproducibility of counting activity and the different target/background ratios from each isotope were observed. Results: The results of the study revealed that the energy crossed contaminations from I-123 into Tc- 99m and vice verse were 22±12.4 % and 0.4±1.0 %, respectively. The correlation of striatum/background ratios between single isotope and simultaneous was excellent (R2 = 0.99). The success of this simultaneous dual-isotope SPECT technique is suggestive of the

Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions

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Carmine Tomasetti

2017-01-01

Full Text Available Dopamine-glutamate interplay dysfunctions have been suggested as pathophysiological key determinants of major psychotic disorders, above all schizophrenia and mood disorders. For the most part, synaptic interactions between dopamine and glutamate signaling pathways take part in the postsynaptic density, a specialized ultrastructure localized under the membrane of glutamatergic excitatory synapses. Multiple proteins, with the role of adaptors, regulators, effectors, and scaffolds compose the postsynaptic density network. They form structural and functional crossroads where multiple signals, starting at membrane receptors, are received, elaborated, integrated, and routed to appropriate nuclear targets. Moreover, transductional pathways belonging to different receptors may be functionally interconnected through postsynaptic density molecules. Several studies have demonstrated that psychopharmacologic drugs may differentially affect the expression and function of postsynaptic genes and proteins, depending upon the peculiar receptor profile of each compound. Thus, through postsynaptic network modulation, these drugs may induce dopamine-glutamate synaptic remodeling, which is at the basis of their long-term physiologic effects. In this review, we will discuss the role of postsynaptic proteins in dopamine-glutamate signals integration, as well as the peculiar impact of different psychotropic drugs used in clinical practice on postsynaptic remodeling, thereby trying to point out the possible future molecular targets of “synapse-based” psychiatric therapeutic strategies.

KV7 Channels Regulate Firing during Synaptic Integration in GABAergic Striatal Neurons

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M. Belén Pérez-Ramírez

2015-01-01

Full Text Available Striatal projection neurons (SPNs process motor and cognitive information. Their activity is affected by Parkinson’s disease, in which dopamine concentration is decreased and acetylcholine concentration is increased. Acetylcholine activates muscarinic receptors in SPNs. Its main source is the cholinergic interneuron that responds with a briefer latency than SPNs during a cortical command. Therefore, an important question is whether muscarinic G-protein coupled receptors and their signaling cascades are fast enough to intervene during synaptic responses to regulate synaptic integration and firing. One of the most known voltage dependent channels regulated by muscarinic receptors is the KV7/KCNQ channel. It is not known whether these channels regulate the integration of suprathreshold corticostriatal responses. Here, we study the impact of cholinergic muscarinic modulation on the synaptic response of SPNs by regulating KV7 channels. We found that KV7 channels regulate corticostriatal synaptic integration and that this modulation occurs in the dendritic/spines compartment. In contrast, it is negligible in the somatic compartment. This modulation occurs on sub- and suprathreshold responses and lasts during the whole duration of the responses, hundreds of milliseconds, greatly altering SPNs firing properties. This modulation affected the behavior of the striatal microcircuit.

Methamphetamine-induced short-term increase and long-term decrease in spatial working memory affects protein Kinase M zeta (PKMζ), dopamine, and glutamate receptors.

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Braren, Stephen H; Drapala, Damian; Tulloch, Ingrid K; Serrano, Peter A

2014-01-01

Methamphetamine (MA) is a toxic, addictive drug shown to modulate learning and memory, yet the neural mechanisms are not fully understood. We investigated the effects of 2 weekly injections of MA (30 mg/kg) on working memory using the radial 8-arm maze (RAM) across 5 weeks in adolescent-age mice. MA-treated mice show a significant improvement in working memory performance 1 week following the first MA injection compared to saline-injected controls. Following 5 weeks of MA abstinence mice were re-trained on a reference and working memory version of the RAM to assess cognitive flexibility. MA-treated mice show significantly more working memory errors without effects on reference memory performance. The hippocampus and dorsal striatum were assessed for expression of glutamate receptors subunits, GluA2 and GluN2B; dopamine markers, dopamine 1 receptor (D1), dopamine transporter (DAT) and tyrosine hydroxylase (TH); and memory markers, protein kinase M zeta (PKMζ) and protein kinase C zeta (PKCζ). Within the hippocampus, PKMζ and GluA2 are both significantly reduced after MA supporting the poor memory performance. Additionally, a significant increase in GluN2B and decrease in D1 identifies dysregulated synaptic function. In the striatum, MA treatment increased cytosolic DAT and TH levels associated with dopamine hyperfunction. MA treatment significantly reduced GluN2B while increasing both PKMζ and PKCζ within the striatum. We discuss the potential role of PKMζ/PKCζ in modulating dopamine and glutamate receptors after MA treatment. These results identify potential underlying mechanisms for working memory deficits induced by MA.

Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

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Jackson George R

2011-06-01

Full Text Available Abstract Background The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Results Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I, and activated caspase-9, which is related to the apoptotic mitochondrial pathway. Conclusions This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.

A neuromorphic implementation of multiple spike-timing synaptic plasticity rules for large-scale neural networks

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Runchun Mark Wang

2015-05-01

Full Text Available We present a neuromorphic implementation of multiple synaptic plasticity learning rules, which include both Spike Timing Dependent Plasticity (STDP and Spike Timing Dependent Delay Plasticity (STDDP. We present a fully digital implementation as well as a mixed-signal implementation, both of which use a novel dynamic-assignment time-multiplexing approach and support up to 2^26 (64M synaptic plasticity elements. Rather than implementing dedicated synapses for particular types of synaptic plasticity, we implemented a more generic synaptic plasticity adaptor array that is separate from the neurons in the neural network. Each adaptor performs synaptic plasticity according to the arrival times of the pre- and post-synaptic spikes assigned to it, and sends out a weighted and/or delayed pre-synaptic spike to the target synapse in the neural network. This strategy provides great flexibility for building complex large-scale neural networks, as a neural network can be configured for multiple synaptic plasticity rules without changing its structure. We validate the proposed neuromorphic implementations with measurement results and illustrate that the circuits are capable of performing both STDP and STDDP. We argue that it is practical to scale the work presented here up to 2^36 (64G synaptic adaptors on a current high-end FPGA platform.

Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence

NARCIS (Netherlands)

Crunelle, Cleo L.; van den Brink, Wim; Veltman, Dick J.; van Emmerik-van Oortmerssen, Katelijne; Dom, Geert; Schoevers, Robert A.; Booij, Jan

2013-01-01

Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the

Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome.

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Fulks, Jenny L; O'Bryhim, Bliss E; Wenzel, Sara K; Fowler, Stephen C; Vorontsova, Elena; Pinkston, Jonathan W; Ortiz, Andrea N; Johnson, Michael A

2010-10-20

In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.

A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice.

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Alexander Kurz

2010-07-01

Full Text Available Parkinson's disease (PD, the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA. PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD was absent in corticostriatal slices from old transgenic mice.Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.

Dopamine Neurons Change the Type of Excitability in Response to Stimuli

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Gutkin, Boris S.; Lapish, Christopher C.; Kuznetsov, Alexey

2016-01-01

The dynamics of neuronal excitability determine the neuron’s response to stimuli, its synchronization and resonance properties and, ultimately, the computations it performs in the brain. We investigated the dynamical mechanisms underlying the excitability type of dopamine (DA) neurons, using a conductance-based biophysical model, and its regulation by intrinsic and synaptic currents. Calibrating the model to reproduce low frequency tonic firing results in N-methyl-D-aspartate (NMDA) excitation balanced by γ-Aminobutyric acid (GABA)-mediated inhibition and leads to type I excitable behavior characterized by a continuous decrease in firing frequency in response to hyperpolarizing currents. Furthermore, we analyzed how excitability type of the DA neuron model is influenced by changes in the intrinsic current composition. A subthreshold sodium current is necessary for a continuous frequency decrease during application of a negative current, and the low-frequency “balanced” state during simultaneous activation of NMDA and GABA receptors. Blocking this current switches the neuron to type II characterized by the abrupt onset of repetitive firing. Enhancing the anomalous rectifier Ih current also switches the excitability to type II. Key characteristics of synaptic conductances that may be observed in vivo also change the type of excitability: a depolarized γ-Aminobutyric acid receptor (GABAR) reversal potential or co-activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) leads to an abrupt frequency drop to zero, which is typical for type II excitability. Coactivation of N-methyl-D-aspartate receptors (NMDARs) together with AMPARs and GABARs shifts the type I/II boundary toward more hyperpolarized GABAR reversal potentials. To better understand how altering each of the aforementioned currents leads to changes in excitability profile of DA neuron, we provide a thorough dynamical analysis. Collectively, these results imply that type I

The taurine transporter substrate guanidinoethyl sulfonate mimics the action of taurine on long-term synaptic potentiation.

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Suárez, Luz M; Muñoz, María-Dolores; González, José C; Bustamante, Julián; Del Río, Rafael Martín; Solís, José M

2016-11-01

Taurine is especially abundant in rodent brain where it appears to be involved in osmoregulation and synaptic plasticity mechanisms. The demonstration of a physiological role for taurine has been hampered by the difficulty in modifying taurine levels in most tissues, including the brain. We used an experimental strategy to reduce taurine levels, involving treatment with guanidinoethyl sulfonate (GES), a structural analogue of taurine that, among other properties, acts as a competitive inhibitor of taurine transport. GES delivered in the drinking water of rats for 1 month effectively reduced taurine levels in brain structures (hippocampus, cerebellum and cortex) and outside the brain (heart, muscle, kidney, liver and plasma) by between 50 and 80 %, depending on the tissue. This partial taurine depletion did not affect either basal synaptic transmission or the late phase of long-term potentiation (late-LTP) in hippocampal slices. In vivo microdialysis studies in the hippocampus revealed that GES treatment reduced extracellular taurine levels and the magnitude of taurine released in response to the application of either N-methyl-D-aspartate (NMDA) or a hypoosmotic solution, without affecting release mechanisms. Finally, we demonstrated in hippocampal slices that a brief GES application can mimic taurine action on the conversion of a decremental LTP into a perdurable late-LTP, concluding that GES might replace taurine function in some mechanisms such as those implicated in synaptic plasticity.

Two Classes of Secreted Synaptic Organizers in the Central Nervous System.

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Yuzaki, Michisuke

2018-02-10

Research in the last two decades has identified many synaptic organizers in the central nervous system that directly regulate the assembly of pre- and/or postsynaptic molecules, such as synaptic vesicles, active zone proteins, and neurotransmitter receptors. They are classified into secreted factors and cell adhesion molecules, such as neurexins and neuroligins. Certain secreted factors are termed extracellular scaffolding proteins (ESPs) because they are components of the synaptic extracellular matrix and serve as a scaffold at the synaptic cleft. These include Lgi1, Cbln1, neuronal pentraxins, Hevin, thrombospondins, and glypicans. Diffusible secreted factors, such as Wnts, fibroblast growth factors, and semaphorins, tend to act from a distance. In contrast, ESPs remain at the synaptic cleft and often help synaptic adhesion and/or accumulation of postsynaptic receptors. Many fundamental questions remain about when, how, and why various synaptic organizers establish and modify the vast numbers of connections during development and throughout life.

Functional properties and synaptic integration of genetically labelled dopaminergic neurons in intrastriatal grafts

DEFF Research Database (Denmark)

Sørensen, Andreas Toft; Thompson, Lachlan; Kirik, Deniz

2005-01-01

in the dopamine-depleted striatum than of those in the intact striatum. Our findings define specific electrophysiological characteristics of transplanted fetal dopaminergic neurons, and we provide the first direct evidence of functional synaptic integration of these neurons into host neural circuitries......., the electrophysiological properties grafted cells need to have in order to induce substantial functional recovery are poorly defined. It has not been possible to prospectively identify and record from dopaminergic neurons in fetal transplants. Here we used transgenic mice expressing green fluorescent protein under control...... of the rat tyrosine hydroxylase promoter for whole-cell patch-clamp recordings of endogenous and grafted dopaminergic neurons. We transplanted ventral mesencephalic tissue from E12.5 transgenic mice into striatum of neonatal rats with or without lesions of the nigrostriatal dopamine system. The transplanted...

Cellular Programming and Reprogramming: Sculpting Cell Fate for the Production of Dopamine Neurons for Cell Therapy

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Julio C. Aguila

2012-01-01

success of clinical applications depends on our ability to steer pluripotent stem cells towards the right neuronal identity. In Parkinson disease, the loss of dopamine neurons is more pronounced in the ventrolateral population that projects to the sensorimotor striatum. Because synapses are highly specific, only neurons with this precise identity will contribute, upon transplantation, to the synaptic reconstruction of the dorsal striatum. Thus, understanding the developmental cell program of the mesostriatal dopamine neurons is critical for the identification of the extrinsic signals and cell-intrinsic factors that instruct and, ultimately, determine cell identity. Here, we review how extrinsic signals and transcription factors act together during development to shape midbrain cell fates. Further, we discuss how these same factors can be applied in vitro to induce, select, and reprogram cells to the mesostriatal dopamine fate.

ILLICIT DOPAMINE TRANSIENTS: RECONCILING ACTIONS OF ABUSED DRUGS

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Covey, Dan P.; Roitman, Mitchell F.; Garris, Paul A.

2014-01-01

Phasic increases in brain dopamine are required for cue-directed reward seeking. While compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyper-activating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyper-activation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural reward and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome. PMID:24656971

Cellular programming and reprogramming: sculpting cell fate for the production of dopamine neurons for cell therapy.

Science.gov (United States)

Aguila, Julio C; Hedlund, Eva; Sanchez-Pernaute, Rosario

2012-01-01

Pluripotent stem cells are regarded as a promising cell source to obtain human dopamine neurons in sufficient amounts and purity for cell replacement therapy. Importantly, the success of clinical applications depends on our ability to steer pluripotent stem cells towards the right neuronal identity. In Parkinson disease, the loss of dopamine neurons is more pronounced in the ventrolateral population that projects to the sensorimotor striatum. Because synapses are highly specific, only neurons with this precise identity will contribute, upon transplantation, to the synaptic reconstruction of the dorsal striatum. Thus, understanding the developmental cell program of the mesostriatal dopamine neurons is critical for the identification of the extrinsic signals and cell-intrinsic factors that instruct and, ultimately, determine cell identity. Here, we review how extrinsic signals and transcription factors act together during development to shape midbrain cell fates. Further, we discuss how these same factors can be applied in vitro to induce, select, and reprogram cells to the mesostriatal dopamine fate.

Dual-isotope single-photon emission computed tomography for dopamine and serotonin transporters in normal and parkinsonian monkey brains

Energy Technology Data Exchange (ETDEWEB)

Li, I-H. [Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan (China); Huang, W.-S. [Department of Nuclear Medicine, Tri-Service General Hospital, Taipei, 114, Taiwan (China); Yeh, C.-B. [Department of Psychiatry, Tri-Service General Hospital, Taipei, 114, Taiwan (China); Liao, M.-H.; Chen, C.-C.; Shen, L.-H. [Division of Isotope Application, Institute of Nuclear Energy Research, Taoyaun, 325 Taiwan (China); Liu, J.-C. [Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan (China); Ma, K.-H. [Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan (China)], E-mail: kuohsing91@yahoo.com.tw

2009-08-15

Introduction: Parkinson's disease (PD) affects both dopaminergic and serotonergic systems. In this study, we simultaneously evaluated dopamine and serotonin transporters in primates using dual-isotope single-photon emission computed tomography (SPECT) imaging and compared the results with traditional single-isotope imaging. Methods: Four healthy and one 6-OHDA-induced PD monkeys were used for this study. SPECT was performed over 4 h after individual or simultaneous injection of [{sup 99m}Tc]TRODAT-1 (a dopamine transporter imaging agent) and [{sup 123}I]ADAM (a serotonin transporter imaging agent). Results: The results showed that the image quality and uptake ratios in different brain regions were comparable between single- and dual-isotope studies. The striatal [{sup 99m}Tc]TRODAT-1 uptake in the PD monkey was markedly lower than that in normal monkeys. The uptake of [{sup 123}I]ADAM in the midbrain of the PD monkey was comparable to that in the normal monkeys, but there were decreased uptakes in the thalamus and striatum of the PD monkey. Conclusions: Our results suggest that dual-isotope SPECT using [{sup 99m}Tc]TRODAT-1 and [{sup 123}I]ADAM can simultaneously evaluate changes in dopaminergic and serotonergic systems in a PD model.

[mRNA expression of dopamine receptor D2 and dopamine transporter in peripheral blood lymphocytes before and after treatment in children with tic disorder].

Science.gov (United States)

Ji, Xiao-Yi; Wu, Min

2016-04-01

To investigate the mRNA expression of dopamine receptor D2 (DRD2) and dopamine transporter (DAT) in peripheral blood lymphocytes before and after treatment in children with tic disorder (TD). RT-PCR was used to measure the mRNA expression of DRD2 and DAT in peripheral blood lymphocytes before and after treatment in 60 children with TD. The correlations between mRNA expression of DRD2 and DAT and the severity of TD were analyzed. Sixty healthy children served as the control group. Before treatment, the children with TD had a significant increase in the mRNA expression of DRD2 and DAT compared with the control group (PTic Severity Scale (YGTSS) score (P<0.05). In the children with moderate TD, the mRNA expression of DAT was positively correlated with YGTSS score (P<0.05). In children with TD, the mRNA expression of DRD2 in peripheral blood lymphocytes can be used as one of the indicators for diagnosing TD, assessing the severity of TD, and evaluating clinical outcomes.

Dopamine transporter gene variation modulates activation of striatum in youth with ADHD.

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Bédard, Anne-Claude; Schulz, Kurt P; Cook, Edwin H; Fan, Jin; Clerkin, Suzanne M; Ivanov, Iliyan; Halperin, Jeffrey M; Newcorn, Jeffrey H

2010-11-15

Polymorphisms in the 3'UTR variable number tandem repeat (VNTR) of exon 15 of the dopamine transporter gene (DAT1) have been linked to attention-deficit hyperactivity disorder (ADHD); moreover, variability in DAT1 3'UTR genotype may contribute to both heterogeneity of the ADHD phenotype and differences in response to stimulant medications. The impact of this VNTR on neuronal function in individuals with ADHD remains unclear despite evidence that the polymorphisms influence dopamine transporter expression. Thus, we used event-related functional magnetic resonance imaging to examine the impact of DAT1 3'UTR genotype on brain activation during response inhibition in unmedicated children and adolescents with ADHD. Twenty-one youth with ADHD who were homozygous for the 10-repeat (10R) allele of the DAT1 3'UTR and 12 youth who were carriers of the 9-repeat (9R) allele were scanned while they performed a Go/No-Go task. Response inhibition was modeled by contrasting activation during correct No-Go trials versus correct Go trials. Participants who were homozygous for the DAT1 3'UTR 10R allele and those who had a single 9R allele did not differ on percent of trials with successful inhibition, which was the primary measure of inhibitory control. Yet, youth with the DAT1 3'UTR 10R/10R genotype had significantly greater inhibitory control-related activation than those with one 9R allele in the left striatum, right dorsal premotor cortex, and bilaterally in the temporoparietal cortical junction. These findings provide preliminary evidence that neural activity related to inhibitory control may differ as a function of DAT1 3'UTR genotype in youth with ADHD. Copyright 2009 Elsevier Inc. All rights reserved.

Toxicity, mutagenicity, and behavioral effects of β-CIT, a ligand for dopamine transporter exploration by SPECT

International Nuclear Information System (INIS)

Emond, P.; Farde, L.; Chalon, S.; Belzung, C.; Mauclaire, V.; Chiron, J. P.; Halldin, C.; Besnard, J.C.; Guilloteau, D.

1998-01-01

The cocaine analog β-CIT is one of the most used compounds for SPET examination of the dopamine transporter in drug abuse and Parkinson's disease. However, the toxicity of this agent has not yet been studied. We report here acute toxicity, mutagenicity, and effect on locomotor activity of β-CIT. Acute toxicity experiments were performed in mice and rats. The LD50 values were about 20 mg and 5 mg for mice and rats, respectively. There was no sex difference. The mutagenicity was evaluated using the Ames' test. No mutagenic effect was observed for β-CIT. Effects on locomotor activity were measured in mice using the open-field test. β-CIT increased locomotion (+65%) when injected at a dose of 0.312 mg/kg; the maximal increase (+205%) was observed at a dose of 1.25 mg/kg; at higher doses, the effect was decreased slightly. These pharmacological findings are in agreement with an inhibitory effect of β-CIT at the dopamine transporter. We conclude that with no mutagenic effects and LD50 more than 6 orders of magnitude higher than the routinely used doses in PET or SPET, it can be assumed that β-CIT can be safely used as a radioligand in humans

Toxicity, mutagenicity, and behavioral effects of {beta}-CIT, a ligand for dopamine transporter exploration by SPECT

Energy Technology Data Exchange (ETDEWEB)

Emond, P.; Farde, L.; Chalon, S.; Belzung, C.; Mauclaire, V.; Chiron, J. P.; Halldin, C.; Besnard, J.C.; Guilloteau, D

1998-05-01

The cocaine analog {beta}-CIT is one of the most used compounds for SPET examination of the dopamine transporter in drug abuse and Parkinson's disease. However, the toxicity of this agent has not yet been studied. We report here acute toxicity, mutagenicity, and effect on locomotor activity of {beta}-CIT. Acute toxicity experiments were performed in mice and rats. The LD50 values were about 20 mg and 5 mg for mice and rats, respectively. There was no sex difference. The mutagenicity was evaluated using the Ames' test. No mutagenic effect was observed for {beta}-CIT. Effects on locomotor activity were measured in mice using the open-field test. {beta}-CIT increased locomotion (+65%) when injected at a dose of 0.312 mg/kg; the maximal increase (+205%) was observed at a dose of 1.25 mg/kg; at higher doses, the effect was decreased slightly. These pharmacological findings are in agreement with an inhibitory effect of {beta}-CIT at the dopamine transporter. We conclude that with no mutagenic effects and LD50 more than 6 orders of magnitude higher than the routinely used doses in PET or SPET, it can be assumed that {beta}-CIT can be safely used as a radioligand in humans.

Pre-colonial transport systems: A veritable instrument for inter-group ...

African Journals Online (AJOL)

It thinks that pre-colonial transport systems, due to its commercial and strategic importance, were extensively used by farmers and traders, who participated actively in both internal and long distance commerce. This paper submits that, pre-colonial transport systems such as human porterage on land and dug-out canoe on ...

A light-stimulated synaptic transistor with synaptic plasticity and memory functions based on InGaZnO_x–Al_2O_3 thin film structure

International Nuclear Information System (INIS)

Li, H. K.; Chen, T. P.; Liu, P.; Zhang, Q.; Hu, S. G.; Liu, Y.; Lee, P. S.

2016-01-01

In this work, a synaptic transistor based on the indium gallium zinc oxide (IGZO)–aluminum oxide (Al_2O_3) thin film structure, which uses ultraviolet (UV) light pulses as the pre-synaptic stimulus, has been demonstrated. The synaptic transistor exhibits the behavior of synaptic plasticity like the paired-pulse facilitation. In addition, it also shows the brain's memory behaviors including the transition from short-term memory to long-term memory and the Ebbinghaus forgetting curve. The synapse-like behavior and memory behaviors of the transistor are due to the trapping and detrapping processes of the holes, which are generated by the UV pulses, at the IGZO/Al_2O_3 interface and/or in the Al_2O_3 layer.

Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability

Science.gov (United States)

The benztropine analog JHW 007 displays high affinity for the dopamine transporter (DAT), but unlike typical DAT ligands, has relatively low abuse liability and blocks effects of cocaine,including its self-administration. To determine sites responsible for the cocaine-antagonist effects of JHW 007, ...

Change of striatum dopaminergic transporter and content of dopamine in rats with experimental hyperthyroidism

International Nuclear Information System (INIS)

Lin Yansong; Wang Huicheng; Zhao Zhiying; Zhu Li; Zhang Yingqiang; Chen Zhengping

2009-01-01

Objective: The central dopamine system plays an important role in regulating movement and mood. In our routine clinical practice,we found that patients with hyperthyroidism often show tremor of their hands or legs. Meanwhile they also experienced emotional problems such as anxiety and depression. These reminded us that there might be close relationship between thyroid hormone and dopamine system. Based on our previous works, in this study we evaluated the change of striatum dopamine transporter (DAT) by using 99 Tc m -2β- [N, N'-bis (2-merecaptoethyl) ethylenediamino]methyl, 3β- (4-chlorophenyl) tropane (TRODAT-1) brain biodistribution, and the content of striatum dopamine and its metabolites 3.4-di-hydroxyphenylacetic (DOPAC) by high performace liquid chromatograph-electrochemical detection (HPLC-ECD) in rats with experimental hyperthyroidism. Methods: All 24 rats were randomly divided into two groups, thyroxin group were induced by daily thyroxin infusion for 14 d to be experimental hyperthyroidism, the others were control group which received saline infusion. The blood samples were randomly taken from thyroxine group and control group, and the concentration of TT 3 and TT 4 were detected by radioimmunoassay. After 14 d,both experimental (thyroxine group) and control group were further divided into 2 sub-groups. One was for evaluation of the function of striatum DAT by 99 Tc m -TRODAT-1 biodistribution study and the other was for HPIJC-ECD measurement of the concentration of dopamine and its metabolites DOPAC. Results: Significantly hyperactivity and weight loss [(223.90 ± 8.40) VS (261.60 ± 14.20)g, t=6.98. P 3 and TT 4 after thyroxin infusion was significantly elevated than that of before thyroxin infusion [(2.72 ± 0.29) V8(1.46 ± 0.17) nmol/L, t=10.51, P 3 , and TT 4 after saline infusion showed no statistical significance as compared with before saline infusion [(1.71 ± 0.20) vs (1.54 ± O.09) nmol/L, t=1.68. P>0.05 and (88.38 ± 6.76) vs (98.38 ± 9

Illicit dopamine transients: reconciling actions of abused drugs.

Science.gov (United States)

Covey, Dan P; Roitman, Mitchell F; Garris, Paul A

2014-04-01

Phasic increases in brain dopamine are required for cue-directed reward seeking. Although compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyperactivating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyperactivation as a unifying hypothesis of abused drugs. We argue here that reclassification also identifies generating burst firing by dopamine neurons as a keystone action. Unlike natural rewards, which are processed by sensory systems, drugs act directly on the brain. Consequently, to mimic natural rewards and exploit reward circuits, dopamine transients must be elicited de novo. Of available drug targets, only burst firing achieves this essential outcome. Copyright © 2014 Elsevier Ltd. All rights reserved.

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice.

Science.gov (United States)

Paul, Kush; Venkitaramani, Deepa V; Cox, Charles L

2013-02-15

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS.

[99mTc[TRODAT-1: a novel technetium-99m complex as a dopamine transporter imaging agent

International Nuclear Information System (INIS)

Kung Meiping; Stevenson, D.A.; Ploessl, K.; Meegalla, S.K.; Beckwith, A.; Essman, W.D.; Mu, M.; Lucki, I.; Kung, H.F.

1997-01-01

Technetium-99m is the most commonly used radionuclide in routine nuclear medicine imaging procedures. Development of 99m Tc-labeled receptor-specific imaging agents for studying the central nervous system is potentially useful for evaluation of brain function in normal and disease states. A novel 99m Tc-labeled tropane derivative, [ 99m Tc[TRODAT-1, which is useful as a potential CNS dopamine transporter imaging agent, was evaluated and characterized. After i.v. injection into rats, [ 99m Tc[TRODAT-1 displayed specific brain uptake in the rat striatal region (striatum-cerebellum/cerebellum ratio 1.8 at 60 min), where dopamine neurons are concentrated. The specific striatal uptake could be blocked by pretreating rats with a dose of competing dopamine transporter ligand, β-CIT (or RTI-55, i.v., 1 mg/kg). However, the specific striatal uptake of [ 99m Tc[TRODAT-1 was not affected by co-injection of excess free ligand (TRODAT-1, up to 200 μg per rat) or by pretreating the rats with haloperidol (i.v., 1 mg/kg). The specific uptake in striatal regions of rats that had prior 6-hydroxydopamine lesion in the substantia nigra area showed a dramatic reduction. The radioactive material recovered from the rat striatal homogenates at 60 min after i.v. injection of [ 99m Tc[TRODAT-1 showed primarily the original compound (>95%), a good indication of in vivo stability in brain tissue. Similar and comparable organ distribution patterns and brain regional uptakes of [ 99m Tc[TRODAT-1 were obtained for male and female rats. (orig./AJ). With 4 figs., 6 tabs

Time-dependent effects of repeated THC treatment on dopamine D2/3 receptor-mediated signalling in midbrain and striatum.

Science.gov (United States)

Tournier, Benjamin B; Tsartsalis, Stergios; Dimiziani, Andrea; Millet, Philippe; Ginovart, Nathalie

2016-09-15

This study examined the time-course of alterations in levels and functional sensitivities of dopamine D2/3 receptors (D2/3R) during the course and up to 6 weeks following cessation of chronic treatment with Delta(9)-Tetrahydrocannabinol (THC) in rats. THC treatment led to an increase in D2/3R levels in striatum, as assessed using [(3)H]-(+)-PHNO, that was readily observable after one week of treatment, remained stably elevated during the subsequent 2 weeks of treatment, but fully reversed within 2 weeks of THC discontinuation. THC-induced D2/3R alterations were more pronounced and longer lasting in the dopamine cell body regions of the midbrain, wherein [(3)H]-(+)-PHNO binding was still elevated at 2 weeks but back to control values at 6 weeks after THC cessation. Parallel analyses of the psychomotor effects of pre- and post-synaptic doses of quinpirole also showed a pattern of D2/3R functional supersensitivity indicative of more rapid subsidence in striatum than in midbrain following drug cessation. These results indicate that chronic THC is associated with a biochemical and functional sensitization of D2/3R signaling, that these responses show a region-specific temporal pattern and are fully reversible following drug discontinuation. These results suggest that an increased post-synaptic D2/3R function and a decreased DA presynaptic signaling, mediated by increased D2/3R autoinhibition, may predominate during distinct phases of withdrawal and may contribute both to the mechanisms leading to relapse and to cannabinoid withdrawal symptoms. The different rates of normalization of D2/3R function in striatum and midbrain may be critical information for the development of new pharmacotherapies for cannabis dependence. Copyright © 2016 Elsevier B.V. All rights reserved.

High dendritic expression of Ih in the proximity of the axon origin controls the integrative properties of nigral dopamine neurons.

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Engel, Dominique; Seutin, Vincent

2015-11-15

The hyperpolarization-activated cation current Ih is expressed in dopamine neurons of the substantia nigra, but the subcellular distribution of the current and its role in synaptic integration remain unknown. We used cell-attached patch recordings to determine the localization profile of Ih along the somatodendritic axis of nigral dopamine neurons in slices from young rats. Ih density is higher in axon-bearing dendrites, in a membrane area close to the axon origin, than in the soma and axon-lacking dendrites. Dual current-clamp recordings revealed a similar contribution of Ih to the waveform of single excitatory postsynaptic potentials throughout the somatodendritic domain. The Ih blocker ZD 7288 increased the temporal summation in all dendrites with a comparable effect in axon- and non-axon dendrites. The strategic position of Ih in the proximity of the axon may influence importantly transitions between pacemaker and bursting activities and consequently the downstream release of dopamine. Dendrites of most neurons express voltage-gated ion channels in their membrane. In combination with passive properties, active currents confer to dendrites a high computational potential. The hyperpolarization-activated cation current Ih present in the dendrites of some pyramidal neurons affects their membrane and integration properties, synaptic plasticity and higher functions such as memory. A gradient of increasing h-channel density towards distal dendrites has been found to be responsible for the location independence of excitatory postsynaptic potential (EPSP) waveform and temporal summation in cortical and hippocampal pyramidal cells. However, reports on other cell types revealed that smoother gradients or even linear distributions of Ih can achieve homogeneous temporal summation. Although the existence of a robust, slowly activating Ih current has been repeatedly demonstrated in nigral dopamine neurons, its subcellular distribution and precise role in synaptic integration

Methamphetamine-induced short-term increase and long-term decrease in spatial working memory affects Protein Kinase M zeta (PKMζ, dopamine, and glutamate receptors

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Stephen H Braren

2014-12-01

Full Text Available Methamphetamine (MA is a toxic, addictive drug shown to modulate learning and memory, yet the neural mechanisms are not fully understood. We investigated the effects of 2 weekly injections of MA (30 mg/kg on working memory using the radial 8-arm maze (RAM across 5 weeks in adolescent-age mice. MA-treated mice show a significant improvement in working memory performance 1 week following the first MA injection compared to saline-injected controls. Following 5 weeks of MA abstinence mice were re-trained on a reference and working memory version of the RAM to assess cognitive flexibility. MA-treated mice show significantly more working memory errors without effects on reference memory performance. The hippocampus and dorsal striatum were assessed for expression of glutamate receptors subunits, GluA2 and GluN2B; dopamine markers, dopamine 1 receptor (D1, dopamine transporter (DAT and tyrosine hydroxylase (TH; and memory markers, protein kinase M zeta (PKMζ and protein kinase C zeta (PKCζ. Within the hippocampus, PKMζ and GluA2 are both significantly reduced after MA supporting the poor memory performance. Additionally, a significant increase in GluN2B and decrease in D1 identifies dysregulated synaptic function. In the striatum, MA treatment increased cytosolic DAT and TH levels associated with dopamine hyperfunction. MA treatment significantly reduced GluN2B while increasing both PKMζ and PKCζ within the striatum. We discuss the potential role of PKMζ/PKCζ in modulating dopamine and glutamate receptors after MA treatment. These results identify potential underlying mechanisms for working memory deficits induced by MA.

Dopamine modulates metabolic rate and temperature sensitivity in Drosophila melanogaster.

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Taro Ueno

Full Text Available Homeothermal animals, such as mammals, maintain their body temperature by heat generation and heat dissipation, while poikilothermal animals, such as insects, accomplish it by relocating to an environment of their favored temperature. Catecholamines are known to regulate thermogenesis and metabolic rate in mammals, but their roles in other animals are poorly understood. The fruit fly, Drosophila melanogaster, has been used as a model system for the genetic studies of temperature preference behavior. Here, we demonstrate that metabolic rate and temperature sensitivity of some temperature sensitive behaviors are regulated by dopamine in Drosophila. Temperature-sensitive molecules like dTrpA1 and shi(ts induce temperature-dependent behavioral changes, and the temperature at which the changes are induced were lowered in the dopamine transporter-defective mutant, fumin. The mutant also displays a preference for lower temperatures. This thermophobic phenotype was rescued by the genetic recovery of the dopamine transporter in dopamine neurons. Flies fed with a dopamine biosynthesis inhibitor (3-iodo-L-tyrosine, which diminishes dopamine signaling, exhibited preference for a higher temperature. Furthermore, we found that the metabolic rate is up-regulated in the fumin mutant. Taken together, dopamine has functions in the temperature sensitivity of behavioral changes and metabolic rate regulation in Drosophila, as well as its previously reported functions in arousal/sleep regulation.

Evaluation of therapeutic effectiveness of neural transplantation using PET imaging technique

International Nuclear Information System (INIS)

Inaji, Motoki

2004-01-01

Neural transplantation is expected as an eradicative treatment of intractable central neural disease. In addition to behavioral observations, the recent development of the in vivo imaging technique also enabled to assess functions of neural graft in living subjects. Then we performed the PET scans using the unilateral 6-OHDA-lesioned rats in order to assess the pre- and post-synaptic functions in the striatum after transplantation of fetal dopaminergic neurons. As a result of PET scan, the images of [11C]PE2I, tracer of dopamine transporter, showed increased accumulation in the region which corresponded to the transplanted site after the graft. Because dopamine transporter exists on the cytoplasma membrane of axonal terminal, the accumulation of [11C]PE2I was regarded as a market of survival and maturation of transplanted cells. Also the images of [11C]raclopride, tracer of dopamine D2 receptor, revealed that up-regulation of D2 receptors normalized 4 weeks after transplantation. [11C]Raclopride was considered a marker of change of secondary dopaminergic environment. We believed that assessments with PET bring us much information, and it will increasingly contribute to a development of the regenerative medicine. (author)

Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: On the path to an animal model of attention-deficit hyperactivity disorder

Science.gov (United States)

Mergy, Marc A.; Gowrishankar, Raajaram; Davis, Gwynne L.; Jessen, Tammy N.; Wright, Jane; Stanwood, Gregg D.; Hahn, Maureen K.; Blakely, Randy D.

2014-01-01

Alterations in dopamine (DA) signaling underlie the most widely held theories of molecular and circuit level perturbations that lead to risk for attention-deficit hyperactivity disorder (ADHD). The DA transporter (DAT), a presynaptic reuptake protein whose activity provides critical support for DA signaling by limiting DA action at pre- and postsynaptic receptors, has been consistently associated with ADHD through pharmacological, behavioral, brain imaging and genetic studies. Currently, the animal models of ADHD exhibit significant limitations, stemming in large part from their lack of construct validity. To remedy this situation, we have pursued the creation of a mouse model derived from a functional nonsynonymous variant in the DAT gene (SLC6A3) of ADHD probands. We trace our path from the identification of these variants to in vitro biochemical and physiological studies to the production of the DAT Val559 mouse model. We discuss our initial findings with these animals and their promise in the context of existing rodent models of ADHD. PMID:24332984

Sex-Dependent Changes in Striatal Dopamine Transport in Preadolescent Rats Exposed Prenatally and/or Postnatally to Methamphetamine

Czech Academy of Sciences Publication Activity Database

Šírová, J.; Krištofíková, Z.; Vrajová, M.; Fujakova-Lipski, M.; Řípová, D.; Klaschka, Jan; Šlamberová, R.

2016-01-01

Roč. 41, č. 8 (2016), s. 1911-1923 ISSN 0364-3190 Grant - others:GA MŠk(CZ) ED2.1.00/03.0078; GA ČR(CZ) GA14-03708S; Univerzita Karlova(CZ) Prvouk P34; GA UK(CZ) 88315; SVV(CZ) 260277/2016 Institutional support: RVO:67985807 Keywords : methamphetamine * dopamine transporte * sex differences * membrane fluidity Subject RIV: FH - Neurology Impact factor: 2.581, year: 2016

Semi-automated preparation of the dopamine transporter ligand [18F]FECNT for human PET imaging studies

International Nuclear Information System (INIS)

Voll, Ronald J.; McConathy, Jonathan; Waldrep, Michael S.; Crowe, Ronald J.; Goodman, Mark M.

2005-01-01

The fluorine-18 labeled dopamine transport (DAT) ligand 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (FECNT) has shown promising properties as an in vivo DAT imaging agent in human and monkey PET studies. A semi-automated synthesis has been developed to reliably produce [ 18 F]FECNT in a 16% decay corrected yield. This method utilizes a new [ 18 F]fluoralkylating agent and provides high purity [ 18 F]FECNT in a formulation suitable for human use

Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.

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Tertia D Purves-Tyson

Full Text Available Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase, breakdown (catechol-O-methyl transferase; monoamine oxygenase, transport [vesicular monoamine transporter (VMAT, dopamine transporter (DAT] and receptors (DRD1-D5] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen

Serotonin/dopamine interactions in a hyperactive mouse: reduced serotonin receptor 1B activity reverses effects of dopamine transporter knockout.

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Frank Scott Hall

Full Text Available Knockout (KO mice that lack the dopamine transporter (SL6A3; DAT display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD and that these drugs may act upon serotonin (5-HT systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA systems in basal and cocaine-stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics.

Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons.

Science.gov (United States)

Eastwood, S L; Harrison, P J

2005-03-01

Synaptic protein gene expression is altered in schizophrenia. In the hippocampal formation there may be particular involvement of glutamatergic neurons and their synapses, but overall the profile remains unclear. In this in situ hybridization histochemistry (ISHH) study, we examined four informative synaptic protein transcripts: vesicular glutamate transporter (VGLUT) 1, VGLUT2, complexin I, and complexin II, in dorsolateral prefrontal cortex (DPFC), superior temporal cortex (STC), and hippocampal formation, in 13 subjects with schizophrenia and 18 controls. In these areas, VGLUT1 and complexin II are expressed primarily by excitatory neurons, whereas complexin I is mainly expressed by inhibitory neurons. In schizophrenia, VGLUT1 mRNA was decreased in hippocampal formation and DPFC, complexin II mRNA was reduced in DPFC and STC, and complexin I mRNA decreased in STC. Hippocampal VGLUT1 mRNA declined with age selectively in the schizophrenia group. VGLUT2 mRNA was not quantifiable due to its low level. The data provide additional evidence for a synaptic pathology in schizophrenia, in terms of a reduced expression of three synaptic protein genes. In the hippocampus, the loss of VGLUT1 mRNA supports data indicating that glutamatergic presynaptic deficits are prominent, whereas the pattern of results in temporal and frontal cortex suggests broadly similar changes may affect inhibitory and excitatory neurons. The impairment of synaptic transmission implied by the synaptic protein reductions may contribute to the dysfunction of cortical neural circuits that characterises the disorder.

Huntingtin is critical both pre- and postsynaptically for long-term learning-related synaptic plasticity in Aplysia.

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Yun-Beom Choi

Full Text Available Patients with Huntington's disease exhibit memory and cognitive deficits many years before manifesting motor disturbances. Similarly, several studies have shown that deficits in long-term synaptic plasticity, a cellular basis of memory formation and storage, occur well before motor disturbances in the hippocampus of the transgenic mouse models of Huntington's disease. The autosomal dominant inheritance pattern of Huntington's disease suggests the importance of the mutant protein, huntingtin, in pathogenesis of Huntington's disease, but wild type huntingtin also has been shown to be important for neuronal functions such as axonal transport. Yet, the role of wild type huntingtin in long-term synaptic plasticity has not been investigated in detail. We identified a huntingtin homolog in the marine snail Aplysia, and find that similar to the expression pattern in mammalian brain, huntingtin is widely expressed in neurons and glial cells. Importantly the expression of mRNAs of huntingtin is upregulated by repeated applications of serotonin, a modulatory transmitter released during learning in Aplysia. Furthermore, we find that huntingtin expression levels are critical, not only in presynaptic sensory neurons, but also in the postsynaptic motor neurons for serotonin-induced long-term facilitation at the sensory-to-motor neuron synapse of the Aplysia gill-withdrawal reflex. These results suggest a key role for huntingtin in long-term memory storage.

Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans.

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Bertolino, Alessandro; Fazio, Leonardo; Di Giorgio, Annabella; Blasi, Giuseppe; Romano, Raffaella; Taurisano, Paolo; Caforio, Grazia; Sinibaldi, Lorenzo; Ursini, Gianluca; Popolizio, Teresa; Tirotta, Emanuele; Papp, Audrey; Dallapiccola, Bruno; Borrelli, Emiliana; Sadee, Wolfgang

2009-01-28

Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D(2) receptors (encoded by DRD(2)) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D(2) proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD(2) polymorphism (rs1076560) causing reduced presynaptic D(2) receptor expression and the DAT 3'-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significant DRD(2)/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD(2) allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D(2) knock-out animals (D2R(-/-)) indicate that DAT and D(2) proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD(2) and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.

Age-dependent methamphetamine-induced alterations in vesicular monoamine transporter-2 function: implications for neurotoxicity.

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Truong, Jannine G; Wilkins, Diana G; Baudys, Jakub; Crouch, Dennis J; Johnson-Davis, Kamisha L; Gibb, James W; Hanson, Glen R; Fleckenstein, Annette E

2005-09-01

Tens of thousands of adolescents and young adults have used illicit methamphetamine. This is of concern since its high-dose administration causes persistent dopaminergic deficits in adult animal models. The effects in adolescents are less studied. In adult rodents, toxic effects of methamphetamine may result partly from aberrant cytosolic dopamine accumulation and subsequent reactive oxygen species formation. The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and perhaps protection against dopamine-associated oxidative consequences. Accordingly, aberrant VMAT-2 function may contribute to the methamphetamine-induced persistent dopaminergic deficits. Hence, this study examined effects of methamphetamine on VMAT-2 in adolescent (postnatal day 40) and young adult (postnatal day 90) rats. Results revealed that high-dose methamphetamine treatment caused greater acute (within 1 h) decreases in vesicular dopamine uptake in postnatal day 90 versus 40 rats, as determined in a nonmembrane-associated subcellular fraction. Greater basal levels of VMAT-2 at postnatal day 90 versus 40 in this purified fraction seemed to contribute to the larger effect. Basal tissue dopamine content was also greater in postnatal day 90 versus 40 rats. In addition, postnatal day 90 rats were more susceptible to methamphetamine-induced persistent dopaminergic deficits as assessed by measuring VMAT-2 activity and dopamine content 7 days after treatment, even if drug doses were adjusted for age-related pharmacokinetic differences. Together, these data demonstrate dynamic changes in VMAT-2 susceptibility to methamphetamine as a function of development. Implications with regard to methamphetamine-induced dopaminergic deficits, as well as dopamine-associated neurodegenerative disorders such as Parkinson's disease, are discussed.

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

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Gross, Noah B; Duncker, Patrick C; Marshall, John F

2011-11-01

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. Copyright © 2011 Wiley-Liss, Inc.

Dopamine transporter SPECT imaging of the peroral addicts of compound codeine phosphate solution

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Sun Taotao; Hu Shu; Jia Shaowei; Chen Qing; Fan Rong

2010-01-01

Objective: To study the damage to striatum in patients perorally addicted to compound codeine phosphate solution by using the brain dopamine transporter SPECT imaging. Methods: Patients perorally addicted to compound codeine phosphate solution (n = 29) and addicted to heroin (n = 27), as well as healthy volunteers (n = 31) were included in the study. Each of them underwent dopamine transporter (DAT) SPECT imaging with 99 Tc m -2β-[N, N'-bis-( 2- mercaptoethyl ) ethylenediamino] methyl, 3β-(4-chlorophenyl)tropane ( 99 Tc m -TRODAT-1). The striatum volume (V, cm 3 ), mass (m, g) and radioactivity ratio (Ra) of striatum to whole brain were calculated using physio-mathematical modeling method. Results: Bilateral striatum of healthy volunteers showed typical 'panda eyes' pattern and the distribution of DAT was uniform and symmetrical. Bilateral striatum of patients addicted to compound codeine phosphate showed impaired tracer uptake, similar to those addicted to heroin. The V, m and Ra of bilateral striatum of patients addicted to compound codeine phosphate were (23.68±4.94) cm 3 , (24.87±5.19) g and (5.01±0.88) %, respectively, which were significantly lower than those of healthy controls: (35.39 ±4.42) cm 3 ,(37.16±4.64) g and (7.93±0.86)% (t =-9.69, -9.69, - 13.01, all P =0.000), but significantly higher than those addicted to heroin: (18.87±4.66) cm 3 , (19.81±4.90) g and (4.26±1.02) % (t =3.74, 3.74, 2.96, P = 0.000, 0.000, 0.005). Conclusion: Long-term peroral intake of compound codeine phosphate solution may damage the function of cerebral striatum, which is someway similar to though less severe than, the impairment caused by heroin. (authors)

Dopamine transporter SPECT in patients with Parkinson's disease

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Hamano, Tadanori; Tsuchida, Tatsuro; Hirayama, Mikio; Fujiyama, Jiro; Mutoh, Tatsuro; Yonekura, Yoshiharu; Kuriyama, Masaru [Fukui Medical Univ., Matsuoka (Japan)

2000-03-01

The major neuropathological feature in Parkinson's disease (PD) is severe degeneration of the dopamine (DA) neurons in the substantia nigra. Dopamine transporter (DAT) is an important protein in the regulation of DA neurotransmission. It has been reported that PD patients show a loss of DAT in striatum. We report here the findings of single photon emission computed tomography (SPECT) of the DAT with 2{beta}-carboxymethoxy-3{beta}-(4[{sup 123}I]iodophenyl)tropane ([{sup 123}I]{beta}-CIT) to investigate striatal DAT in 10 patients with PD, one patient with vascular parkinsonism (VP), and one patient with dystonia syndrome. Patients were evaluated using the Webster rating scale. Specific/nondisplaceable striatal binding ratio (V3'') was obtained in each case. In PD patients, the uptake of [{sup 123}I]{beta}-CIT was reduced, especially in the tail of putamen compared with caudate nucleus. Even in the early stage of PD, the uptake of {beta}-CIT was reduced not only in the severely affected side, but also in the mildly disturbed side of the brain. Putamen caudate ratio was generally low in PD patients. In VP patient, the uptake was reduced, but putamen caudate ratio was not decreased. V3'' values showed significant correlation with the severity of clinical symptoms such as self-care, facies, posture, gait, speech, and Hoehn-Yahr's stage. On the other hand, V3'' values were not significantly correlated with the degree of tremor, seborrhea, and duration of the illness. In conclusion, we found that SPECT of the [{sup 123}I]{beta}-CIT is a useful method for the diagnosis in the patients presenting parkinsonism, and for the clinico-physiological estimation of parkinsonian symptoms such as self-care, facies, posture, gait, and speech. (author)

Structure-activity relationships for serotonin transporter and dopamine receptor selectivity.

Science.gov (United States)

Agatonovic-Kustrin, Snezana; Davies, Paul; Turner, Joseph V

2009-05-01

Antipsychotic medications have a diverse pharmacology with affinity for serotonergic, dopaminergic, adrenergic, histaminergic and cholinergic receptors. Their clinical use now also includes the treatment of mood disorders, thought to be mediated by serotonergic receptor activity. The aim of our study was to characterise the molecular properties of antipsychotic agents, and to develop a model that would indicate molecular specificity for the dopamine (D(2)) receptor and the serotonin (5-HT) transporter. Back-propagation artificial neural networks (ANNs) were trained on a dataset of 47 ligands categorically assigned antidepressant or antipsychotic utility. The structure of each compound was encoded with 63 calculated molecular descriptors. ANN parameters including hidden neurons and input descriptors were optimised based on sensitivity analyses, with optimum models containing between four and 14 descriptors. Predicted binding preferences were in excellent agreement with clinical antipsychotic or antidepressant utility. Validated models were further tested by use of an external prediction set of five drugs with unknown mechanism of action. The SAR models developed revealed the importance of simple molecular characteristics for differential binding to the D(2) receptor and the 5-HT transporter. These included molecular size and shape, solubility parameters, hydrogen donating potential, electrostatic parameters, stereochemistry and presence of nitrogen. The developed models and techniques employed are expected to be useful in the rational design of future therapeutic agents.

Synaptic activity and bioenergy homeostasis: implications in brain trauma and neurodegenerative diseases

Directory of Open Access Journals (Sweden)

Natasha eKhatri

2013-12-01

Full Text Available Powered by glucose metabolism, the brain is the most energy-demanding organ in our body, accounting for a quarter of total oxygen consumption. Adequate ATP production and regulation of the metabolic processes are essential for the maintenance of synaptic transmission and neuronal function. Glutamatergic synaptic activity utilizes the largest portion of bioenergy for synaptic events including neurotransmitter synthesis, vesicle recycling, and most importantly the postsynaptic activities leading to channel activation and rebalancing of ionic gradients. Bioenergy homeostasis is coupled with synaptic function via activities of the sodium pumps, glutamate transporters, glucose transport and mitochondria translocation. Energy insufficiency will be sensed by the AMP-activated dependent protein kinase (AMPK, a master metabolic regulator that stimulates the catalytic process to enhance energy production. A decline in energy supply and a disruption in bioenergy homeostasis play a critical role in multiple neuropathological conditions including ischemia, stroke and neurodegenerative diseases including Alzheimer’s disease and traumatic brain injuries.

[{sup 99m}Tc]TRODAT-1: a novel technetium-99m complex as a dopamine transporter imaging agent

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Meiping, Kung [Department of Radiology, University of Pennsylvania, Philadelphia (United States); Stevenson, D A [Department of Radiology, University of Pennsylvania, Philadelphia (United States); Ploessl, K [Department of Radiology, University of Pennsylvania, Philadelphia (United States); Meegalla, S K [Department of Radiology, University of Pennsylvania, Philadelphia (United States); Beckwith, A [Department of Radiology, University of Pennsylvania, Philadelphia (United States); Essman, W D [Department of Psychiatry, University of Pennsylvania, Philadelphia (United States); Mu, M [Department of Radiology, University of Pennsylvania, Philadelphia (United States); Lucki, I [Department of Psychiatry, University of Pennsylvania, Philadelphia (United States); [Department of Pharmacology, University of Pennsylvania, Philadelphia (United States); Kung, H F [Department of Radiology, University of Pennsylvania, Philadelphia (United States); [Department of Pharmacology, University of Pennsylvania, Philadelphia (United States)

1997-04-01

Technetium-99m is the most commonly used radionuclide in routine nuclear medicine imaging procedures. Development of {sup 99m}Tc-labeled receptor-specific imaging agents for studying the central nervous system is potentially useful for evaluation of brain function in normal and disease states. A novel {sup 99m}Tc-labeled tropane derivative, [{sup 99m}Tc]TRODAT-1, which is useful as a potential CNS dopamine transporter imaging agent, was evaluated and characterized. After i.v. injection into rats, [{sup 99m}Tc]TRODAT-1 displayed specific brain uptake in the rat striatal region (striatum-cerebellum/cerebellum ratio 1.8 at 60 min), where dopamine neurons are concentrated. The specific striatal uptake could be blocked by pretreating rats with a dose of competing dopamine transporter ligand, {beta}-CIT (or RTI-55, i.v., 1 mg/kg). However, the specific striatal uptake of [{sup 99m}Tc]TRODAT-1 was not affected by co-injection of excess free ligand (TRODAT-1, up to 200 {mu}g per rat) or by pretreating the rats with haloperidol (i.v., 1 mg/kg). The specific uptake in striatal regions of rats that had prior 6-hydroxydopamine lesion in the substantia nigra area showed a dramatic reduction. The radioactive material recovered from the rat striatal homogenates at 60 min after i.v. injection of [{sup 99m}Tc]TRODAT-1 showed primarily the original compound (>95%), a good indication of in vivo stability in brain tissue. Similar and comparable organ distribution patterns and brain regional uptakes of [{sup 99m}Tc]TRODAT-1 were obtained for male and female rats. (orig./AJ). With 4 figs., 6 tabs.

Cutaneous synergistic analgesia of bupivacaine in combination with dopamine in rats.

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Tzeng, Jann-Inn; Wang, Jieh-Neng; Wang, Jhi-Joung; Chen, Yu-Wen; Hung, Ching-Hsia

2016-05-04

The main goal of the study was to investigate the interaction between bupivacaine and dopamine on local analgesia. After the blockade of the cutaneous trunci muscle reflex (CTMR) responses, which occurred following the drugs were subcutaneously injected in rats, the cutaneous analgesic effect of dopamine in a dosage-dependent fashion was compared to that of bupivacaine. Drug-drug interactions were evaluated by isobolographic methods. We showed the dose-dependent effects of dopamine on infiltrative cutaneous analgesia. On the 50% effective dose (ED50) basis, the rank of drug potency was bupivacaine (1.99 [1.92-2.09] μmol/kg) greater than dopamine (190 [181-203] μmol/kg) (Pbupivacaine. The addition of dopamine to the bupivacaine solution exhibited a synergistic effect. Our pre-clinical data showed that dopamine produced a dose-dependent effect in producing cutaneous analgesia. When compared with bupivacaine, dopamine produced a lesser potency with a similar duration of cutaneous analgesia. Dopamine added to the bupivacaine preparation resulted in a synergistic analgesic effect. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Imaging dopamine transmission in schizophrenia

International Nuclear Information System (INIS)

Laruelle, M.

1998-01-01

Over the last ten years, several positron emission tomography (PET) and single photon computerized tomography (SPECT) studies of the dopamine (DA) system in patients with schizophrenia were performed to test the hypothesis that DA hyperactivity is associated with this illness. In this paper are reviewed the results of fifteen brain imaging studies comparing indices of DA function in drug naive or drug free patients with schizophrenia and healthy controls: thirteen studies included measurements of Da D 2 receptor density, two studies compared amphetamine-induced DA release, and two studies measured DOPA decarboxylase activity, an enzyme involved in DA synthesis. It was conducted a meta-analysis of the studies measuring D 2 receptor density parameters, under the assumption that all tracers labeled the same population of D 2 receptors. This analysis revealed that, compared to healthy controls, patients with schizophrenia present a significant but mild elevation of D 2 receptor density parameters and a significant larger variability of these indices. It was found no statistical evidence that studies performed with radiolabeled butyrophenones detected a larger increase in D 2 receptor density parameters than studies performed with other radioligands, such as benzamides. Studies of presynaptic activity revealed an increase in DA transmission response to amphetamine challenge, and an increase in DOPA decarboxylase activity. Together, these data are compatible with both pre- and post-synaptic alterations of DA transmission in schizophrenia. Future studies should aim at a better characterization of these alterations, and at defining their role in the pathophysiology of the illness

Dopamine modulates persistent synaptic activity and enhances the signal-to-noise ratio in the prefrontal cortex.

Directory of Open Access Journals (Sweden)

Sven Kroener

2009-08-01

Full Text Available The importance of dopamine (DA for prefrontal cortical (PFC cognitive functions is widely recognized, but its mechanisms of action remain controversial. DA is thought to increase signal gain in active networks according to an inverted U dose-response curve, and these effects may depend on both tonic and phasic release of DA from midbrain ventral tegmental area (VTA neurons.We used patch-clamp recordings in organotypic co-cultures of the PFC, hippocampus and VTA to study DA modulation of spontaneous network activity in the form of Up-states and signals in the form of synchronous EPSP trains. These cultures possessed a tonic DA level and stimulation of the VTA evoked DA transients within the PFC. The addition of high (> or = 1 microM concentrations of exogenous DA to the cultures reduced Up-states and diminished excitatory synaptic inputs (EPSPs evoked during the Down-state. Increasing endogenous DA via bath application of cocaine also reduced Up-states. Lower concentrations of exogenous DA (0.1 microM had no effect on the up-state itself, but they selectively increased the efficiency of a train of EPSPs to evoke spikes during the Up-state. When the background DA was eliminated by depleting DA with reserpine and alpha-methyl-p-tyrosine, or by preparing corticolimbic co-cultures without the VTA slice, Up-states could be enhanced by low concentrations (0.1-1 microM of DA that had no effect in the VTA containing cultures. Finally, in spite of the concentration-dependent effects on Up-states, exogenous DA at all but the lowest concentrations increased intracellular current-pulse evoked firing in all cultures underlining the complexity of DA's effects in an active network.Taken together, these data show concentration-dependent effects of DA on global PFC network activity and they demonstrate a mechanism through which optimal levels of DA can modulate signal gain to support cognitive functioning.

Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation

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Matthews, Gillian A.; Nieh, Edward H.; Vander Weele, Caitlin M.; Halbert, Sarah A.; Pradhan, Roma V.; Yosafat, Ariella S.; Glober, Gordon F.; Izadmehr, Ehsan M.; Thomas, Rain E.; Lacy, Gabrielle D.; Wildes, Craig P.; Ungless, Mark A.; Tye, Kay M.

2016-01-01

Summary The motivation to seek social contact may arise from either positive or negative emotional states, as social interaction can be rewarding and social isolation can be aversive. While ventral tegmental area (VTA) dopamine (DA) neurons may mediate social reward, a cellular substrate for the negative affective state of loneliness has remained elusive. Here, we identify a functional role for DA neurons in the dorsal raphe nucleus (DRN), in which we observe synaptic changes following acute social isolation. DRN DA neurons show increased activity upon social contact following isolation, revealed by in vivo calcium imaging. Optogenetic activation of DRN DA neurons increases social preference but causes place avoidance. Furthermore, these neurons are necessary for promoting rebound sociability following an acute period of isolation. Finally, the degree to which these neurons modulate behavior is predicted by social rank, together supporting a role for DRN dopamine neurons in mediating a loneliness-like state. PaperClip PMID:26871628

Dopamine and reward: the anhedonia hypothesis 30 years on.

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Wise, Roy A

2008-10-01

The anhedonia hypothesis--that brain dopamine plays a critical role in the subjective pleasure associated with positive rewards--was intended to draw the attention of psychiatrists to the growing evidence that dopamine plays a critical role in the objective reinforcement and incentive motivation associated with food and water, brain stimulation reward, and psychomotor stimulant and opiate reward. The hypothesis called to attention the apparent paradox that neuroleptics, drugs used to treat a condition involving anhedonia (schizophrenia), attenuated in laboratory animals the positive reinforcement that we normally associate with pleasure. The hypothesis held only brief interest for psychiatrists, who pointed out that the animal studies reflected acute actions of neuroleptics whereas the treatment of schizophrenia appears to result from neuroadaptations to chronic neuroleptic administration, and that it is the positive symptoms of schizophrenia that neuroleptics alleviate, rather than the negative symptoms that include anhedonia. Perhaps for these reasons, the hypothesis has had minimal impact in the psychiatric literature. Despite its limited heuristic value for the understanding of schizophrenia, however, the anhedonia hypothesis has had major impact on biological theories of reinforcement, motivation, and addiction. Brain dopamine plays a very important role in reinforcement of response habits, conditioned preferences, and synaptic plasticity in cellular models of learning and memory. The notion that dopamine plays a dominant role in reinforcement is fundamental to the psychomotor stimulant theory of addiction, to most neuroadaptation theories of addiction, and to current theories of conditioned reinforcement and reward prediction. Properly understood, it is also fundamental to recent theories of incentive motivation.

Variability in Dopamine Genes Dissociates Model-Based and Model-Free Reinforcement Learning.

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Doll, Bradley B; Bath, Kevin G; Daw, Nathaniel D; Frank, Michael J

2016-01-27

Considerable evidence suggests that multiple learning systems can drive behavior. Choice can proceed reflexively from previous actions and their associated outcomes, as captured by "model-free" learning algorithms, or flexibly from prospective consideration of outcomes that might occur, as captured by "model-based" learning algorithms. However, differential contributions of dopamine to these systems are poorly understood. Dopamine is widely thought to support model-free learning by modulating plasticity in striatum. Model-based learning may also be affected by these striatal effects, or by other dopaminergic effects elsewhere, notably on prefrontal working memory function. Indeed, prominent demonstrations linking striatal dopamine to putatively model-free learning did not rule out model-based effects, whereas other studies have reported dopaminergic modulation of verifiably model-based learning, but without distinguishing a prefrontal versus striatal locus. To clarify the relationships between dopamine, neural systems, and learning strategies, we combine a genetic association approach in humans with two well-studied reinforcement learning tasks: one isolating model-based from model-free behavior and the other sensitive to key aspects of striatal plasticity. Prefrontal function was indexed by a polymorphism in the COMT gene, differences of which reflect dopamine levels in the prefrontal cortex. This polymorphism has been associated with differences in prefrontal activity and working memory. Striatal function was indexed by a gene coding for DARPP-32, which is densely expressed in the striatum where it is necessary for synaptic plasticity. We found evidence for our hypothesis that variations in prefrontal dopamine relate to model-based learning, whereas variations in striatal dopamine function relate to model-free learning. Decisions can stem reflexively from their previously associated outcomes or flexibly from deliberative consideration of potential choice outcomes

SPECT imaging of dopamine and serotonin transporters with [[sup 123]I][beta]-CIT. Binding kinetics in the human brain

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Bruecke, T; Asenbaum, S; Frassine, H; Podreka, I [Vienna Univ. (Austria). Neurologische Klinik; Kornhuber, J [Wuerzburg Univ. (Germany); Angelberger, P [Oesterreichisches Forschungszentrum Seibersdorf GmbH (Austria)

1993-01-01

Single photon emission computerized tomography (SPECT) studies in non-human primates have previously shown that the cocaine derivative [[sup 123]I]-2-[beta]-carbomethoxy-3-[beta]-(4-iodophenyl)-tropane ([[sup 123]I][beta]-CIT) labels dopamine transporters in the striatum and serotonin transporters in the hypothalamus-midbrain area. Here, we report on the regional kinetic uptake of [[sup 123]I][beta]-CIT in the brain of 4 normal volunteers and 2 patients with Parkinson's disease. In healthy subjects striatal activity increased slowly to reach peak values at about 20 hours post injection. In the hypothalamus-midbrain area peak activities were observed at about 4 hours with a slow decrease thereafter. Low activity was observed in cortical and cerebellar areas. The striatal to cerebellar ratio was about 4 after 5 hours and 9 after 20 hours. In 2 patients with idiopathic Parkinson's disease striatal activity was markedly decreased while the activity in hypothalamus-midbrain areas was only diminished. Uptake into cortical and cerebellar areas appeared to be unchanged in Parkinson's disease. Consequently, in Parkinson's disease the striatal to cerebellar ratio was decreased to values around 2.5 after 20 hours. These preliminary methodological studies suggest that [[sup 123]I][beta]-CIT is a useful SPECT ligand for studying dopamine and possibly also serotonin transporters in the living human brain.

Birth order dependent growth cone segregation determines synaptic layer identity in the Drosophila visual system.

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Kulkarni, Abhishek; Ertekin, Deniz; Lee, Chi-Hon; Hummel, Thomas

2016-03-17

The precise recognition of appropriate synaptic partner neurons is a critical step during neural circuit assembly. However, little is known about the developmental context in which recognition specificity is important to establish synaptic contacts. We show that in the Drosophila visual system, sequential segregation of photoreceptor afferents, reflecting their birth order, lead to differential positioning of their growth cones in the early target region. By combining loss- and gain-of-function analyses we demonstrate that relative differences in the expression of the transcription factor Sequoia regulate R cell growth cone segregation. This initial growth cone positioning is consolidated via cell-adhesion molecule Capricious in R8 axons. Further, we show that the initial growth cone positioning determines synaptic layer selection through proximity-based axon-target interactions. Taken together, we demonstrate that birth order dependent pre-patterning of afferent growth cones is an essential pre-requisite for the identification of synaptic partner neurons during visual map formation in Drosophila.

VMAT2 and Parkinson’s disease: harnessing the dopamine vesicle

OpenAIRE

Lohr, Kelly M; Miller, Gary W

2014-01-01

Despite a movement away from dopamine-focused Parkinson’s disease (PD) research, a recent surge of evidence now suggests that altered vesicular storage of dopamine may contribute to the demise of the nigral neurons in this disease. Human studies demonstrate that the vesicular monoamine transporter 2 (VMAT2; SLC18A2) is dysfunctional in PD brain. Moreover, studies with transgenic mice suggest that there is an untapped reserve capacity of the dopamine vesicle that could be unbridled by increasi...

Neurotransmitter transporters in schistosomes: structure, function and prospects for drug discovery.

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Ribeiro, Paula; Patocka, Nicholas

2013-12-01

Neurotransmitter transporters (NTTs) play a fundamental role in the control of neurotransmitter signaling and homeostasis. Sodium symporters of the plasma membrane mediate the cellular uptake of neurotransmitter from the synaptic cleft, whereas proton-driven vesicular transporters sequester the neurotransmitter into synaptic vesicles for subsequent release. Together these transporters control how much transmitter is released and how long it remains in the synaptic cleft, thereby regulating the intensity and duration of signaling. NTTs have been the subject of much research in mammals and there is growing interest in their activities among invertebrates as well. In this review we will focus our attention on NTTs of the parasitic flatworm Schistosoma mansoni. Bloodflukes of the genus Schistosoma are the causative agents of human schistosomiasis, a devastating disease that afflicts over 200 million people worldwide. Schistosomes have a well-developed nervous system and a rich diversity of neurotransmitters, including many of the small-molecule ("classical") neurotransmitters that normally employ NTTs in their mechanism of signaling. Recent advances in schistosome genomics have unveiled numerous NTTs in this parasite, some of which have now been cloned and characterized in vitro. Moreover new genetic and pharmacological evidence suggests that NTTs are required for proper control of neuromuscular signaling and movement of the worm. Among these carriers are proteins that have been successfully targeted for drug discovery in other organisms, in particular sodium symporters for biogenic amine neurotransmitters such as serotonin and dopamine. Our goal in this chapter is to review the current status of research on schistosome NTTs, with emphasis on biogenic amine sodium symporters, and to evaluate their potential for anti-schistosomal drug targeting. Through this discussion we hope to draw attention to this important superfamily of parasite proteins and to identify new

Differential up-regulation of striatal dopamine transporter and α-synuclein by the pyrethroid insecticide permethrin

International Nuclear Information System (INIS)

Gillette, Jeffrey S.; Bloomquist, Jeffrey R.

2003-01-01

The effects of permethrin on striatal dopaminergic biomarkers were assessed in this study. Retired breeder male C57 B1/6 mice were given an ip dose of permethrin (0.1-200 mg/kg) at 7-day intervals, over a 2-week period (Days 0, 7, and 14). Animals were then sacrificed 1 day (t = 1), 14 days (t 14), or 28 days after the last treatment (t = 28). Dopamine transporter (DAT) protein as assayed by Western blotting was increased to 115% in the 0.8 mg/kg group over that of control mice at t = 1 (P 3 H]GBR 12935, used to assay DAT binding, followed the same trend as that for the Western blotting data for 0.8 and 1.5 mg/kg doses of permethrin over the 4 weeks posttreatment. At 200 mg/kg permethrin, DAT protein was unchanged vs controls (t = 1), but had significantly increased by t = 14 and continued to increase at t = 28, suggesting that the reduced dopamine transport at this dose was due to nerve terminal stress and that recovery had occurred. The protein α-synuclein was also significantly induced at the 1.5 mg/kg dose at t = 1; however, unlike DAT up-regulation, this effect had declined to control values by t 14. Maximal induction of α-synuclein protein occurred at a dose of 50 mg/kg permethrin. These data provide evidence that the pyrethroid class of insecticides can modulate the dopaminergic system at low doses, in a persistent manner, which may render neurons more vulnerable to toxicant injury

Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex.

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Xu, Tonghui; Wang, Shaofang; Lalchandani, Rupa R; Ding, Jun B

2017-04-01

In Parkinson's disease (PD), dopamine depletion causes major changes in the brain, resulting in the typical cardinal motor features of the disease. PD neuropathology has been restricted to postmortem examinations, which are limited to only a single time of PD progression. Models of PD in which dopamine tone in the brain is chemically or physically disrupted are valuable tools in understanding the mechanisms of the disease. The basal ganglia have been well studied in the context of PD, and circuit changes in response to dopamine loss have been linked to the motor dysfunctions in PD. However, the etiology of the cognitive dysfunctions that are comorbid in PD patients has remained unclear until now. In this article, we review recent studies exploring how dopamine depletion affects the motor cortex at the synaptic level. In particular, we highlight our recent findings on abnormal spine dynamics in the motor cortex of PD mouse models through in vivo time-lapse imaging and motor skill behavior assays. In combination with previous studies, a role of the motor cortex in skill learning and the impairment of this ability with the loss of dopamine are becoming more apparent. Taken together, we conclude with a discussion on the potential role for the motor cortex in PD, with the possibility of targeting the motor cortex for future PD therapeutics. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

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Uchigashima, Motokazu; Ohtsuka, Toshihisa; Kobayashi, Kazuto; Watanabe, Masahiko

2016-01-01

Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABAA receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets. PMID:27035941

Role of synaptic structural plasticity in impairments of spatial learning and memory induced by developmental lead exposure in Wistar rats.

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Yongmei Xiao

Full Text Available Lead (Pb is found to impair cognitive function. Synaptic structural plasticity is considered to be the physiological basis of synaptic functional plasticity and has been recently found to play important roles in learning and memory. To study the effect of Pb on spatial learning and memory at different developmental stages, and its relationship with alterations of synaptic structural plasticity, postnatal rats were randomly divided into three groups: Control; Pre-weaning Pb (Parents were exposed to 2 mM PbCl2 3 weeks before mating until weaning of pups; Post-weaning Pb (Weaned pups were exposed to 2 mM PbCl2 for 9 weeks. The spatial learning and memory of rats was measured by Morris water maze (MWM on PND 85-90. Rat pups in Pre-weaning Pb and Post-weaning Pb groups performed significantly worse than those in Control group (p<0.05. However, there was no significant difference in the performance of MWM between the two Pb-exposure groups. Before MWM (PND 84, the number of neurons and synapses significantly decreased in Pre-weaning Pb group, but not in Post-weaning Pb group. After MWM (PND 91, the number of synapses in Pre-weaning Pb group increased significantly, but it was still less than that of Control group (p<0.05; the number of synapses in Post-weaning Pb group was also less than that of Control group (p<0.05, although the number of synapses has no differences between Post-weaning Pb and Control groups before MWM. In both Pre-weaning Pb and Post-weaning Pb groups, synaptic structural parameters such as thickness of postsynaptic density (PSD, length of synaptic active zone and synaptic curvature increased significantly while width of synaptic cleft decreased significantly compared to Control group (p<0.05. Our data demonstrated that both early and late developmental Pb exposure impaired spatial learning and memory as well as synaptic structural plasticity in Wistar rats.

A Neural Circuit Mechanism for the Involvements of Dopamine in Effort-Related Choices: Decay of Learned Values, Secondary Effects of Depletion, and Calculation of Temporal Difference Error

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2018-01-01

Abstract Dopamine has been suggested to be crucially involved in effort-related choices. Key findings are that dopamine depletion (i) changed preference for a high-cost, large-reward option to a low-cost, small-reward option, (ii) but not when the large-reward option was also low-cost or the small-reward option gave no reward, (iii) while increasing the latency in all the cases but only transiently, and (iv) that antagonism of either dopamine D1 or D2 receptors also specifically impaired selection of the high-cost, large-reward option. The underlying neural circuit mechanisms remain unclear. Here we show that findings i–iii can be explained by the dopaminergic representation of temporal-difference reward-prediction error (TD-RPE), whose mechanisms have now become clarified, if (1) the synaptic strengths storing the values of actions mildly decay in time and (2) the obtained-reward-representing excitatory input to dopamine neurons increases after dopamine depletion. The former is potentially caused by background neural activity–induced weak synaptic plasticity, and the latter is assumed to occur through post-depletion increase of neural activity in the pedunculopontine nucleus, where neurons representing obtained reward exist and presumably send excitatory projections to dopamine neurons. We further show that finding iv, which is nontrivial given the suggested distinct functions of the D1 and D2 corticostriatal pathways, can also be explained if we additionally assume a proposed mechanism of TD-RPE calculation, in which the D1 and D2 pathways encode the values of actions with a temporal difference. These results suggest a possible circuit mechanism for the involvements of dopamine in effort-related choices and, simultaneously, provide implications for the mechanisms of TD-RPE calculation. PMID:29468191

[{sup 125}I]{beta}-CIT-FE and [{sup 125}I]{beta}-CIT-FP are superior to [{sup 125}I]{beta}-CIT for dopamine transporter visualization: Autoradiographic evaluation in the human brain

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Guenther, Ilonka; Hall, Haakan; Halldin, Christer; Swahn, Carl-Gunnar; Farde, Lars; Sedvall, Goeran

1997-10-01

The binding of the three dopamine transporter radioligands ([{sup 125}I]{beta}-CIT, [{sup 125}I]{beta}-CIT-FE, and [{sup 125}I]{beta}-CIT-FP) was studied using whole-hemisphere autoradiography on postmortem human brains. The autoradiograms revealed an intense and homogeneous labeling of the nucleus caudatus and putamen but also to varying extent to serotonergic and noradrenergic transporters of neocortex and thalamus. The order of specificity estimated (striatum over neocortex ratios) was {beta}-CIT-FP > {beta}-CIT-FE >> {beta}-CIT, suggesting that {beta}-CIT-FE and {beta}-CIT-FP should be preferred for in vivo studies of the dopamine transporter in the human brain.

The dopamine transporter gene may not contribute to susceptibility and the specific personality traits of amphetamine dependence.

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Tzeng, Nian-Sheng; Lu, Ru-Band; Yeh, Hui-Wen; Yeh, Yi-Wei; Huang, Chang-Chih; Yen, Che-Hung; Kuo, Shin-Chang; Chen, Chun-Yen; Chang, Hsin-An; Ho, Pei-Shen; Cheng, Serena; Shih, Mei-Chen; Huang, San-Yuan

2015-04-01

A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be involved in the pathophysiology of amphetamine dependence (AD). The aim of this study was to examine whether the dopamine transporter gene (DAT1, SLC6A3) is associated with development of AD and whether this gene influences personality traits in patients with AD. Eighteen polymorphisms of the DAT1 gene were analyzed in a case-control study that included 909 Han Chinese men (568 patients with AD and 341 control subjects). The patients fulfilled the DSM-IV-TR criteria for AD. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits and to examine the association between these traits and DAT1 gene variants. A weak association was found between the rs27072 polymorphism and development of AD, but these borderline associations were unconfirmed by logistic regression and haplotype analysis. Although harm avoidance and novelty seeking scores were significantly higher in patients than in controls, DAT1 polymorphisms did not influence these scores. This study suggests that high harm avoidance and novelty seeking personality traits may be a risk factor for the development of AD. However, the DAT1 gene may not contribute to AD susceptibility and specific personality traits observed in AD among Han Chinese men. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Neuronal cytoskeleton in synaptic plasticity and regeneration.

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Gordon-Weeks, Phillip R; Fournier, Alyson E

2014-04-01

During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo-dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre- and post-synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system. © 2013 International Society for Neurochemistry.

Dopamine signaling in reward-related behaviors.

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Baik, Ja-Hyun

2013-01-01

Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

Dopamine Signaling in reward-related behaviors

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Ja-Hyun eBaik

2013-10-01

Full Text Available Dopamine (DA regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DAmesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural rewards such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

Irregular persistent activity induced by synaptic excitatory feedback

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Francesca Barbieri

2007-11-01

Full Text Available Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV of interspike intervals (ISI of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i the post-spike reset is close enough to threshold , (ii synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between presynaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD. First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

Presynaptic protein synthesis required for NT-3-induced long-term synaptic modulation

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Je H

2011-01-01

Full Text Available Abstract Background Neurotrophins elicit both acute and long-term modulation of synaptic transmission and plasticity. Previously, we demonstrated that the long-term synaptic modulation requires the endocytosis of neurotrophin-receptor complex, the activation of PI3K and Akt, and mTOR mediated protein synthesis. However, it is unclear whether the long-term synaptic modulation by neurotrophins depends on protein synthesis in pre- or post-synaptic cells. Results Here we have developed an inducible protein translation blocker, in which the kinase domain of protein kinase R (PKR is fused with bacterial gyrase B domain (GyrB-PKR, which could be dimerized upon treatment with a cell permeable drug, coumermycin. By genetically targeting GyrB-PKR to specific cell types, we show that NT-3 induced long-term synaptic modulation requires presynaptic, but not postsynaptic protein synthesis. Conclusions Our results provide mechanistic insights into the cell-specific requirement for protein synthesis in the long-term synaptic modulation by neurotrophins. The GyrB-PKR system may be useful tool to study protein synthesis in a cell-specific manner.

Volume Transmission in Central Dopamine and Noradrenaline Neurons and Its Astroglial Targets.

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Fuxe, Kjell; Agnati, Luigi F; Marcoli, Manuela; Borroto-Escuela, Dasiel O

2015-12-01

Already in the 1960s the architecture and pharmacology of the brainstem dopamine (DA) and noradrenaline (NA) neurons with formation of vast numbers of DA and NA terminal plexa of the central nervous system (CNS) indicated that they may not only communicate via synaptic transmission. In the 1980s the theory of volume transmission (VT) was introduced as a major communication together with synaptic transmission in the CNS. VT is an extracellular and cerebrospinal fluid transmission of chemical signals like transmitters, modulators etc. moving along energy gradients making diffusion and flow of VT signals possible. VT interacts with synaptic transmission mainly through direct receptor-receptor interactions in synaptic and extrasynaptic heteroreceptor complexes and their signaling cascades. The DA and NA neurons are specialized for extrasynaptic VT at the soma-dendrtitic and terminal level. The catecholamines released target multiple DA and adrenergic subtypes on nerve cells, astroglia and microglia which are the major cell components of the trophic units building up the neural-glial networks of the CNS. DA and NA VT can modulate not only the strength of synaptic transmission but also the VT signaling of the astroglia and microglia of high relevance for neuron-glia interactions. The catecholamine VT targeting astroglia can modulate the fundamental functions of astroglia observed in neuroenergetics, in the Glymphatic system, in the central renin-angiotensin system and in the production of long-distance calcium waves. Also the astrocytic and microglial DA and adrenergic receptor subtypes mediating DA and NA VT can be significant drug targets in neurological and psychiatric disease.

[{sup 18}F]{beta}-CIT-FP is superior to [{sup 11}C]{beta}-CIT-FP for quantitation of the dopamine transporter

Energy Technology Data Exchange (ETDEWEB)

Lundkvist, Camilla; Halldin, Christer; Ginovart, Nathalie; Swahn, Carl-Gunnar; Farde, Lars

1997-10-01

{beta}-CIT-FP [N-(3-fluoropropyl)-2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)nortropane] is a cocaine analogue with high affinity for the dopamine transporter. Positron emission tomography (PET) studies with [O-methyl-{sup 11}C]{beta}-CIT-FP ([{sup 11}C]{beta}-CIT-FP) has shown that equilibrium conditions were approached but, however, not reached at the end of measurement. Moreover, metabolite studies of [{sup 11}C]{beta}-CIT-FP in monkey plasma demonstrated a lipophilic-labelled metabolite that may enter the brain. We therefore labelled {beta}-CIT-FP with fluorine-18 in a position that may avoid the formation of labelled lipophilic metabolites. The more long-lived radionuclide ({sup 18}F) was used to allow for measurements over longer time. [N-fluoropropyl-{sup 18}F]{beta}-CIT-FP ([{sup 18}F]{beta}-CIT-FP) was prepared by N-alkylation of nor-{beta}-CIT with [{sup 18}F]fluoropropyl bromide. PET studies were performed in cynomolgus monkeys. [{sup 18}F]{beta}-CIT-FP entered the brain rapidly. There was a high concentration of radioactivity in the striatum and much lower in the thalamus, neocortex, and cerebellum. The striatum-to-cerebellum ratio was about 5 at time of transient equilibrium, which occurred after 60 to 100 min. After pretreatment with GBR 12909, radioactivity in the striatum was markedly reduced, thus indicating specific [{sup 18}F]{beta}-CIT-FP binding to the dopamine transporter. The fraction of unchanged [{sup 18}F]{beta}-CIT-FP determined by HPLC was 10-15% after 140 min. No lipophilic labelled metabolites were detected. The absence of measurable lipophilic labelled metabolites and the occurrence of transient equilibrium within the time of the PET measurement indicate that [{sup 18}F]{beta}-CIT-FP is superior to [{sup 11}C]{beta}-CIT-FP as a PET radioligand for quantification of the dopamine transporter in the human brain.

A light-stimulated synaptic transistor with synaptic plasticity and memory functions based on InGaZnO{sub x}–Al{sub 2}O{sub 3} thin film structure

Energy Technology Data Exchange (ETDEWEB)

Li, H. K.; Chen, T. P., E-mail: echentp@ntu.edu.sg; Liu, P.; Zhang, Q. [School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore 639798 (Singapore); Hu, S. G. [School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore 639798 (Singapore); State Key Laboratory of Electronic Thin Films and Integrated Devices, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054 (China); Liu, Y. [State Key Laboratory of Electronic Thin Films and Integrated Devices, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054 (China); Lee, P. S. [School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798 (Singapore)

2016-06-28

In this work, a synaptic transistor based on the indium gallium zinc oxide (IGZO)–aluminum oxide (Al{sub 2}O{sub 3}) thin film structure, which uses ultraviolet (UV) light pulses as the pre-synaptic stimulus, has been demonstrated. The synaptic transistor exhibits the behavior of synaptic plasticity like the paired-pulse facilitation. In addition, it also shows the brain's memory behaviors including the transition from short-term memory to long-term memory and the Ebbinghaus forgetting curve. The synapse-like behavior and memory behaviors of the transistor are due to the trapping and detrapping processes of the holes, which are generated by the UV pulses, at the IGZO/Al{sub 2}O{sub 3} interface and/or in the Al{sub 2}O{sub 3} layer.

The role of dopamine receptors in the neurotoxicity of methamphetamine.

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Ares-Santos, S; Granado, N; Moratalla, R

2013-05-01

Methamphetamine is a synthetic drug consumed by millions of users despite its neurotoxic effects in the brain, leading to loss of dopaminergic fibres and cell bodies. Moreover, clinical reports suggest that methamphetamine abusers are predisposed to Parkinson's disease. Therefore, it is important to elucidate the mechanisms involved in methamphetamine-induced neurotoxicity. Dopamine receptors may be a plausible target to prevent this neurotoxicity. Genetic inactivation of dopamine D1 or D2 receptors protects against the loss of dopaminergic fibres in the striatum and loss of dopaminergic neurons in the substantia nigra. Protection by D1 receptor inactivation is due to blockade of hypothermia, reduced dopamine content and turnover and increased stored vesicular dopamine in D1R(-/-) mice. However, the neuroprotective impact of D2 receptor inactivation is partially dependent on an effect on body temperature, as well as on the blockade of dopamine reuptake by decreased dopamine transporter activity, which results in reduced intracytosolic dopamine levels in D2R(-/-) mice. © 2013 The Association for the Publication of the Journal of Internal Medicine.

No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using [I-123]FP-CIT (DaTSCAN) and SPECT

NARCIS (Netherlands)

Thomsen, Gerda; Knudsen, Gitte Moos; Jensen, Peter S.; Ziebell, Morten; Holst, Klaus K.; Asenbaum, Susanne; Booij, Jan; Darcourt, Jacques; Dickson, John C.; Kapucu, Ozlem L.; Nobili, Flavio; Sabri, Osama; Sera, Terez; Tatsch, Klaus; Tossici-Bolt, Livia; van Laere, Koen; Borght, Thierry Vander; Varrone, Andrea; Pagani, Marco; Pinborg, Lars Hageman

2013-01-01

Background: Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D-2-like

Alterations in brain extracellular dopamine and glycine levels following combined administration of the glycine transporter type-1 inhibitor Org-24461 and risperidone.

Science.gov (United States)

Nagy, Katalin; Marko, Bernadett; Zsilla, Gabriella; Matyus, Peter; Pallagi, Katalin; Szabo, Geza; Juranyi, Zsolt; Barkoczy, Jozsef; Levay, Gyorgy; Harsing, Laszlo G

2010-12-01

The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced

Axonal accumulation of synaptic markers in APP transgenic Drosophila depends on the NPTY motif and is paralleled by defects in synaptic plasticity

DEFF Research Database (Denmark)

Rusu, Patricia; Jansen, Anna; Soba, Peter

2007-01-01

. Specifically, axonal transport defects have been reported in AD animal models, including mice and flies that overexpress APP and tau. Here we demonstrate that the APP-induced traffic jam of vesicles in peripheral nerves of Drosophila melanogaster larvae depends on the four residues NPTY motif in the APP...... neurotransmission at the neuromuscular junction in transgenic larvae that express human APP. Consistent with the observation that these larvae do not show any obvious movement deficits, we found no changes in basal synaptic transmission. However, short-term synaptic plasticity was affected by overexpression of APP...

Brain Dopamine Transporter Binding and Glucose Metabolism in Progressive Supranuclear Palsy-Like Creutzfeldt-Jakob Disease

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Eero Rissanen

2014-01-01

Full Text Available Here, we present a patient with Creutzfeldt-Jakob disease (CJD who developed initial symptoms mimicking progressive supranuclear palsy (PSP. Before the development of typical CJD symptoms, functional imaging supported a diagnosis of PSP when [123I]-FP-CIT-SPECT showed a defect in striatal dopamine transporter binding, while [18F]-fluorodeoxyglucose PET showed cortical hypometabolism suggestive of Lewy body dementia. However, the postmortem neuropathological examination was indicative of CJD only, without tau protein or Lewy body findings. This case demonstrates that CJD should be taken into account in rapidly progressing atypical cases of parkinsonism, even when functional imaging supports a diagnosis of a movement disorder.

Dopamine transporter density by [99mTc]-TRODAT-1 SPECT and neurocognitive performance - a preliminary pilot study

International Nuclear Information System (INIS)

Shih, Ming C; Amaro, Edson Jr; Souza, Sayuri de E

2006-01-01

Introduction: Cognitive deficits are associated with functional impairment as well as with poor quality of life in Parkinson's disease (PD). The main brain alteration in PD is a progressive loss of nigrostriatal dopamine neurons. Both animal and human studies have demonstrated that basal ganglia dopamine system is important for cognitive and motor functioning. Dopamine transporter (DAT) PET and SPECT radiotracers have been successfully used to estimate, in vivo, dopamine neuronal loss in humans. Objectives: The present study is aimed to examine the relationship between cognitive impairment and striatal dopamine neuronal loss, as estimated by [ 99m Tc]-TRODAT-1 SPECT in PD patients. Methods: Fifteen PD patients were scanned with [ 99m Tc]-TRODAT-1 SPECT (Dual-Head-SPECT Hwakeye, GE). SPECT images were reconstructed with FBP and Butterworth filter 0,40c/px order 10. Regions of interest (ROIs) were striatum (STR) and occipital lobe (BKG nonspecific binding) and were delineated in 3-mm transaxials slices analyzed according to this formula BP=([STR-BKG]/BKG), where BP is the striatal DAT binding potential. Neurocognitive tests, including the Rey Auditory Verbal Learning Test, Wisconsin Card Sorting Test, Ravens Progressive Matrices, Digit Span and Tavis 3, were applied to all subjects by trained neuropsychologists. Results: Striatal DAT binding potential (BP) was negatively correlated with the RAVLT tests 4 (R= 0.57, p≤0.05) and 5 (R=0.57, p≤0.05), which evaluate verbal learning. Striatal DAT BP was also negatively correlated with the WCST learning item (R=0.54, p≤0.05) and the Tavis 3 items, action error (R=0.52, p≤0.05) and number of correct responses (R=0.47, p≤0.05). Conclusions: Although preliminary, the present findings suggest that striatal DAT loss is associated with a poorer performance on verbal learning and cognitive flexibility tasks. These results are in line with a previous study that examined healthy volunteers and found a relationship between

A new synthetic drug 5-(2-aminopropyl)indole (5-IT) induces rewarding effects and increases dopamine D1 receptor and dopamine transporter mRNA levels.

Science.gov (United States)

Botanas, Chrislean Jun; Yoon, Seong Shoon; de la Peña, June Bryan; Dela Peña, Irene Joy; Kim, Mikyung; Custodio, Raly James; Woo, Taeseon; Seo, Joung-Wook; Jang, Choon-Gon; Yang, Ji Seul; Yoon, Yoon Mi; Lee, Yong Sup; Kim, Hee Jin; Cheong, Jae Hoon

2018-04-02

In recent years, there has been a marked increase in the use of recreational synthetic psychoactive substances, which is a cause of concern among healthcare providers and legal authorities. In particular, there have been reports on the misuse of 5-(2-aminopropyl)indole (5-API; 5-IT), a new synthetic drug, and of fatal and non-fatal intoxication. Despite these reports, little is known about its psychopharmacological effects and abuse potential. Here, we investigated the abuse potential of 5-IT by evaluating its rewarding and reinforcing effects through conditioned place preference (CPP) (1, 10, and 30 mg/kg, i.p.) in mice and self-administration test (0.1, 0.3, 1, and 3 mg/kg/inf., i.v.) in rats. We also examined whether 5-IT (1, 3, and 10 mg/kg, i.p.) induces locomotor sensitization in mice following a 7-day treatment and drug challenge. Then, we explored the effects of 5-IT (10 mg/kg, i.p.) on dopamine-related genes in the striatum, prefrontal cortex (PFC), and substantia nigra pars compacta (SNc)/ventral tegmental (VTA) of mice by quantitative real-time polymerase chain reaction. 5-IT produced CPP in mice but was not reliably self-administered by rats. 5-IT also induced locomotor sensitization following repeated administration and drug challenge. Moreover, 5-IT increased mRNA levels of dopamine D1 receptor in the striatum and PFC and dopamine transporter in the SNc/VTA of mice. These results indicate that 5-IT has psychostimulant and rewarding properties, which may be attributed to its ability to affect the dopaminergic system in the brain. These findings suggest that 5-IT poses a substantial risk for abuse and addiction in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

Interactive Effects of Dopamine Baseline Levels and Cycle Phase on Executive Functions: The Role of Progesterone

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Esmeralda Hidalgo-Lopez

2017-07-01

Full Text Available Estradiol and progesterone levels vary along the menstrual cycle and have multiple neuroactive effects, including on the dopaminergic system. Dopamine relates to executive functions in an “inverted U-shaped” manner and its levels are increased by estradiol. Accordingly, dopamine dependent changes in executive functions along the menstrual cycle have been previously studied in the pre-ovulatory phase, when estradiol levels peak. Specifically it has been demonstrated that working memory is enhanced during the pre-ovulatory phase in women with low dopamine baseline levels, but impaired in women with high dopamine baseline levels. However, the role of progesterone, which peaks in the luteal cycle phase, has not been taken into account previously. Therefore, the main goals of the present study were to extend these findings (i to the luteal cycle phase and (ii to other executive functions. Furthermore, the usefulness of the eye blink rate (EBR as an indicator of dopamine baseline levels in menstrual cycle research was explored. 36 naturally cycling women were tested during three cycle phases (menses–low sex hormones; pre-ovulatory–high estradiol; luteal–high progesterone and estradiol. During each session, women performed a verbal N-back task, as measure of working memory, and a single trial version of the Stroop task, as measure of response inhibition and cognitive flexibility. Hormone levels were assessed from saliva samples and spontaneous eye blink rate was recorded during menses. In the N-back task, women were faster during the luteal phase the higher their progesterone levels, irrespective of their dopamine baseline levels. In the Stroop task, we found a dopamine-cycle interaction, which was also driven by the luteal phase and progesterone levels. For women with higher EBR performance decreased during the luteal phase, whereas for women with lower EBR performance improved during the luteal phase. These findings suggest an important

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers.

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Erblich, J; Lerman, C; Self, D W; Diaz, G A; Bovbjerg, D H

2005-04-01

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian smokers. Based on the animal literature, the study's objective was to test the hypothesis that smokers carrying specific variants in dopamine-related genes previously associated with risk for addictive behaviors would exhibit heightened levels of cigarette craving following laboratory exposure to cues. To this end, cigarette craving was induced in healthy African-American smokers (n=88) through laboratory exposure to smoking cues. Smokers carrying either the DRD2 (D2 dopamine receptor gene) TaqI A1 RFLP or the SLC6A3 (dopamine transporter gene) 9-repeat VNTR polymorphisms had stronger cue-induced cravings than noncarriers (Ps cue-induced craving in humans, and suggest a possible genetic risk factor for persistent smoking behavior in African-American smokers.

Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2.

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Hankosky, Emily R; Joolakanti, Shyam R; Nickell, Justin R; Janganati, Venumadhav; Dwoskin, Linda P; Crooks, Peter A

2017-12-15

A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [ 3 H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [ 3 H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [ 3 H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [ 3 H]DA uptake at VMAT2, Ki changes in the nanomolar range (K i  = 0.014-0.073 µM). Compound 15d exhibited the highest affinity (K i  = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (K i  = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2. Copyright © 2017 Elsevier Ltd. All rights reserved.

APRESS: apical regulatory super system, serotonin, and dopamine interaction

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Hinz M

2011-08-01

Full Text Available Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics, Inc, Cape Coral, FL, USA; 2Stein Orthopedic Associates, Plantation, FL, USA; 3DBS Labs, Duluth, MN, USABackground: The monoamines serotonin and dopamine are known to exist in two separate states: the endogenous state and the competitive inhibition state. The presence of the competitive inhibition state has been known to science for many years, but from a functional standpoint it has been noted in the literature as being "meaningless."Methods: A large database of monoamine transporter response to amino acid precursor administration variations with clinical outcomes was accumulated. In the process, a new organic cation transporter (OCT model has been published, and OCT functional status determination along with amino acid precursor manipulation methods have been invented and refined.Results: Methodology was developed whereby manipulation of the OCT, in the competitive inhibition state, is carried out in a predictable manner. This, in turn, has disproved the long-held assertion that the monoamine competitive inhibition state is functionally meaningless.Conclusion: The most significant aspect of this paper is the documentation of newly recognized relationships between serotonin and dopamine. When transport of serotonin and dopamine are both in the competitive inhibition state, manipulation of the concentrations of one will lead to predictable changes in concentrations of the other. From a functional standpoint, processes regulated and controlled by changes to only serotonin can now be controlled by changes to dopamine, and vice versa, in a predictable manner.Keywords: catecholamine, monoamine, competitive inhibition state

A novel dopamine transporter transgenic mouse line for identification and purification of midbrain dopaminergic neurons reveals midbrain heterogeneity

DEFF Research Database (Denmark)

Christiansen, Mia Apuschkin; Stilling, Sara; Rahbek-Clemmensen, Troels

2015-01-01

Midbrain dopaminergic (DAergic) neurons are a heterogeneous cell group, composed of functionally distinct cell populations projecting to the basal ganglia, prefrontal cortex and limbic system. Despite their functional significance, the midbrain population of DAergic neurons is sparse, constituting...... of the dopamine transporter (DAT) promoter was characterized. Confocal microscopy analysis of brain sections showed strong eGFP signal reporter in midbrain regions and striatal terminals that co-localized with the DAergic markers DAT and tyrosine hydroxylase (TH). Thorough quantification of co...

FMRP acts as a key messenger for dopamine modulation in the forebrain.

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Wang, Hansen; Wu, Long-Jun; Kim, Susan S; Lee, Frank J S; Gong, Bo; Toyoda, Hiroki; Ren, Ming; Shang, Yu-Ze; Xu, Hui; Liu, Fang; Zhao, Ming-Gao; Zhuo, Min

2008-08-28

The fragile X mental retardation protein (FMRP) is an RNA-binding protein that controls translational efficiency and regulates synaptic plasticity. Here, we report that FMRP is involved in dopamine (DA) modulation of synaptic potentiation. AMPA glutamate receptor subtype 1 (GluR1) surface expression and phosphorylation in response to D1 receptor stimulation were reduced in cultured Fmr1(-/-) prefrontal cortex (PFC) neurons. Furthermore, D1 receptor signaling was impaired, accompanied by D1 receptor hyperphosphorylation at serine sites and subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in both PFC and striatum of Fmr1(-/-) mice. FMRP interacted with GRK2, and pharmacological inhibition of GRK2 rescued D1 receptor signaling in Fmr1(-/-) neurons. Finally, D1 receptor agonist partially rescued hyperactivity and enhanced the motor function of Fmr1(-/-) mice. Our study has identified FMRP as a key messenger for DA modulation in the forebrain and may provide insights into the cellular and molecular mechanisms underlying fragile X syndrome.

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

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Can, Adem; Zanos, Panos; Moaddel, Ruin; Kang, Hye Jin; Dossou, Katinia S. S.; Wainer, Irving W.; Cheer, Joseph F.; Frost, Douglas O.; Huang, Xi-Ping

2016-01-01

Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID

Enhanced striatal dopamine release during food stimulation in binge eating disorder

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Wang, g.j.; Wang, G.-J.; Geliebter, A.; Volkow, N.D.; Telang, F.W.; Logan, Jaynbe, M.C.; Galanti, K.; Selig, P.A.; Han, H.; Zhu, W.; Wong, C.T.; Fowler, J.S.

2011-01-13

Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [{sup 11}C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.

Enhanced striatal dopamine release during food stimulation in binge eating disorder

International Nuclear Information System (INIS)

Wang, G.-J.; Geliebter, A.; Volkow, N.D.; Telang, F.W.; Logan, J.; Jaynbe, M.C.; Galanti, K.; Selig, P.A.; Han, H.; Zhu, W.; Wong, C.T.; Fowler, J.S.

2011-01-01

Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [ 11 C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.

Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance

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Andrii eDomanskyi

2014-09-01

Full Text Available The proteins Foxa1 and Foxa2 belong to the forkhead family of transcription factors and are involved in the development of several tissues, including liver, pancreas, lung, prostate, and the neural system. Both Foxa1 and Foxa2 are also crucial for the specification and differentiation of dopamine (DA neurons during embryonic development, while about 30% of mice with an embryonic deletion of a single allele of the Foxa2 gene exhibit an age-related asymmetric loss of DA neurons and develop locomotor symptoms resembling Parkinson’s disease (PD. Notably, both Foxa1 and Foxa2 factors continue to be expressed in the adult dopamine system. To directly assess their functions selectively in adult DA neurons, we induced genetic deletions of Foxa1/2 transcription factors in mice using a tamoxifen inducible tissue-specific CreERT2 recombinase expressed under control of the dopamine transporter (DAT promoter (DATCreERT2. The conditional DA neurons-specific ablation of both genes, but not of Foxa2 alone, in early adulthood, caused a decline of striatal dopamine and its metabolites, along with locomotor deficits. At early pre-symptomatic stages, we observed a decline in aldehyde dehydrogenase family 1, subfamily A1 (Aldh1a1 protein expression in DA neurons. Further analyses revealed a decline of aromatic amino acid decarboxylase (AADC and a complete loss of DAT expression in these neurons. These molecular changes ultimately led to a reduction of DA neuron numbers in the substantia nigra pars compacta (SNpc of aged cFoxa1/2-/- mice, resembling the progressive course of PD in humans. Altogether, in this study, we address the molecular, cellular and functional role of both Foxa1 and Foxa2 factors in the maintenance of the adult dopamine system which may help to find better approaches for PD treatment.

The use of LeuT as a model in elucidating binding sites for substrates and inhibitors in neurotransmitter transporters

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Løland, Claus Juul

2015-01-01

Background: The mammalian neurotransmitter transporters are complex proteins playing a central role in synaptic transmission between neurons by rapid reuptake of neurotransmitters. The proteins which transport dopamine, noradrenaline and serotonin belong to the Neurotransmitter:Sodium Symporters...... (NSS). Due to their important role, dysfunctions are associated with several psychiatric and neurological diseases and they also serve as targets for a wide range of therapeutic and illicit drugs. Despite the central physiological and pharmacological importance, direct evidence on structure......–function relationships on mammalian NSS proteins has so far been unsuccessful. The crystal structure of the bacterial NSS protein, LeuT, has been a turning point in structural investigations. Scope of review: To provide an update on what is known about the binding sites for substrates and inhibitors in the Leu...

Regulation of Synaptic Structure by the Ubiquitin C-terminal Hydrolase UCH-L1

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Cartier, Anna E.; Djakovic, Stevan N.; Salehi, Afshin; Wilson, Scott M.; Masliah, Eliezer; Patrick, Gentry N.

2009-01-01

UCH-L1 is a de-ubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We have found that UCH-L1 activity is rapidly up-regulated by NMDA receptor activation which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of pre and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1 inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner. PMID:19535597

Increased binding of [3H]apomorphine in caudate membranes after dopamine pretreatment in vitro

International Nuclear Information System (INIS)

McManus, C.; Hartley, E.J.; Seeman, P.

1978-01-01

Most patients with Parkinson's disease treated with L-dopa show a progressively deteriorating response which may possibly be attributed to an L-dopa-induced process of unknown origin. Long-term administration of dopamine-mimetic drugs to animals sometimes produces behavioural facilitation. To investigate one possible molecular mechanism of this facilitation or sensitization the effects of prolonged exposure, in vitro, of dopamine on the dopamine/neuroleptic receptors in the caudate nucleus of the calf were tested. Calf caudate homogenates pretreated with dopamine or other drugs were tested for the binding of [ 3 H]apomorphine, [ 3 H]haloperidol, 3H-WB-4101, or [ 3 H]naloxine. Pre-exposure with dopamine or noradrenaline lead to an increased binding of [ 3 H]apomorphine. The significance of the results is discussed. (author)

Functional Rescue of a Misfolded Drosophila melanogaster Dopamine Transporter Mutant Associated with a Sleepless Phenotype by Pharmacological Chaperones.

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Kasture, Ameya; El-Kasaby, Ali; Szöllősi, Daniel; Asjad, H M Mazhar; Grimm, Alexandra; Stockner, Thomas; Hummel, Thomas; Freissmuth, Michael; Sucic, Sonja

2016-09-30

Folding-defective mutants of the human dopamine transporter (DAT) cause a syndrome of infantile dystonia/parkinsonism. Here, we provide a proof-of-principle that the folding deficit is amenable to correction in vivo by two means, the cognate DAT ligand noribogaine and the HSP70 inhibitor, pifithrin-μ. We examined the Drosophila melanogaster (d) mutant dDAT-G108Q, which leads to a sleepless phenotype in flies harboring this mutation. Molecular dynamics simulations suggested an unstable structure of dDAT-G108Q consistent with a folding defect. This conjecture was verified; heterologously expressed dDAT-G108Q and the human (h) equivalent hDAT-G140Q were retained in the endoplasmic reticulum in a complex with endogenous folding sensors (calnexin and HSP70-1A). Incubation of the cells with noribogaine (a DAT ligand selective for the inward-facing state) and/or pifithrin-μ (an HSP70 inhibitor) restored folding of, and hence dopamine transport by, dDAT-G108Q and hDAT-G140Q. The mutated versions of DAT were confined to the cell bodies of the dopaminergic neurons in the fly brain and failed to reach the axonal compartments. Axonal delivery was restored, and sleep time was increased to normal length (from 300 to 1000 min/day) if the dDAT-G108Q-expressing flies were treated with noribogaine and/or pifithrin-μ. Rescuing misfolded versions of DAT by pharmacochaperoning is of therapeutic interest; it may provide opportunities to remedy disorders arising from folding-defective mutants of human DAT and of other related SLC6 transporters. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Novel L-Dopa and dopamine prodrugs containing a 2-phenyl-imidazopyridine moiety.

Science.gov (United States)

Denora, Nunzio; Laquintana, Valentino; Lopedota, Angela; Serra, Mariangela; Dazzi, Laura; Biggio, Giovanni; Pal, Dhananjay; Mitra, Ashim K; Latrofa, Andrea; Trapani, Giuseppe; Liso, Gaetano

2007-07-01

The aim of this study was to gain insight into the feasibility of enhancing the delivery of L-Dopa and dopamine to the brain by linking these neurotransmitters and L-Dopa ethyl ester to 2-phenyl-3-carboxymethyl-imidazopyridine compounds giving rise to the so-called Dopimid compounds. A number of Dopimid compounds were synthesized and both stability and binding studies to dopaminergic and benzodiazepine receptors were performed. To evaluate whether Dopimid compounds are P-gp substrates, [(3)H]ritonavir uptake experiments and bi-directional transport studies on confluent MDCKII-MDR1 monolayers were carried out. The brain penetration properties of Dopimid compounds were estimated by the Clark's computational model and evaluated by investigation of their transport across BBMECs monolayers. The dopamine levels following the intraperitoneal administration of the selected Dopimid compounds were measured in vivo by using brain microdialysis in rat. Tested compounds were adequately stable in solution buffered at pH 7.4 but undergo faster cleavage in dilute rat serum at 37 degrees C. Receptor binding studies showed that Dopimid compounds are essentially devoid of affinity for dopaminergic and benzodiazepine receptors. [(3)H]ritonavir uptake experiments indicated that selected Dopimid compounds, like L-Dopa and dopamine hydrochloride, are not substrates of P-gp and it was also confirmed by bi-directional transport experiments across MDCKII-MDR1 monolayers. By Clark's model a significant brain penetration was deduced for L-Dopa ethyl ester and dopamine derivatives. Transport studies involving BBMECs monolayers indicated that some of these compounds should be able to cross the BBB. Interestingly, the rank order of apparent permeability (P (app)) values observed in these assays parallels that calculated by the computational approach. Brain microdialysis experiments in rat showed that intraperitoneal acute administration of some Dopimid compounds induced a dose-dependent increase

Abnormal Mitochondrial Dynamics and Synaptic Degeneration as Early Events in Alzheimer’s Disease: Implications to Mitochondria-Targeted Antioxidant Therapeutics

Science.gov (United States)

Reddy, P. Hemachandra; Tripathy, Raghav; Troung, Quang; Thirumala, Karuna; Reddy, Tejaswini P.; Anekonda, Vishwanath; Shirendeb, Ulziibat P.; Calkins, Marcus J.; Reddy, Arubala P.; Mao, Peizhong; Manczak, Maria

2011-01-01

Synaptic pathology and mitochondrial oxidative damage are early events in Alzheimer’s disease (AD) progression. Loss of synapses and synaptic damage are the best correlate of cognitive deficits found in AD patients. Recent research on amyloid bet (Aβ) and mitochondria in AD revealed that Aβ accumulates in synapses and synaptic mitochondria, leading to abnormal mitochondrial dynamics and synaptic degeneration in AD neurons. Further, recent studies using live-cell imaging and primary neurons from amyloid beta precursor protein (AβPP) transgenic mice revealed that reduced mitochondrial mass, defective axonal transport of mitochondria and synaptic degeneration, indicating that Aβ is responsible for mitochondrial and synaptic deficiencies. Tremendous progress has been made in studying antioxidant approaches in mouse models of AD and clinical trials of AD patients. This article highlights the recent developments made in Aβ-induced abnormal mitochondrial dynamics, defective mitochondrial biogenesis, impaired axonal transport and synaptic deficiencies in AD. This article also focuses on mitochondrial approaches in treating AD, and also discusses latest research on mitochondria-targeted antioxidants in AD. PMID:22037588

TrkB and PKMζ regulate synaptic localization of PSD-95 in developing cortex

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Yoshii, Akira; Murata, Yasunobu; Kim, Jihye; Zhang, Chao; Shokat, Kevan M.; Constantine-Paton, Martha

2011-01-01

Post-synaptic density 95 (PSD-95), the major scaffold at excitatory synapses, is critical for synapse maturation and learning. In rodents, eye opening, the onset of pattern vision, triggers a rapid movement of PSD-95 from visual neuron somata to synapses. We previously showed that the PI3 kinase-Akt pathway downstream of BDNF/TrkB signaling stimulates synaptic delivery of PSD-95 via vesicular transport. However, vesicular transport requires PSD-95 palmitoylation to attach it to a lipid membrane. Also PSD-95 insertion at synapses is known to require this lipid modification. Here, we show that BDNF/TrkB signaling is also necessary for PSD-95 palmitoylation and its transport to synapses in mouse visual cortical layer 2/3 neurons. However, palmitoylation of PSD-95 requires the activation of another pathway downstream of BDNF/TrkB, namely signaling through PLCγ and the brain-specific PKC variant PKMζ. We find that PKMζ selectively regulates phosphorylation of the palmitoylation enzyme ZDHHC8. Inhibition of PKMζ results in a reduction of synaptic PSD-95 accumulation in vivo, which can be rescued by over-expression ZDHHC8. Therefore, TrkB and PKMζ, two critical regulators of synaptic plasticity, facilitate PSD-95 targeting to synapses. These results also indicate that palmitoylation can be regulated by a trophic factor. Our findings have implications for neurodevelopmental disorders as well as ageing brains. PMID:21849550

The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism

International Nuclear Information System (INIS)

Booij, J.; Speelman, J.DE.; Horstink, M. W.I.M.; Wolters, E.C.

2001-01-01

[ 123 I]FP-CIT (N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several ''presynaptic parkinsonian'' syndromes, such as Parkinson's disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [ 123 I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with ''presynaptic parkinsonism'' from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [ 123 I]FP-CIT SPET. Using [ 123 I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2-4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [ 123 I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases

Firing properties of dopamine neurons in freely moving dopamine-deficient mice: Effects of dopamine receptor activation and anesthesia

OpenAIRE

Robinson, Siobhan; Smith, David M.; Mizumori, Sheri J. Y.; Palmiter, Richard D.

2004-01-01

To examine the regulation of midbrain dopamine neurons, recordings were obtained from single neurons of freely moving, genetically engineered dopamine-deficient (DD) mice. DD mice were tested without dopamine signaling (basal state) and with endogenous dopamine signaling (after L-dopa administration). In the basal state, when dopamine concentration in DD mice is

The brain cytoplasmic RNA BC1 regulates dopamine D-2 receptor-mediated transmission in the striatum

OpenAIRE

Centonze, Diego; Rossi, Silvia; Napoli, Ilaria; Mercaldo, Valentina; Lacoux, Caroline; Ferrari, Francesca; Ciotti, Maria Teresa; De Chiara, Valentina; Prosperetti, Chiara; Maccarrone, Mauro; Fezza, Filomena; Calabresi, Paolo; Bernardi, Giorgio; Bagni, Claudia

2007-01-01

Dopamine D-2 receptor (D2DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D-2 receptors in this brain area are essentially obscure. We have studied the physiological responses of the D2DR stimulations in mice...

Ethanol and phencyclidine interact with respect to nucleus accumbens dopamine release: differential effects of administration order and pretreatment protocol

Directory of Open Access Journals (Sweden)

Chris Pickering

2010-06-01

Full Text Available Executive dysfunction is a common symptom among alcohol-dependent individuals. Phencyclidine (PCP injection induces dysfunction in the prefrontal cortex of animals but little is known about how PCP affects the response to ethanol. Using the in vivo microdialysis technique in male Wistar rats, we investigated how systemic injection of 5 mg/kg PCP would affect the dopamine release induced by local infusion of 300 mM ethanol into the nucleus accumbens. PCP given 60 min before ethanol entirely blocked ethanol-induced dopamine release. However, when ethanol was administered 60 min before PCP, both drugs induced dopamine release and PCP’s effect was potentiated by ethanol (180% increase vs 150%. To test the role of prefrontal cortex dysfunction in ethanol reinforcement, animals were pre-treated for 5 days with 2.58 mg/kg PCP according to previously used ‘PFC hypofunction protocols’. This, however, did not change the relative response to PCP or ethanol compared to saline-treated controls. qPCR illustrated that this PCP dose did not significantly change expression of glucose transporters Glut1 (SLC2A1 or Glut3 (SLC2A3, monocarboxylate transporter MCT2 (SLC16A7, glutamate transporters GLT-1 (SLC1A2 or GLAST (SLC1A3, the immediate early gene Arc (Arg3.1 or GABAergic neuron markers GAT-1 (SLC6A1 and parvalbumin. Therefore, we concluded that PCP at a dose of 2.58 mg/kg for 5 days did not induce hypofunction in Wistar rats. However, PCP and ethanol do have overlapping mechanisms of action and these drugs differentially affect mesolimbic dopaminergic transmission depending on the order of administration.

Separate groups of dopamine neurons innervate caudate head and tail encoding flexible and stable value memories

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Hyoung F Kim

2014-10-01

Full Text Available Dopamine neurons are thought to be critical for reward value-based learning by modifying synaptic transmissions in the striatum. Yet, different regions of the striatum seem to guide different kinds of learning. Do dopamine neurons contribute to the regional differences of the striatum in learning? As a first step to answer this question, we examined whether the head and tail of the caudate nucleus of the monkey (Macaca mulatta receive inputs from the same or different dopamine neurons. We chose these caudate regions because we previously showed that caudate head neurons learn values of visual objects quickly and flexibly, whereas caudate tail neurons learn object values slowly but retain them stably. Here we confirmed the functional difference by recording single neuronal activity while the monkey performed the flexible and stable value tasks, and then injected retrograde tracers in the functional domains of caudate head and tail. The projecting dopaminergic neurons were identified using tyrosine hydroxylase immunohistochemistry. We found that two groups of dopamine neurons in the substantia nigra pars compacta project largely separately to the caudate head and tail. These groups of dopamine neurons were mostly separated topographically: head-projecting neurons were located in the rostral-ventral-medial region, while tail-projecting neurons were located in the caudal-dorsal-lateral regions of the substantia nigra. Furthermore, they showed different morphological features: tail-projecting neurons were larger and less circular than head-projecting neurons. Our data raise the possibility that different groups of dopamine neurons selectively guide learning of flexible (short-term and stable (long-term memories of object values.

Spike Train Auto-Structure Impacts Post-Synaptic Firing and Timing-Based Plasticity

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Scheller, Bertram; Castellano, Marta; Vicente, Raul; Pipa, Gordon

2011-01-01

Cortical neurons are typically driven by several thousand synapses. The precise spatiotemporal pattern formed by these inputs can modulate the response of a post-synaptic cell. In this work, we explore how the temporal structure of pre-synaptic inhibitory and excitatory inputs impact the post-synaptic firing of a conductance-based integrate and fire neuron. Both the excitatory and inhibitory input was modeled by renewal gamma processes with varying shape factors for modeling regular and temporally random Poisson activity. We demonstrate that the temporal structure of mutually independent inputs affects the post-synaptic firing, while the strength of the effect depends on the firing rates of both the excitatory and inhibitory inputs. In a second step, we explore the effect of temporal structure of mutually independent inputs on a simple version of Hebbian learning, i.e., hard bound spike-timing-dependent plasticity. We explore both the equilibrium weight distribution and the speed of the transient weight dynamics for different mutually independent gamma processes. We find that both the equilibrium distribution of the synaptic weights and the speed of synaptic changes are modulated by the temporal structure of the input. Finally, we highlight that the sensitivity of both the post-synaptic firing as well as the spike-timing-dependent plasticity on the auto-structure of the input of a neuron could be used to modulate the learning rate of synaptic modification. PMID:22203800

Synaptic Transmission Optimization Predicts Expression Loci of Long-Term Plasticity.

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Costa, Rui Ponte; Padamsey, Zahid; D'Amour, James A; Emptage, Nigel J; Froemke, Robert C; Vogels, Tim P

2017-09-27

Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression-pre- or postsynaptic-is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Striatal Dopamine Depletion Patterns and Early Non-Motor Burden in Parkinsons Disease.

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Su Jin Chung

Full Text Available The mechanism underlying non-motor symptoms in Parkinson's disease has not yet been elucidated. In this study, we hypothesized that Parkinson patients with more non-motor symptoms have a different pattern of striatal dopamine depletion, particularly in areas other than the sensorimotor striatum, compared to those with fewer non-motor symptoms.We conducted a prospective survey of the degree of non-motor symptoms (using the Korean version of the Non-Motor Symptoms Scale; K-NMSS in 151 patients with early-stage Parkinson's disease who had undergone a dopamine transporter PET scan as an initial diagnostic procedure. We classified the patients into two groups; high non-motor patients (HNM-PD; K-NMSS score ≥ 41 and low non-motor patients (LNM-PD.Patients in the HNM-PD group (n = 71 were older, had longer symptom duration, exhibited more severe motor deficits, and had been prescribed higher levodopa-equivalent doses at follow-up than those in the LNM-PD group. However, dopamine transporter binding to the striatal sub-regions and inter-sub-regional binding ratios were comparable between the two groups. A general linear model showed that the HNM-PD group had significantly more severe motor deficits than the LNM-PD group after controlling for age, gender, symptom duration, and dopamine transporter binding to the sensorimotor striatum.This study demonstrated that the pattern of striatal dopamine depletion does not contribute to early non-motor burden in Parkinson's disease. Our results suggest that LNM-PD patients may have a more benign course of motor symptom progression than HNM-PD patients.

Enduring increases in anxiety-like behavior and rapid nucleus accumbens dopamine signaling in socially isolated rats.

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Yorgason, Jordan T; España, Rodrigo A; Konstantopoulos, Joanne K; Weiner, Jeffrey L; Jones, Sara R

2013-03-01

Social isolation (SI) rearing, a model of early life stress, results in profound behavioral alterations, including increased anxiety-like behavior, impaired sensorimotor gating and increased self-administration of addictive substances. These changes are accompanied by alterations in mesolimbic dopamine function, such as increased dopamine and metabolite tissue content, increased dopamine responses to cues and psychostimulants, and increased dopamine neuron burst firing. Using voltammetric techniques, we examined the effects of SI rearing on dopamine transporter activity, vesicular release and dopamine D2-type autoreceptor activity in the nucleus accumbens core. Long-Evans rats were housed in group (GH; 4/cage) or SI (1/cage) conditions from weaning into early adulthood [postnatal day (PD) 28-77]. After this initial housing period, rats were assessed on the elevated plus-maze for an anxiety-like phenotype, and then slice voltammetry experiments were performed. To study the enduring effects of SI rearing on anxiety-like behavior and dopamine terminal function, another cohort of similarly reared rats was isolated for an additional 4 months (until PD 174) and then tested. Our findings demonstrate that SI rearing results in lasting increases in anxiety-like behavior, dopamine release and dopamine transporter activity, but not D2 activity. Interestingly, GH-reared rats that were isolated as adults did not develop the anxiety-like behavior or dopamine changes seen in SI-reared rats. Together, our data suggest that early life stress results in an anxiety-like phenotype, with lasting increases in dopamine terminal function. © 2013 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Exploration of the dopamine transporter: in vitro and in vivo characterization of a high-affinity and high-specificity iodinated tropane derivative (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy- 3β-(4'-methylphenyl)nortropane (PE2I)

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Guilloteau, Denis; Emond, Patrick; Baulieu, Jean-Louis; Garreau, Lucette; Frangin, Yves; Pourcelot, Leandre; Mauclaire, Laurent; Besnard, Jean-Claude; Chalon, Sylvie

1998-01-01

For the diagnosis and follow-up of neurodegenerative diseases, many cocaine derivatives have been proposed as radioligands to explore the dopamine transporter. As none of them have all the criteria of specificity and kinetics for human use, we have developed a new derivative, (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4'-methylphenyl)nortropane (PE2I), which displays promising properties. We report the characterization of PE2I in vitro on rat striatal membranes and in vivo in rats and in monkeys. PE2I had a high affinity (Kd=0.09±0.01 nM) and high specificity for the dopamine transporter. In rats we observed a high accumulation in the striatum; by contrast, a very low fixation was measured in the cortex. Moreover, a preinjection of a saturating dose of GBR 12909 prevented the striatal accumulation of PE2I by 74%. These results confirmed the specificity of PE2I for the dopamine transporter. In vivo in monkeys, SPECT studies showed a high accumulation in striatum. Moreover, an equilibrium state was obtained 1 h after injection. PE2I seemed to be the most promising ligand for the dopamine transporter exploration by SPECT using a single-day protocol.

Integrated neuron circuit for implementing neuromorphic system with synaptic device

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Lee, Jeong-Jun; Park, Jungjin; Kwon, Min-Woo; Hwang, Sungmin; Kim, Hyungjin; Park, Byung-Gook

2018-02-01

In this paper, we propose and fabricate Integrate & Fire neuron circuit for implementing neuromorphic system. Overall operation of the circuit is verified by measuring discrete devices and the output characteristics of the circuit. Since the neuron circuit shows asymmetric output characteristic that can drive synaptic device with Spike-Timing-Dependent-Plasticity (STDP) characteristic, the autonomous weight update process is also verified by connecting the synaptic device and the neuron circuit. The timing difference of the pre-neuron and the post-neuron induce autonomous weight change of the synaptic device. Unlike 2-terminal devices, which is frequently used to implement neuromorphic system, proposed scheme of the system enables autonomous weight update and simple configuration by using 4-terminal synapse device and appropriate neuron circuit. Weight update process in the multi-layer neuron-synapse connection ensures implementation of the hardware-based artificial intelligence, based on Spiking-Neural- Network (SNN).

Determinants of functional coupling between astrocytes and respiratory neurons in the pre-Bötzinger complex.

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Christian Schnell

Full Text Available Respiratory neuronal network activity is thought to require efficient functioning of astrocytes. Here, we analyzed neuron-astrocyte communication in the pre-Bötzinger Complex (preBötC of rhythmic slice preparations from neonatal mice. In astrocytes that exhibited rhythmic potassium fluxes and glutamate transporter currents, we did not find a translation of respiratory neuronal activity into phase-locked astroglial calcium signals. In up to 20% of astrocytes, 2-photon calcium imaging revealed spontaneous calcium fluctuations, although with no correlation to neuronal activity. Calcium signals could be elicited in preBötC astrocytes by metabotropic glutamate receptor activation or after inhibition of glial glutamate uptake. In the latter case, astrocyte calcium elevation preceded a surge of respiratory neuron discharge activity followed by network failure. We conclude that astrocytes do not exhibit respiratory-rhythmic calcium fluctuations when they are able to prevent synaptic glutamate accumulation. Calcium signaling is, however, observed when glutamate transport processes in astrocytes are suppressed or neuronal discharge activity is excessive.

Incident impulse control disorder symptoms and dopamine transporter imaging in Parkinson disease.

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Smith, Kara M; Xie, Sharon X; Weintraub, Daniel

2016-08-01

To describe the incidence of, and clinical and neurobiological risk factors for, new-onset impulse control disorder (ICD) symptoms and related behaviours in early Parkinson disease (PD). The Parkinson's Progression Markers Initiative is an international, multicenter, prospective study of de novo patients with PD untreated at baseline and assessed annually, including serial dopamine transporter imaging (DAT-SPECT) and ICD assessment (Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease short form, QUIP). Participants were included if they screened negative on the QUIP at baseline. Kaplan-Meier curves and generalised estimating equations examined frequency and predictors of incident ICD symptoms. Participants were seen at baseline (n=320), year 1 (n=284), year 2 (n=217) and year 3 (n=96). Estimated cumulative incident rates of ICD symptoms and related behaviours were 8% (year 1), 18% (year 2) and 25% (year 3) and increased each year in those on dopamine replacement therapy (DRT) and decreased in those not on DRT. In participants on DRT, risk factors for incident ICD symptoms were younger age (OR=0.97, p=0.05), a greater decrease in right caudate (OR=4.03, p=0.01) and mean striatal (OR=6.90, p=0.04) DAT availability over the first year, and lower right putamen (OR=0.06, p=0.01) and mean total striatal (OR=0.25, p=0.04) DAT availability at any post-baseline visit. The rate of incident ICD symptoms increases with time and initiation of DRT in early PD. In this preliminary study, a greater decrease or lower DAT binding over time increases risk of incident ICD symptoms, conferring additional risk to those taking DRT. NCT01141023. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The genetics of axonal transport and axonal transport disorders.

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Jason E Duncan

2006-09-01

Full Text Available Neurons are specialized cells with a complex architecture that includes elaborate dendritic branches and a long, narrow axon that extends from the cell body to the synaptic terminal. The organized transport of essential biological materials throughout the neuron is required to support its growth, function, and viability. In this review, we focus on insights that have emerged from the genetic analysis of long-distance axonal transport between the cell body and the synaptic terminal. We also discuss recent genetic evidence that supports the hypothesis that disruptions in axonal transport may cause or dramatically contribute to neurodegenerative diseases.

The dual-gate lumen model of renal monoamine transport

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Marty Hinz

2010-07-01

Full Text Available Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics, Inc. Cape Coral, Florida, USA; 2Stein Orthopedic Associates, Plantation, Florida, USA; 3DBS Labs, Duluth, Minnesota, USAAbstract: The three-phase response of urinary serotonin and dopamine in subjects ­simultaneously taking amino acid precursors of serotonin and dopamine has been defined.1,2 No model exists regarding the renal etiology of the three-phase response. This writing outlines a model explaining the origin of the three-phase response of urinary serotonin and dopamine. A “dual-gate lumen transporter model” for the basolateral monoamine transporters of the kidneys is proposed as being the etiology of the three-phase urinary serotonin and dopamine responses.Purpose: The purpose of this writing is to document the internal renal function model that has evolved in research during large-scale assay with phase interpretation of urinary serotonin and dopamine.Patients and methods: In excess of 75,000 urinary monoamine assays from more than 7,500 patients were analyzed. The serotonin and the dopamine phase were determined for specimens submitted in the competitive inhibition state. The phase determination findings were then correlated with peer-reviewed literature.Results: The correlation between the three-phase response of urinary serotonin and dopamine with internal renal processes of the bilateral monoamine transporter and the apical monoamine transporter of the proximal convoluted renal tubule cells is defined.Conclusion: The phase of urinary serotonin and dopamine is dependent on the status of the serotonin gate, dopamine gate, and lumen of the basolateral monoamine transporter while in the competitive inhibition state.Keywords: serotonin, dopamine, basolateral, apical, kidney, proximal

A Japanese Encephalitis Patient Presenting with Parkinsonism with Corresponding Laterality of Magnetic Resonance and Dopamine Transporter Imaging Findings.

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Tadokoro, Koh; Ohta, Yasuyuki; Sato, Kota; Maeki, Takahiro; Sasaki, Ryo; Takahashi, Yoshiaki; Shang, Jingwei; Takemoto, Mami; Hishikawa, Nozomi; Yamashita, Toru; Lim, Chang Kweng; Tajima, Shigeru; Abe, Koji

2018-03-09

Japanese encephalitis (JE) survivors often present with nigrostriatal aftereffects with parkinsonian features. A 67-year-old woman with JE showed right-dominant clinical parkinsonism and left-dominant substantia nigra lesions after magnetic resonance imaging (MRI). Dopamine transporter (DAT) imaging using 123 I-labeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ( 123 I-FP-CIT) revealed a corresponding left-dominant decrease. The present case is the first to reveal a clear match of laterality between clinical parkinsonism, MRI-based substantia nigra lesions, and impaired DAT in presynaptic dopaminergic neurons in JE.

A peptide disrupting the D2R-DAT interaction protects against dopamine neurotoxicity.

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Su, Ping; Liu, Fang

2017-09-01

Dopamine reuptake from extracellular space to cytosol leads to accumulation of dopamine, which triggers neurotoxicity in dopaminergic neurons. Previous studies have shown that both dopamine D2 receptor (D2R) and dopamine transporter (DAT) are involved in dopamine neurotoxicity. However, blockade of either D2R or DAT causes side effects due to antagonism of other physiological functions of these two proteins. We previously found that DAT can form a protein complex with D2R and its cell surface expression is facilitated via D2R-DAT interaction, which regulates dopamine reuptake and intracellular dopamine levels. Here we found that an interfering peptide (DAT-S1) disrupting the D2R-DAT interaction protects neurons against dopamine neurotoxicity, and this effect is mediated by inhibiting DAT cell surface expression and inhibiting both caspase-3 and PARP-1 cleavage. This study demonstrates the role of the D2R-DAT complex in dopamine neurotoxicity and investigated the potential mechanisms, which might help better understand the mechanisms of dopamine neurotoxicity. The peptide may provide some insights to improve treatments for dopamine neurotoxicity and related diseases, such as Parkinson's disease, as well as methamphetamine- and 3,4-methsylenedioxy methamphetamine-induced neurotoxicity. Copyright © 2017. Published by Elsevier Inc.

Defective glycinergic synaptic transmission in zebrafish motility mutants

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Hiromi Hirata

2010-01-01

Full Text Available Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR β subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch once’ mutants, including beo and sho, and report the identification of a new α2 subunit that revises the phylogeny of zebrafish GlyRs.

Defective Glycinergic Synaptic Transmission in Zebrafish Motility Mutants

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Hirata, Hiromi; Carta, Eloisa; Yamanaka, Iori; Harvey, Robert J.; Kuwada, John Y.

2009-01-01

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo) mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR) β subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho) mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch-once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch-once’ mutants, including beo and sho, and report the identification of a new α2 subunit that revises the phylogeny of zebrafish GlyRs. PMID:20161699

Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease

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Anna-Maija Penttinen

2018-06-01

Full Text Available Glial cell line-derived neurotrophic factor (GDNF is one of the most studied neurotrophic factors. GDNF has two splice isoforms, full-length pre-α-pro-GDNF (α-GDNF and pre-β-pro-GDNF (β-GDNF, which has a 26 amino acid deletion in the pro-region. Thus far, studies have focused solely on the α-GDNF isoform, and nothing is known about the in vivo effects of the shorter β-GDNF variant. Here we compare for the first time the effects of overexpressed α-GDNF and β-GDNF in non-lesioned rat striatum and the partial 6-hydroxydopamine lesion model of Parkinson's disease. GDNF isoforms were overexpressed with their native pre-pro-sequences in the striatum using an adeno-associated virus (AAV vector, and the effects on motor performance and dopaminergic phenotype of the nigrostriatal pathway were assessed. In the non-lesioned striatum, both isoforms increased the density of dopamine transporter-positive fibers at 3 weeks after viral vector delivery. Although both isoforms increased the activity of the animals in cylinder assay, only α-GDNF enhanced the use of contralateral paw. Four weeks later, the striatal tyrosine hydroxylase (TH-immunoreactivity was decreased in both α-GDNF and β-GDNF treated animals. In the neuroprotection assay, both GDNF splice isoforms increased the number of TH-immunoreactive cells in the substantia nigra but did not promote behavioral recovery based on amphetamine-induced rotation or cylinder assays. Thus, the shorter GDNF isoform, β-GDNF, and the full-length α-isoform have comparable neuroprotective efficacy on dopamine neurons of the nigrostriatal circuitry.

Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.

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Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M; Hanson, Glen R; Fleckenstein, Annette E

2014-06-05

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. Copyright © 2014 Elsevier B.V. All rights reserved.

Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

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Baladi, Michelle G.; Newman, Amy H.; Nielsen, Shannon M.; Hanson, Glen R.; Fleckenstein, Annette E.

2014-01-01

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

Self-esteem in remitted patients with mood disorders is not associated with the dopamine receptor D4 and the serotonin transporter genes.

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Serretti, A; Macciardi, F; Di Bella, D; Catalano, M; Smeraldi, E

1998-08-17

Disturbances of the dopaminergic and serotoninergic neurotransmitter systems have been implicated in the pathogenesis of depressive symptoms. Associations have been reported between markers of the two neurotransmitter systems and the presence of illness or severity of depressive episodes, but no attention has been focused on the periods of remission. The present report focuses on a possible association of self-esteem in remitted mood disorder patients with the functional polymorphism located in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the dopamine receptor D4 (DRD4). Inpatients (N=162) affected by bipolar (n=103) and unipolar (n=59) disorder (DSM III-R) were assessed by the Self-Esteem Scale (SES, Rosenberg, 1965) and were typed for DRD4 and 5-HTTLPR (n=58 subjects) variants at the third exon using polymerase chain reaction (PCR) techniques. Neither DRD4 nor 5-HTTLPR variants were associated with SES scores, and consideration of possible stratification effects such as sex and psychiatric diagnosis did not reveal any association either. The serotonin transporter and dopamine receptor D4 genes do not, therefore, influence self-esteem in remitted mood disorder subjects.

Functional differences between global pre- and postsynaptic inhibition in the Drosophila olfactory circuit

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Masafumi eOizumi

2012-03-01

Full Text Available The Drosophila antennal lobe is subdivided into multiple glomeruli, each of which represents a unique olfactory information processing channel. In each glomerulus, feedforward input from olfactory receptor neurons (ORNs is transformed into activity of projection neurons (PNs, which represent the output. Recent investigations have indicated that lateral pre-synaptic inhibitory input from other glomeruli controls the gain of this transformation. Here, we address why this gain control acts `pre'-synaptically rather than `post'-synaptically. Postsynaptic inhibition could work similarly to presynaptic inhibition with regard to regulating the firing rates of PNs depending on the stimulus intensity. We investigate the differences between pre- and postsynaptic gain control in terms of odor discriminability by simulating a network model of the Drosophila antennal lobe with experimental data. We first demonstrate that only presynaptic inhibition can reproduce the type of gain control observed in experiments. We next show that presynaptic inhibition decorrelates PN responses whereas postsynaptic inhibition does not. Due to this effect, presynaptic gain control enhances the accuracy of odor discrimination by a linear decoder while its postsynaptic counterpart only diminishes it. Our results provide the reason gain control operates `pre'-synaptically but not `post'-synaptically in the Drosophila antennal lobe.

Mapping synaptic pathology within cerebral cortical circuits in subjects with schizophrenia

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Robert Sweet

2010-06-01

Full Text Available Converging lines of evidence indicate that schizophrenia is characterized by impairments of synaptic machinery within cerebral cortical circuits. Efforts to localize these alterations in brain tissue from subjects with schizophrenia have frequently been limited to the quantification of structures that are non-selectively identified (e.g. dendritic spines labeled in Golgi preparations, axon boutons labeled with synaptophysin, or to quantification of proteins using methods unable to resolve relevant cellular compartments. Multiple label fluorescence confocal microscopy represents a means to circumvent many of these limitations, by concurrently extracting information regarding the number, morphology, and relative protein content of synaptic structures. An important adaptation required for studies of human disease is coupling this approach to stereologic methods for systematic random sampling of relevant brain regions. In this review article we consider the application of multiple label fluorescence confocal microscopy to the mapping of synaptic alterations in subjects with schizophrenia and describe the application of a novel, readily automated, iterative intensity/morphological segmentation algorithm for the extraction of information regarding synaptic structure number, size, and relative protein level from tissue sections obtained using unbiased stereological principles of sampling. In this context, we provide examples of the examination of pre- and post-synaptic structures within excitatory and inhibitory circuits of the cerebral cortex.

Pre- and postsynaptic dopamine SPECT in the early phase of idiopathic parkinsonism: a population-based study

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Jakobson, Mo Susanna; Riklund, Katrine [Umeaa University, Department of Radiation Sciences, Diagnostic Radiology, Umeaa (Sweden); Linder, Jan; Forsgren, Lars [Umeaa University, Department of Pharmacology and Clinical Neuroscience, Neurology, Umeaa (Sweden); Larsson, Anne; Johansson, Lennart [Umeaa University, Department of Radiation Sciences, Radiation Physics, Umeaa (Sweden)

2010-11-15

The aim of this study was to assess the diagnostic contribution of pre- and postsynaptic dopamine SPECT in drug-naive patients with early idiopathic parkinsonism and to investigate possible differences between idiopathic Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) and possible differences in motor subtypes of parkinsonism. A group of 128 newly diagnosed idiopathic parkinsonian patients and 48 healthy controls was studied. Presynaptic baseline SPECT with {sup 123}I-FP-CIT was performed in all patients and in 120 patients also a baseline postsynaptic SPECT with {sup 123}I-IBZM. Clinical diagnoses were reassessed after 12 months. Presynaptic uptake in the putamen and caudate was significantly reduced in patients compared to controls. Presynaptic uptake ratios were not different between PD patients and patients with APS, and postsynaptic uptake in APS was not significantly reduced compared to PD or controls. In half of the APS patients both pre- and postsynaptic uptake ratios were reduced on the same side in the striatum. Impaired motor performance was associated with decreased presynaptic uptake in the putamen in PD. The postural instability and gait difficulty (PIGD) subtype of PD had lower presynaptic uptake ratios than patients with tremor-dominated (TD) symptoms. Not only presynaptic putamen uptake ratios, but also caudate ratios were reduced in a majority of the patients in our study. At baseline scan, i.e. in an early stage of the disease, the accuracy of excluding APS in the whole study population was 85% using a combination of pre- and postsynaptic SPECT. Already at baseline, lower presynaptic SPECT ratios were seen in PD with PIGD at onset compared to those with TD subtype. (orig.)

Reduced Striatal Dopamine Transporters in People with Internet Addiction Disorder

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Haifeng Hou

2012-01-01

Full Text Available In recent years, internet addiction disorder (IAD has become more prevalent worldwide and the recognition of its devastating impact on the users and society has rapidly increased. However, the neurobiological mechanism of IAD has not bee fully expressed. The present study was designed to determine if the striatal dopamine transporter (DAT levels measured by T99mc-TRODAT-1 single photon emission computed tomography (SPECT brain scans were altered in individuals with IAD. SPECT brain scans were acquired on 5 male IAD subjects and 9 healthy age-matched controls. The volume (V and weight (W of bilateral corpus striatum as well as the T99mc-TRODAT-1 uptake ratio of corpus striatum/the whole brain (Ra were calculated using mathematical models. It was displayed that DAT expression level of striatum was significantly decreased and the V, W, and Ra were greatly reduced in the individuals with IAD compared to controls. Taken together, these results suggest that IAD may cause serious damages to the brain and the neuroimaging findings further illustrate IAD is associated with dysfunctions in the dopaminergic brain systems. Our findings also support the claim that IAD may share similar neurobiological abnormalities with other addictive disorders.

The post-synaptic density of human postmortem brain tissues: an experimental study paradigm for neuropsychiatric illnesses.

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Chang-Gyu Hahn

Full Text Available Recent molecular genetics studies have suggested various trans-synaptic processes for pathophysiologic mechanisms of neuropsychiatric illnesses. Examination of pre- and post-synaptic scaffolds in the brains of patients would greatly aid further investigation, yet such an approach in human postmortem tissue has yet to be tested. We have examined three methods using density gradient based purification of synaptosomes followed by detergent extraction (Method 1 and the pH based differential extraction of synaptic membranes (Methods 2 and 3. All three methods separated fractions from human postmortem brains that were highly enriched in typical PSD proteins, almost to the exclusion of pre-synaptic proteins. We examined these fractions using electron microscopy (EM and verified the integrity of the synaptic membrane and PSD fractions derived from human postmortem brain tissues. We analyzed protein composition of the PSD fractions using two dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS and observed known PSD proteins by mass spectrometry. Immunoprecipitation and immunoblot studies revealed that expected protein-protein interactions and certain posttranscriptional modulations were maintained in PSD fractions. Our results demonstrate that PSD fractions can be isolated from human postmortem brain tissues with a reasonable degree of integrity. This approach may foster novel postmortem brain research paradigms in which the stoichiometry and protein composition of specific microdomains are examined.

Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: a meta-analysis.

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Karrer, Teresa M; Josef, Anika K; Mata, Rui; Morris, Evan D; Samanez-Larkin, Gregory R

2017-09-01

Many theories of cognitive aging are based on evidence that dopamine (DA) declines with age. Here, we performed a systematic meta-analysis of cross-sectional positron emission tomography and single-photon emission-computed tomography studies on the average effects of age on distinct DA targets (receptors, transporters, or relevant enzymes) in healthy adults (N = 95 studies including 2611 participants). Results revealed significant moderate to large, negative effects of age on DA transporters and receptors. Age had a significantly larger effect on D1- than D2-like receptors. In contrast, there was no significant effect of age on DA synthesis capacity. The average age reductions across the DA system were 3.7%-14.0% per decade. A meta-regression found only DA target as a significant moderator of the age effect. This study precisely quantifies prior claims of reduced DA functionality with age. It also identifies presynaptic mechanisms (spared synthesis capacity and reduced DA transporters) that may partially account for previously unexplained phenomena whereby older adults appear to use dopaminergic resources effectively. Recommendations for future studies including minimum required samples sizes are provided. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression.

Science.gov (United States)

Li, Bo; Piriz, Joaquin; Mirrione, Martine; Chung, ChiHye; Proulx, Christophe D; Schulz, Daniela; Henn, Fritz; Malinow, Roberto

2011-02-24

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression

International Nuclear Information System (INIS)

Li, B.; Schulz, D.; Piriz, J.; Mirrione, M.; Chung, C.H.; Proulx, C.D.; Schulz, D.; Henn, F.; Malinow, R.

2011-01-01

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

Epigenetic dysregulation of the dopamine system in diet-induced obesity.

Science.gov (United States)

Vucetic, Zivjena; Carlin, Jesse Lea; Totoki, Kathy; Reyes, Teresa M

2012-03-01

Chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior. Using a mouse model of diet-induced obesity (DIO), significant alterations in the expression of DA-related genes were documented in adult animals, and the general pattern of gene expression changes was opposite within the hypothalamus versus the reward circuitry (increased vs. decreased, respectively). Differential DNA methylation was identified within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT), and the pattern of this response was consistent with the pattern of gene expression. Behaviors consistent with increased hypothalamic DA and decreased reward circuitry DA were observed. These data identify differential DNA methylation as an epigenetic mechanism linking the chronic intake of HF diet with altered DA-related gene expression, and this response varies by brain region and DNA sequence. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Interactions of MK-801 with glutamate-, glutamine- and methamphetamine-evoked release of [3H]dopamine from striatal slices

International Nuclear Information System (INIS)

Bowyer, J.F.; Scallet, A.C.; Holson, R.R.; Lipe, G.W.; Slikker, W. Jr.; Ali, S.F.

1991-01-01

The interactions of MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine], glutamate and glutamine with methamphetamine (METH)-evoked release of [ 3 H]dopamine were assessed in vitro to determine whether MK-801 inhibition of METH neurotoxicity might be mediated presynaptically, and to evaluate the effects of glutamatergic stimulation on METH-evoked dopamine release. MK-801 inhibition of glutamate- or METH-evoked dopamine release might reduce synaptic dopamine levels during METH exposure and decrease the formation of 6-hydroxydopamine or other related neurotoxins. Without Mg 2+ present, 40 microM and 1 mM glutamate evoked a N-methyl-D-aspartate receptor-mediated [ 3 H]dopamine and [ 3 H]metabolite (tritium) release of 3 to 6 and 12 to 16% of total tritium stores, respectively, from striatal slices. With 1.50 mM Mg 2+ present, 10 mM glutamate alone or in combination with the dopamine uptake blocker nomifensine released only 2.1 or 4.2%, respectively, of total tritium stores, and release was only partially dependent on N-methyl-D-aspartate-type glutamate receptors. With or without 1.50 mM Mg 2+ present, 0.5 or 5 microM METH evoked a substantial release of tritium (5-8 or 12-21% of total stores, respectively). METH-evoked dopamine release was not affected by 5 microM MK-801 but METH-evoked release was additive with glutamate-evoked release. Without Mg 2+ present, 1 mM glutamine increased glutamate release and induced the release of [ 3 H]dopamine and metabolites. Both 0.5 and 5 microM METH also increased tritium release with 1 mM glutamine present. When striatal slices were exposed to 5 microM METH this glutamine-evoked release of glutamate was increased more than 50%

Increased binding of (/sup 3/H)apomorphine in caudate membranes after dopamine pretreatment in vitro

Energy Technology Data Exchange (ETDEWEB)

McManus, C; Hartley, E J; Seeman, P [Toronto Univ., Ontario (Canada)

1978-07-01

Most patients with Parkinson's disease treated with L-dopa show a progressively deteriorating response which may possibly be attributed to an L-dopa-induced process of unknown origin. Long-term administration of dopamine-mimetic drugs to animals sometimes produces behavioural facilitation. To investigate one possible molecular mechanism of this facilitation or sensitization the effects of prolonged exposure, in vitro, of dopamine on the dopamine/neuroleptic receptors in the caudate nucleus of the calf were tested. Calf caudate homogenates pretreated with dopamine or other drugs were tested for the binding of (/sup 3/H)apomorphine, (/sup 3/H)haloperidol, 3H-WB-4101, or (/sup 3/H)naloxine. Pre-exposure with dopamine or noradrenaline lead to an increased binding of (/sup 3/H)apomorphine. The significance of the results is discussed.

Membrane mobility and microdomain association of the dopamine transporter studied with fluorescence correlation spectroscopy and fluorescence recovery after photobleaching

DEFF Research Database (Denmark)

Adkins, Erika M; Samuvel, Devadoss J; Fog, Jacob U

2007-01-01

To investigate microdomain association of the dopamine transporter (DAT), we employed FCS (fluorescence correlation spectroscopy) and FRAP (fluorescence recovery after photobleaching). In non-neuronal cells (HEK293), FCS measurements revealed for the YFP-DAT (DAT tagged with yellow fluorescent...... protein) a diffusion coefficient (D) of approximately 3.6 x 10(-9) cm2/s, consistent with a relatively freely diffusible protein. In neuronally derived cells (N2a), we were unable to perform FCS measurements on plasma membrane-associated protein due to photobleaching, suggesting partial immobilization...

Cocaine Self-Administration Produces Long-Lasting Alterations in Dopamine Transporter Responses to Cocaine

OpenAIRE

Siciliano, Cody A.; Fordahl, Steve C.; Jones, Sara R.

2016-01-01

Cocaine addiction is a debilitating neuropsychiatric disorder characterized by uncontrolled cocaine intake, which is thought to be driven, at least in part, by cocaine-induced deficits in dopamine system function. A decreased ability of cocaine to elevate dopamine levels has been repeatedly observed as a consequence of cocaine use in humans, and preclinical work has highlighted tolerance to cocaine's effects as a primary determinant in the development of aberrant cocaine taking behaviors. Her...

Applications of SPECT imaging of dopaminergic neurotransmission in neuropsychiatric disorders

Energy Technology Data Exchange (ETDEWEB)

Kugaya, Akira; Fujita, Masahiro; Innis, R.B. [Yale Univ., New Haven, CT (United States). School of Medicine

2000-02-01

Single photon emission computed tomography (SPECT) tracers selective for pre- and post-synaptic targets have allowed measurements of several aspects of dopaminergic (DA) neurotransmission. In this article, we will first review our DA transporter imaging in Parkinson's disease. We have developed the in vivo dopamine transporter (DAT) imaging with [{sup 123}I]{beta}-CIT ((1R)-2{beta}-Carbomethoxy-3{beta}-(4-iodophenyl)tropane). This method showed that patients with Parkinson's disease have markedly reduced DAT levels in striatum, which correlated with disease severity and disease progression. Second, we applied DA imaging techniques in patients with schizophrenia. Using amphetamine as a releaser of DA, we observed the enhanced DA release, which was measured by imaging D2 receptors with [{sup 123}I]IBZM (iodobenzamide), in schizophrenics. Further we developed the measurement of basal synaptic DA levels by AMPT (alpha-methyl-paratyrosine)-induced unmasking of D2 receptors. Finally, we expanded our techniques to the measurement of extrastriatal DA receptors using [{sup 123}I]epidepride. The findings suggest that SPECT is a useful technique to measure DA transmission in human brain and may further our understanding of the pathophysiology of neuropsychiatric disorders. (author)

Persistent Drug-Induced Parkinsonism in Patients with Normal Dopamine Transporter Imaging.

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Jin Yong Hong

Full Text Available Functional neuroimaging for the dopamine transporter (DAT is used to distinguish drug-induced parkinsonism (DIP from subclinical Parkinson's disease (PD. Although DIP patients who show a normal DAT image are expected to recover completely, some do not. We investigated whether these patients showed changes in striatal DAT activity using semi-quantitative analysis of 18F-FP-CIT PET data. DIP patients with visually normal DAT images were selected from medical records. The subjects were classified as patients who recovered partially (PR or completely within 12 months (CR. The 18F-FP-CIT uptake in each striatal subregion was compared between the CR and the PR groups. In total, 41 and 9 patients of the CR and PR groups were assessed, respectively. The two patient groups were comparable in terms of clinical characteristics including age, sex, and severity of parkinsonism. From semi-quantitative analysis of the PET image, the PR patients showed a relatively lower ligand uptake in the ventral striatum, the anterior putamen and the posterior putamen compared with the CR patients. This result suggests that persistent DIP in patients with visually normal DAT imaging may be associated with subtle decrement of DAT activity.

Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

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Rothmond Debora A

2012-02-01

Full Text Available Abstract Background Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5, catechol-O-methyltransferase, and monoamine oxidase (A and B in the developing human DLPFC (6 weeks -50 years. Results Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p O-methyltransferase (p = 0.024 were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32 kDa, p = 0.027. In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002 and dopamine D1 receptor protein expression increased throughout development (p Conclusions We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.

Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2.

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Deepti Chugh

Full Text Available Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age and tonic-clonic (3.5-4 months phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread.

Anaplastic Lymphoma Kinase Is a Regulator of Alcohol Consumption and Excitatory Synaptic Plasticity in the Nucleus Accumbens Shell

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Regina A. Mangieri

2017-08-01

Full Text Available Anaplastic lymphoma kinase (ALK is a receptor tyrosine kinase recently implicated in biochemical, physiological, and behavioral responses to ethanol. Thus, manipulation of ALK signaling may represent a novel approach to treating alcohol use disorder (AUD. Ethanol induces adaptations in glutamatergic synapses onto nucleus accumbens shell (NAcSh medium spiny neurons (MSNs, and putative targets for treating AUD may be validated for further development by assessing how their manipulation modulates accumbal glutamatergic synaptic transmission and plasticity. Here, we report that Alk knockout (AlkKO mice consumed greater doses of ethanol, relative to wild-type (AlkWT mice, in an operant self-administration model. Using ex vivo electrophysiology to examine excitatory synaptic transmission and plasticity at NAcSh MSNs that express dopamine D1 receptors (D1MSNs, we found that the amplitude of spontaneous excitatory post-synaptic currents (EPSCs in NAcSh D1MSNs was elevated in AlkKO mice and in the presence of an ALK inhibitor, TAE684. Furthermore, when ALK was absent or inhibited, glutamatergic synaptic plasticity – long-term depression of evoked EPSCs – in D1MSNs was attenuated. Thus, loss of ALK activity in mice is associated with elevated ethanol consumption and enhanced excitatory transmission in NAcSh D1MSNs. These findings add to the mounting evidence of a relationship between excitatory synaptic transmission onto NAcSh D1MSNs and ethanol consumption, point toward ALK as one important molecular mediator of this interaction, and further validate ALK as a target for therapeutic intervention in the treatment of AUD.

The dopamine transporter protein gene (SLC6A3): Primary linage mapping and linkage studies in Tourette syndrome

Energy Technology Data Exchange (ETDEWEB)

Gelernter, J.; Kruger, S.D.; Pakstis, A.J. [Yale Univ., New Haven, CT (United States)]|[West Haven Veterans Affairs Medical Center, CT (United States)] [and others

1995-12-10

The dopamine transporter, the molecule responsible for presynaptic reuptake of dopamine and a major site of action of psychostimulant drugs, including cocaine, is encoded by locus SLC6A3 (alias DAT1). The protein`s actions and DAT`s specific localization to dopaminergic neurons make it a candidate gene for several psychiatric illnesses. SLC6A3 has been mapped to distal chromosome 5p, using physical methods. Genetic linkage methods were used to place SLC6A3 in the genetic linkage map. Four extended pedigrees (one of which overlaps with CEPH) were typed. Linkage with Tourette syndrome (TS) was also examined. SLC6A3 showed close linkage with several markers previously mapped to distal chromosome 5p, including D5S11 (Z{sub max} = 16.0, {theta}{sub M} = {theta}{sub F} = 0.03, results from four families) and D5S678 (Z{sub max} = 7.84, {theta}{sub M} = {theta}{sub F} = 0, results from two families). Observed crossovers established that SLC6A3 is a distal marker close to D5S10 and D5S678, but these three distal markers could not be ordered. Linkage between TS and SLC6A3 could be excluded independently in two branches of a large kindred segregating TS; the lod score in a third family was also negative, but not significant. Cumulative results show a lod score of -6.2 at {theta} = 0 and of -3.9 at {theta} = 0.05 (dominant model, narrow disease definition). SLC6A3 thus maps to distal chromosome 5p by linkage analysis, in agreement with previous physical mapping data. A mutation at SLC6A3 is not causative for TS in the two large families that generated significant negative lod scores (if the parameters of our analyses were correct) and is unlikely to be causative in the family that generated a negative lod score that did not reach significance. These results do not exclude a role for the dopamine transporter in influencing risk for TS in combination with other loci. 23 refs., 1 fig., 2 tabs.

Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons.

Science.gov (United States)

Avelar, Alicia J; Cao, Jianjing; Newman, Amy Hauck; Beckstead, Michael J

2017-09-01

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. Here we used patch clamp electrophysiology in mouse brain slices to explore the effects of two atypical DAT inhibitors (R-modafinil and JHW 007) on the physiology of single DA neurons in the substantia nigra and ventral tegmental area. Despite their commonalities of being DAT inhibitors that lack cocaine-like behavioral profiles, these compounds exhibited surprisingly divergent cellular effects. Similar to cocaine, R-modafinil slowed DA neuron firing in a D2 receptor-dependent manner and rapidly enhanced the amplitude and duration of D2 receptor-mediated currents in the midbrain. In contrast, JHW 007 exhibited little effect on firing, slow DAT blockade, and an unexpected inhibition of D2 receptor-mediated currents that may be due to direct D2 receptor antagonism. Furthermore, pretreatment with JHW 007 blunted the cellular effects of cocaine, suggesting that it may be valuable to investigate similar DAT inhibitors as potential therapeutic agents. Further exploration of these and other atypical DAT inhibitors may reveal important cellular effects of compounds that will have potential as pharmacotherapies for treating cocaine use disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synaptic potentiation onto habenula neurons in learned helplessness model of depression

Science.gov (United States)

Li, Bo; Piriz, Joaquin; Mirrione, Martine; Chung, ChiHye; Proulx, Christophe D.; Schulz, Daniela; Henn, Fritz; Malinow, Roberto

2010-01-01

The cellular basis of depressive disorders is poorly understood1. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (i.e. disappointment or anticipation of a negative outcome)2, 3, 4. LHb neurons project to and modulate dopamine-rich regions such as the ventral-tegmental area (VTA)2, 5 that control reward-seeking behavior6 and participate in depressive disorders7. Here we show in two learned helplessness models of depression that excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal’s helplessness behavior and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective on depressed patients8, 9, dramatically suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behavior in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression. PMID:21350486

Brain signaling and behavioral responses induced by exposure to (56)Fe-particle radiation

Science.gov (United States)

Denisova, N. A.; Shukitt-Hale, B.; Rabin, B. M.; Joseph, J. A.

2002-01-01

Previous experiments have demonstrated that exposure to 56Fe-particle irradiation (1.5 Gy, 1 GeV) produced aging-like accelerations in neuronal and behavioral deficits. Astronauts on long-term space flights will be exposed to similar heavy-particle radiations that might have similar deleterious effects on neuronal signaling and cognitive behavior. Therefore, the present study evaluated whether radiation-induced spatial learning and memory behavioral deficits are associated with region-specific brain signaling deficits by measuring signaling molecules previously found to be essential for behavior [pre-synaptic vesicle proteins, synaptobrevin and synaptophysin, and protein kinases, calcium-dependent PRKCs (also known as PKCs) and PRKA (PRKA RIIbeta)]. The results demonstrated a significant radiation-induced increase in reference memory errors. The increases in reference memory errors were significantly negatively correlated with striatal synaptobrevin and frontal cortical synaptophysin expression. Both synaptophysin and synaptobrevin are synaptic vesicle proteins that are important in cognition. Striatal PRKA, a memory signaling molecule, was also significantly negatively correlated with reference memory errors. Overall, our findings suggest that radiation-induced pre-synaptic facilitation may contribute to some previously reported radiation-induced decrease in striatal dopamine release and for the disruption of the central dopaminergic system integrity and dopamine-mediated behavior.

Precise synaptic efficacy alignment suggests potentiation dominated learning

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Christoph eHartmann

2016-01-01

coordinated potentiation -- in this case, from STDP in the presence of correlated pre- and post-synaptic activity -- naturally leads to an alignment of parallel synapses.

Identification of a 3rd Na+ Binding Site of the Glycine Transporter, GlyT2.

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Nandhitha Subramanian

Full Text Available The Na+/Cl- dependent glycine transporters GlyT1 and GlyT2 regulate synaptic glycine concentrations. Glycine transport by GlyT2 is coupled to the co-transport of three Na+ ions, whereas transport by GlyT1 is coupled to the co-transport of only two Na+ ions. These differences in ion-flux coupling determine their respective concentrating capacities and have a direct bearing on their functional roles in synaptic transmission. The crystal structures of the closely related bacterial Na+-dependent leucine transporter, LeuTAa, and the Drosophila dopamine transporter, dDAT, have allowed prediction of two Na+ binding sites in GlyT2, but the physical location of the third Na+ site in GlyT2 is unknown. A bacterial betaine transporter, BetP, has also been crystallized and shows structural similarity to LeuTAa. Although betaine transport by BetP is coupled to the co-transport of two Na+ ions, the first Na+ site is not conserved between BetP and LeuTAa, the so called Na1' site. We hypothesized that the third Na+ binding site (Na3 site of GlyT2 corresponds to the BetP Na1' binding site. To identify the Na3 binding site of GlyT2, we performed molecular dynamics (MD simulations. Surprisingly, a Na+ placed at the location consistent with the Na1' site of BetP spontaneously dissociated from its initial location and bound instead to a novel Na3 site. Using a combination of MD simulations of a comparative model of GlyT2 together with an analysis of the functional properties of wild type and mutant GlyTs we have identified an electrostatically favorable novel third Na+ binding site in GlyT2 formed by Trp263 and Met276 in TM3, Ala481 in TM6 and Glu648 in TM10.

Dopamine transporter gene polymorphism and psychiatric symptoms seen in schizophrenic patients at their first episode

Energy Technology Data Exchange (ETDEWEB)

Inada, Toshiya; Sugita, Tetsuyoshi; Dobashi, Izumi [National Institute of Mental Health, Chiba (Japan)] [and others

1996-07-26

To investigate the possible role of the dopamine transporter (DAT) gene in determining the phenotype in human subjects, allele frequencies for the 40-bp variable number of tandem repeats (VNTR) polymorphism at this site were compared between 117 Japanese normal controls and 118 schizophrenic patients, including six subgroups: early-onset, those with a family history, and those suffering from one of the following psychiatric symptoms at their first episode: delusion and hallucination; disorganization; bizarre behavior; and negative symptoms. No significant differences were observed between the group as a whole or any subgroup of schizophrenic patients and controls. The results indicate that VNTR polymorphism in the DAT gene is unlikely to be a major contributor to any of the psychiatric parameters examined in the present population of schizophrenic subjects. 12 refs., 1 fig., 2 tabs.

Ultrafast Synaptic Events in a Chalcogenide Memristor

Science.gov (United States)

Li, Yi; Zhong, Yingpeng; Xu, Lei; Zhang, Jinjian; Xu, Xiaohua; Sun, Huajun; Miao, Xiangshui

2013-04-01

Compact and power-efficient plastic electronic synapses are of fundamental importance to overcoming the bottlenecks of developing a neuromorphic chip. Memristor is a strong contender among the various electronic synapses in existence today. However, the speeds of synaptic events are relatively slow in most attempts at emulating synapses due to the material-related mechanism. Here we revealed the intrinsic memristance of stoichiometric crystalline Ge2Sb2Te5 that originates from the charge trapping and releasing by the defects. The device resistance states, representing synaptic weights, were precisely modulated by 30 ns potentiating/depressing electrical pulses. We demonstrated four spike-timing-dependent plasticity (STDP) forms by applying programmed pre- and postsynaptic spiking pulse pairs in different time windows ranging from 50 ms down to 500 ns, the latter of which is 105 times faster than the speed of STDP in human brain. This study provides new opportunities for building ultrafast neuromorphic computing systems and surpassing Von Neumann architecture.

Synaptic and functional linkages between spinal premotor interneurons and hand-muscle activity during precision grip

Directory of Open Access Journals (Sweden)

Tomohiko eTakei

2013-04-01

Full Text Available Grasping is a highly complex movement that requires the coordination of a number of hand joints and muscles. Previous studies showed that spinal premotor interneurons (PreM-INs in the primate cervical spinal cord have divergent synaptic effects on hand motoneurons and that they might contribute to hand-muscle synergies. However, the extent to which these PreM-IN synaptic connections functionally contribute to modulating hand-muscle activity is not clear. In this paper, we explored the contribution of spinal PreM-INs to hand-muscle activation by quantifying the synaptic linkage (SL and functional linkage (FL of the PreM-INs with hand-muscle activities. The activity of 23 PreM-INs was recorded from the cervical spinal cord (C6–T1, with EMG signals measured simultaneously from hand and arm muscles in two macaque monkeys performing a precision grip task. Spike-triggered averages (STAs of rectified EMGs were compiled for 456 neuron–muscle pairs; 63 pairs showed significant post-spike effects (i.e., SL. Conversely, 231 of 456 pairs showed significant cross-correlations between the IN firing rate and rectified EMG (i.e., FL. Importantly, a greater proportion of the neuron–muscle pairs with SL showed FL (43/63 pairs, 68% compared with the pairs without SL (203/393, 52%, and the presence of SL was significantly associated with that of FL. However, a significant number of pairs had SL without FL (SL∩!FL, n = 20 or FL without SL (!SL∩FL, n = 203, and the proportions of these incongruities exceeded the number expected by chance. These results suggested that spinal PreM-INs function to significantly modulate hand-muscle activity during precision grip, but the contribution of other neural structures is also needed to recruit an adequate combination of hand-muscle motoneurons.

Hydrodynamic flow in a synaptic cleft during exocytosis.

Science.gov (United States)

Shneider, M N; Gimatdinov, R S; Skorinkin, A I; Kovyazina, I V; Nikolsky, E E

2012-01-01

It is shown that exocytosis in a chemical synapse may be accompanied by "microjet" formation due to the overpressure that exists in the vesicles. This mechanism may take place either at complete fusion of a vesicle with the presynaptic membrane or in the so-called kiss-and-run mode of neurotransmitter release. A simple hydrodynamic model of the viscous incompressible flow arising in the synaptic cleft is suggested. The occurrence of hydrodynamic flow (microjet) leads to more efficient transport of neurotransmitter than in the case of classical diffusive transport.

Excessive D1 Dopamine Receptor Activation in the Dorsal Striatum Promotes Autistic-Like Behaviors.

Science.gov (United States)

Lee, Yunjin; Kim, Hannah; Kim, Ji-Eun; Park, Jin-Young; Choi, Juli; Lee, Jung-Eun; Lee, Eun-Hwa; Han, Pyung-Lim

2018-07-01

The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.

Effects of fluoxetine treatment on striatal dopamine transporter binding and cerebrospinal fluid insulin-like growth factor-1 in children with autism.

Science.gov (United States)

Makkonen, I; Kokki, H; Kuikka, J; Turpeinen, U; Riikonen, R

2011-10-01

A positive effect of fluoxetine has been shown in some children with autism. The present study was undertaken to correlate striatal dopamine transporter (DAT) binding and cerebrospinal fluid insulin-like growth factor-1 (CSF-IGF-1) with clinical response in autistic children (n=13, age 5-16 years) after a 6-month fluoxetine treatment. Good clinical responders (n=6) had a decrease (p=0.031) in DAT binding as assessed using single-photon emission computed tomography with [123I]-nor-β-CIT, whereas poor responders had a trend to an increase. An increase in CSF-IGF-1 (p=0.003) was detected after the treatment period, but no correlation between the clinical response and CSF-IGF-1 was found. In conclusion, fluoxetine decreases DAT binding indicating alleviation of the hyperdopaminergic state and increases CSF-IGF-1 concentration, which may also have a neuroprotective effect against dopamine-induced neurotoxicity in autistic children. © Georg Thieme Verlag KG Stuttgart · New York.

Dopamine alleviates nutrient deficiency-induced stress in Malus hupehensis.

Science.gov (United States)

Liang, Bowen; Li, Cuiying; Ma, Changqing; Wei, Zhiwei; Wang, Qian; Huang, Dong; Chen, Qi; Li, Chao; Ma, Fengwang

2017-10-01

Dopamine mediates many physiological processes in plants. We investigated its role in regulating growth, root system architecture, nutrient uptake, and responses to nutrient deficiencies in Malus hupehensis Rehd. Under a nutrient deficiency, plants showed significant reductions in growth, chlorophyll concentrations, and net photosynthesis, along with disruptions in nutrient uptake, transport, and distribution. However, pretreatment with 100 μM dopamine markedly alleviated such inhibitions. Supplementation with that compound enabled plants to maintain their photosynthetic capacity and development of the root system while promoting the uptake of N, P, K, Ca, Mg, Fe, Mn, Cu, Zn, and B, altering the way in which those nutrients were partitioned throughout the plant. The addition of dopamine up-regulated genes for antioxidant enzymes involved in the ascorbate-glutathione cycle (MdcAPX, MdcGR, MdMDHAR, MdDHAR-1, and MdDHAR-2) but down-regulated genes for senescence (SAG12, PAO, and MdHXK). These results indicate that exogenous dopamine has an important antioxidant and anti-senescence effect that might be helpful for improving nutrient uptake. Our findings demonstrate that dopamine offers new opportunities for its use in agriculture, especially when addressing the problem of nutrient deficiencies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Correlating Fluorescence and High-Resolution Scanning Electron Microscopy (HRSEM) for the study of GABAA receptor clustering induced by inhibitory synaptic plasticity

KAUST Repository

Orlando, Marta

2017-10-17

Both excitatory and inhibitory synaptic contacts display activity dependent dynamic changes in their efficacy that are globally termed synaptic plasticity. Although the molecular mechanisms underlying glutamatergic synaptic plasticity have been extensively investigated and described, those responsible for inhibitory synaptic plasticity are only beginning to be unveiled. In this framework, the ultrastructural changes of the inhibitory synapses during plasticity have been poorly investigated. Here we combined confocal fluorescence microscopy (CFM) with high resolution scanning electron microscopy (HRSEM) to characterize the fine structural rearrangements of post-synaptic GABAA Receptors (GABAARs) at the nanometric scale during the induction of inhibitory long-term potentiation (iLTP). Additional electron tomography (ET) experiments on immunolabelled hippocampal neurons allowed the visualization of synaptic contacts and confirmed the reorganization of post-synaptic GABAAR clusters in response to chemical iLTP inducing protocol. Altogether, these approaches revealed that, following the induction of inhibitory synaptic potentiation, GABAAR clusters increase in size and number at the post-synaptic membrane with no other major structural changes of the pre- and post-synaptic elements.