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1
Hansson, Stefan R. "The serotonin transporter and vesicular monoamine transporters during development." Lund : Lund University, 1998. http://catalog.hathitrust.org/api/volumes/oclc/68945023.html.
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Holloway, Alexa. "Pharmacodynamics of Monoamine Transporter Releasing Agents and Reuptake Inhibitors." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5880.
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Ligands of the human monoamine transporters encompass a wide range of both illicit and therapeutic drugs that act upon neural circuitry related to reward, motivation, and the processing of salient stimuli. The present study utilizes two methods for analyzing transporter substrates and inhibitors in order to characterize activity and assess potency. The first measures transient changes in intracellular calcium as a surrogate for transporter activity by harnessing the electrical coupling of monoamine transporters and L-type calcium channels. This is used to analyze novel chimera of the strong hDAT inhibitors methylphenidate and 𝛼-PPP in order to assess the contribution of specific moieties to potency. The observed reduction in potency suggests that methylphenidate may bind to the transporter in a manner distinct from 𝛼-PPP, as chimera would otherwise be expected to show similar activity to parent compounds. These results highlight the importance of 𝛼-carbon substituents and the relatively small contribution of beta-carbon groups to inhibitor potency at hDAT, while the lack of activity at hSERT suggests potency is not strongly influenced by beta-carbon or N-alkyl substituents. In order to further characterize drug-transporter interaction, a method was developed to analyze the kinetics of binding and unbinding using both known and novel hNET ligands, including a series of N-alkyl derivatives of 4-methylamphetamine. The study emphasizes the importance of both association and dissociation kinetics to affinity and sets up a methodological framework with two ways for determining Kd, with notable advantages over current models. The results indicate that lengthening the N-alkyl chain of 4-methylamphetamine leads to a decrease in potency and a shift in activity from substrate to blocker, with the results of N-propyl 4-methylamphetamine in particular indicating the potential existence of multiple low-affinity binding sites, each with distinct on and off kinetics. The implications of these results help elucidate the mechanism of action of transporter ligands and set up a framework for future studies that can more specifically classify the interaction between transporters and inhibitors or releasing agents.
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Cameron, Krasnodara. "Conduction states of the human dopamine transporter." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3676.
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Dysregulation of dopaminergic homeostasis has been established as the primary source of numerous neurological disorders including Parkinson’s and drug addiction. A tonic increase of dopamine (DA) in the nucleus accumbens is required for associating everyday events and behaviors with rewards. Yet many addictive exogenous compounds such as amphetamine (AMPH) and cocaine (COC) produce a much greater augmentation of synaptic DA levels that are linked to euphoria and a shift in behavior towards drug seeking. The protein responsible for maintaining extracellular levels of DA is the dopamine transporter (DAT). It is primarily located in the perisynaptic area at terminals of pre-synaptic neurons where its main function is to sequester DA from the extracellular space and to transport it back into the cell, a process that is electrogenic. AMPH and COC directly interact with DAT and alter its ionic currents. Not much is known about the effect of psychostimulant-induced DAT currents on neuronal excitability and neurotransmitter release. We use synthetic chemistry, molecular biology, and biophysics in heterologous expression systems to decipher the actions of drugs of abuse on DAT. Furthermore we demonstrate drug-induced DAT currents can activate Ca2+ channels associated with dopaminergic excitability. Lastly, we focused on investigating drug effects on excitability in a human midbrain dopaminergic cell line. Understanding how psychostimulants interact with DAT to produce the dysfunctional states of the transporter may facilitate the development of unique therapeutic strategies to treat psychostimulant dependence.
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Hojati, Ashkhan. "Pharmacologic profiling of novel compounds via fluorometric analyses of monoamine transporter responses." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5983.
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In humans and other organisms, monoaminergic systems are crucial in neuronal function and behavior. The monoamine transporters (MATs), which can be found on the presynaptic plasma membrane of neurons in the central nervous system (CNS), are crucial in the regulation of neurotransmitter concentration in the synaptic cleft. As the duration and concentration of neurotransmitters in the cleft affect further downstream signaling responses, these proteins are important targets for both understanding neuronal physiology and compounds of interest. Multiple theories exist proponing the contribution of MATs to a variety of mental and neurological disorders, including depression. This theory establishes that depression is caused by imbalances in monoamine neurotransmitters. Compounds such as Fluoxetine (FLX) are classified as selective serotonin reuptake inhibitors (SSRIs), these drugs selectively block the reuptake of neurotransmitters at the serotonin transporter (SERT). Since differences in MAT selectivity of inhibitory compounds are influential to selecting efficacious antidepressant treatments, we utilized a unique fluorescent analysis technique to explore three therapeutic compounds of interest (in-vitro) which contain structural similarity to FLX. Our results confirm the selectivity of FLX at SERT, and classify the novel compounds studied into different potential categories of reuptake inhibitors. We hope these compounds will be studied further to elucidate their potentially therapeutic roles and mitigation of undesired side effects seen in other medications.
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Watson-Siriboe, Abena. "MUTATION OF THE VESICULAR MONOAMINE TRANSPORTER-1 GENE ALTERS ITS PROTEIN PRODUCT." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/77.
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The vesicular monoamine transporter 1 (VMAT1) is essential for storage of monoamines, such as epinephrine and serotonin, in secretory vesicles of neuroendocrine cells. Recently the VMAT1 protein was detected in human and mouse brain, and mutations of the VMAT1 gene at single DNA nucleotides (single nucleotide polymorphisms or SNPs) were associated with schizophrenia. In this study, Chinese hamster ovarian cells were stably transfected with either human VMAT1 DNA (GenBank: #NM_003053.1 or DNA with the Thr4Pro SNP, which results in a threonine to proline change in amino acid number 4 of the VMAT1 protein. Western blot analysis revealed that cells with the SNP produced immunoreactive human VMAT1 proteins of altered molecular size, suggesting that SNP Thr4Pro modifies either folding or processing of the VMAT1 protein. This finding is the first evidence for biochemical consequences of a mutation in the human VMAT1 gene.
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Bhatt, Sandeep. "SEX DIFFERENCES IN DOPAMINE REUPTAKE PATHWAYS OF THE NIGROSTRIATAL DOPAMINERGIC SYSTEM IN MICE." Kent State University / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=kent1164141349.
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Croft, Benjamin. "Examining synaptic vesicle morphology and function in dopamine neurons of mice lacking vesicular monoamine transporter 2." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=78342.
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The brain isoform of the vesicular monoamine transporter (VMAT2) packages monoamines into synaptic vesicles (SVs), an essential step in synaptic transmission by central dopamine (DA) neurons. While the modulation of VMAT2 levels influences the amount of DA that can be released, the underlying mechanisms remain unclear. The objective of the present study is to elucidate these mechanisms by examining the SVs of VMAT2 knock out (KO) mice. We used transmission electron microscopy to determine that DA terminals from VMAT2 KO and wild type samples are morphologically indistinguishable from one another. We then monitored the uptake and release of the activity dependent fluorescent dye FM1-43 by VMAT2 KO neurons and found that their SVs cycle, despite being devoid of DA. Our results demonstrate that SV biogenesis and cycling are independent of SV filling, suggesting that one way by which changes in VMAT2 levels could influence is DA release by altering the proportion of SVs that are able to fill.
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Zhou, Mingyan. "Structural and functional analysis of a novel organic cation/monoamine transporter PMAT in the SLC29 family /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/7979.
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Ruiz, Brian A. "Utilizing Voltage-gated Calcium Channels to Assess the Activity of Cathinone Derivatives at Human Monoamine Transporters." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5547.
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Cathinones are psychostimulant compounds heavily implicated as drugs of abuse. They exert their physiological actions at the monoamine transporters, which are responsible for maintaining synaptic neurotransmitter homeostasis. Monoamine transporters produce currents during transport and have been shown to depolarize cell membranes and activate voltage-gated calcium channels in mammalian expression systems. This phenomenon is harnessed in an assay which measures these induced calcium transients, allowing for quantification of pharmacodynamic effects of compounds at monoamine transporters. It is unknown if this electrical coupling occurs in neurons, but the implications if it does are significant. In the current work, fluorescent resonance energy transfer studies of HEK cells expressing hDAT suggest that a subpopulation of monoamine transporters and calcium channels may be interacting directly. Additionally, this work presents calcium assay data comparing several novel methcathinone analogs. Of the compounds tested, a single α-methyl substituent at the α-carbon yields the greatest potency at hDAT. The implications of these results shed light on future psychostimulant studies and further define the physiological relationship of the components of a system used to study these compounds.
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Haapaniemi, T. (Tarja). "Autonomic dysfunction in Parkinson's disease and its correlates to medication and dopamine transporter binding." Doctoral thesis, University of Oulu, 2001. http://urn.fi/urn:isbn:9514259637.
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Abstract
Patients with idiopathic Parkinson's disease (PD) may suffer from autonomic nervous system dysfunction
even in the early phase of the disease. We assessed the autonomic cardiovascular and sudomotor regulation in
de novo PD patients with and without medication. We also measured the dopamine (DAT)
and serotonin transporter (SERT) uptake in the PD patients using
2β-carboxymethoxy-3β-(4-iodophenyl)tropane
(β-CIT) SPECT and studied the clinical correlates of the uptake. Sixty PD patients were included in the
study and randomised to receive levodopa, bromocriptine or selegiline (n=20 in each) as their treatment.
Thirty patients were examined with β-CIT SPECT. The results of the patients were compared with those of
healthy controls and within the subgroups at different time points.
Cardiovascular autonomic regulation was assessed using standard cardiovascular reflex tests at
baseline, after six months' medication and following a 6-week washout period. The heart rate (HR) and blood
pressure (BP) regulation was impaired in PD patients at baseline, and PD medications modified the responses
further. Bromocriptine and selegiline, in contrast to levodopa, increased the orthostatic BP fall and
suppressed the BP response to isometric exercise. The long-term cardiovascular autonomic function was
evaluated from ambulatory ECG recordings by analysis of traditional spectral and non-spectral components of
HR fluctuation together with two-dimensional vector analysis and power-law relationship analysis of the HR
dynamics. All spectral measures and the slope of the power-law relationship demonstrated impaired tonic
cardiovascular regulation in the PD patients.
Sympathetic sudomotor activity was evaluated using the sympathetic skin response (SSR). The
major finding was suppression of the SSR amplitudes with an inverse correlation to clinical disability,
whereas PD medication seemed to have only minor effects. The changes in amplitude and repetitiveness of the
SSRs with normal adaptation suggest deficits at several levels of the SSR reflex arc.
DAT uptake, assessed by β-CIT SPECT, was diminished in the striatum and especially the
putamen
of the PD patients, and correlated with the results of the cardiovascular reflex tests and ambulatory ECG
recordings. Simultaneous measurement of SERT binding demonstrated decreased SERT availability in the
thalamic and frontal areas.
The results demonstrate disturbances of the reflectory and tonic cardiovascular autonomic regulation caused
by PD itself. PD medications further modify the reflectory responses. The degenerative process in PD also
involves the sympathetic sudomotor pathway. β-CIT SPECT provides a useful method for simultaneous
assessment
of DAT and SERT binding, demonstrating the deficit of serotonin metabolism in PD.
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Williams, Yolanda D. "PRECLINICAL EVALUATION OF LOBELINE FOR THE TREATMENT OF ADHD: COMPARISON WITH PSYCHOSTIMULANT THERAPIES." UKnowledge, 2011. http://uknowledge.uky.edu/pharmacy_etds/3.
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This dissertation work investigated the effect of acute and repeated in vivo administration of lobeline on dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. The effects of lobeline were then compared to the effects of acute and repeated in vivo administration of methylphenidate and amphetamine to determine if lobeline produced similar effects compared to these Attention Deficit Hyperactivity Disorder (ADHD) medications. These medications are considered the first line of pharmacotherapy for ADHD, although there is a growing concern associated with their potential for abuse and other side effects. This merits the need for novel ADHD treatments that have a safer side effect profile. If lobeline alters DAT and VMAT2 function in the same way as methylphenidate or amphetamine, further investigation may be necessary to evaluate lobeline as a potential treatment for ADHD. Kinetic analysis of [3H]dopamine (DA) was utilized to determine the effect on DAT and VMAT2 function in rat striatum. Results from the DAT experiments, revealed that lobeline as well as amphetamine had no effect on DAT function. However, methylphenidate increased DAT function after acute and 7-day treatment. None of the drug treatment regimens altered Km. To determine if the methylphenidateinduced increase in DAT function was due to DAT trafficking, biotinylation and Western blot analyses were performed. Acute administration of methylphenidate did not alter surface DAT, however repeated administration of methylphenidate for 7 days decreased intracellular DAT, suggesting that methylphenidate redistributes DAT in a time-dependent manner. Similar results were found in the VMAT2 experiments. Lobeline and amphetamine had no effect on VMAT2 function after acute or repeated administration. Amphetamine decreased the Km after repeated administration for 7 days. Methylphenidate increased VMAT2 function after acute and repeated administration for 7 days. The overall results of these experiments suggest that methylphenidate interacts with DAT and VMAT2 in a different manner than amphetamine and lobeline. In addition, since lobeline and amphetamine had no effect on DAT and VMAT2 function, further investigation is warranted to elucidate the underlying mechanisms of the therapeutic actions of these agents. This additional information will aid in the development of novel treatments for ADHD.
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Shukry, Sally Gamal. "FUNCTIONAL AND BIOCHEMICAL CONSEQUENCES OF SINGLE NUCLEOTIDE POLYMORPHISMS IN THE HUMAN VESICULAR MONOAMINE TRANSPORTER 1 GENE (SLC18A1) By Sally Gamal Shukry, B.S." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/360.
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Abstract FUNCTIONAL AND BIOCHEMICAL CONSEQUENCES OF SINGLE NUCLEOTIDE POLYMORPHISMS IN THE HUMAN VESICULAR MONOAMINE TRANSPORTER 1 GENE (SLC18A1) By Sally Gamal Shukry, B.S. A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Biology at Virginia Commonwealth University. Virginia Commonwealth University, 2012 Major Advisor: Jennifer K. Stewart Associate Professor and Graduate Director, Department of Biology Single nucleotide polymorphisms (SNP) in the human VMAT1 gene (SLC18A1) have been associated with schizophrenia in three different populations: Han Chinese, Western European and Japanese. Effects of these mutations on transport function of the hVMAT1 protein have not been reported. The goal of this study was to investigate functional and biochemical differences in human VMAT1 proteins with a threonine or proline at amino acid position 4 (Thr4Pro) and a serine or threonine at position 98 (Ser98Thr). COS1 cells were transfected with variant SNPs coding for 4Thr/98Ser, 4Pro/98Ser, or 4Thr98Thr. Western blotting demonstrated robust over expression of the genes and no differences in electrophoretic mobility of the proteins. Maximal transport of serotonin by the VMAT1 protein with 4Pro/98Ser was less than that of the 4Thr/98Ser or the 4Thr/98Thr. Response of the 4Pro/Ser98 to the VMAT inhibitor reserpine was lower than that of the 4Thr/98Thr. These findings suggest mechanisms for human VMAT1 links to schizophrenia.
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Sitta, Ramsey. "N-Alkyl 4-Methylamphetamine enantiomers and the implication for potential modulation of abuse liability and enhancement of psychoactive drug targeting." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/5001.
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Drugs of abuse have a long history in humanity. Currently however, a subject of great interest is the phenylalkylamine family of drugs. Not only is the abuse liability of interest but also the potential therapeutic expansion of the capabilities of this family of drugs by utilizing the unique stereospecific effects of the newly discovered hybrid compounds. Based upon prior data of N-Alkyl 4-MA the enantiomers of N-Methyl, N-Ethyl, and N-Propyl were analyzed in hDAT, hNET, and hSERT. It was found that there was a negative correlation between chain length and potency and dopaminergic component. In agreement with the currently established paradigm it was also found that in almost all cases the S(+) enantiomer was the more potent.
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Ruchala, Iwona. "EXPANDING MONOAMINE TRANSPORTERS PHARMACOLOGY USING CALCIUM CHANNELS." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/5032.
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Research in drug development meets many challenges including lengthy, complex and costly procedures to identify novel pharmacotherapies. In our lab, we developed a method for fast screening of small molecules that interact with monoamine transports – dopamine and serotonin (DAT, SERT). These membrane proteins play important roles in brain neurotransmission responsible for cognition, motion and pleasure. Dysfunction in dopaminergic and serotonergic systems result in neurological disorders such as depression, Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia and addiction.
DAT and SERT are responsible for uptake of dopamine (DA) or serotonin (5HT) into the synapse and they limit neurotransmitter signaling. Drugs that mimic or antagonize actions of endogenous neurotransmitters (DA and 5HT) increase the concentrations of DA and/or 5HT either by blocking the transporter (blockers) or by competing uptake with neurotransmitter (substrate). The uptake of substrates is associated to an inward current that depolarizes the cell membrane. Voltage-gated calcium channels (CaV) can respond to small changes in membrane potential. In our method, we combined permanent cell line expressing the human dopamine transporter (hDAT) or the human serotonin transporter (hSERT) (FlpIn TREx expression system) with transient transfection of CaV. This system works as a tightly electrically coupled system. Cells challenged with substrate of the transports produce detectable Ca2+ signal while monoamine transporter blockers can inhibit these Ca2+ signals. The novelty of this method relies on the ability to discriminate between substrate and blockers of monoamine transporters.
Preliminary experiments measuring our optimized cell system in a Flex Station 3 plate reader suggest that the co-expression of a voltage-gated Ca2+ channel, a monoamine transporter and a genetically encoded Ca2+ sensor constitute a rapid screening biosensor to identify active drugs at monoamine transporters.
Our novel methodology can rapidly assess drug-effect profile on monoamine transporters and benefit development of new psychotherapeutics for treatment of mental illnesses. It can also be used to characterize mechanism of action of emerging drug of abuse, as well as to discover small molecules with novel drug-effect profile useful in basic neuroscience research.
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Rezai, Amin Sara. "Rôle du transporteur plasmique des monoamines (PMAT) dans le système nerveux central." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC247.
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Dans le système nerveux central, les monoamines modulent de nombreuses fonctions essentielles comme la locomotion, la motivation, la cognition, l’humeur et le sommeil. Le niveau extracellulaire de ces neurotransmetteurs est régulé par des transporteurs à haute affinité,cependant d’autres transporteurs, à faible affinité, peuvent contribuer à la recapture des monoamines, comme les transporteurs de cations organiques (OCT) et le transporteur plasmique des monoamines (PMAT). Récemment, l’implication des OCT dans différentes fonctions centrales, notamment le contrôle de l’humeur, la réponse au stress et aux antidépresseurs a été mise en évidence. Le rôle de PMAT dans le cerveau reste quant à lui encore peu caractérisé. Il transporte in vitro les monoamines, avec une préférence pour la dopamine et la sérotonine, avec des affinités submillimolaires. Ce transporteur est exprimé dans de nombreuses régions du cerveau humain et murin et dans différents types neuronaux. Par hybridation in situ fluorescente nous avons déterminé sa distribution cellulaire précise, dans des régions à fort niveau d’expression comme le complexe du cerveau antérieur basal (BFC) et des régions appartenant aux ganglions de la base comme le globus pallidus et la substance noire réticulée (SNr). Nous avons montré qu’il est fortement exprimé dans les neurones GABAergiques exprimant la parvalbumine, dans tous les interneurones cholinergiques dustriatum ainsi qu’une petite fraction des neurones cholinergiques du BFC. Il est également retrouvé dans certains noyaux monoaminergiques comme le locus coeruleus et les noyaux duraphé mais est absent des noyaux dopaminergiques, la substance noire compacte et l’aire tegmentale ventrale.Afin d’étudier sa fonction, nous avons exploité le système Cre-lox, approche couramment utilisée en biologie, en injectant un virus adéno-associé exprimant la recombinase Cre (AAVCre)dans la substance noire (SN) de souris comportant des allèles de PMAT floxés. Cette étude ne nous a pas permis de conclure quant à la fonction de PMAT dans la SN, mais nous a conduit à mettre en évidence une toxicité majeure de cet outil. Nous avons montré que l’injection d’AAV-Cre dans la SN entraine une perturbation anatomique et fonctionnelle des systèmes dopaminergiques et de la SNr, noyau de sortie des ganglions de la base, induisant des altérations comportementales importantes, avec une hyperlocomotion basale robuste et une insensibilité à la cocaïne, potentiellement par une action génotoxique.Nous avons également généré des souris invalidées constitutivement pour PMAT (PMAT-/-). Les tests comportementaux que nous avons commencés récemment nous ont révélé des altérations comportementales significatives chez ces souris de l’activité locomotrice dans un nouvel environnement ainsi que du niveau d’anxiété. Ces altérations pourraient résulter d'une perturbation des voies aminergiques en l’absence de PMAT. Nous poursuivrons cette étude par l'exploration d'autres aspects comportementaux ainsi que par l’évaluation des modifications neurochimiques engendrées par l'invalidation. Ces approches devraient fournir des pistes afin d’identifier les conséquences de l'absence de PMAT sur la signalisation aminergique, que l'on pourra explorer plus précisément par la suite sur le plan fonctionnel<br>High-affinity reuptake transporters exert a crucial role in the control of synaptic transmissionby ensuring the recycling of the released transmitters into the presynaptic terminals. Other typesof transporters such as Organic Cation Transporters (OCTs) and the Plasma MembranemonoAmine Transporter (PMAT), have been shown to transport, with low-affinity but highcapacity, aminergic neurotransmitters. While the role of OCTs in central nervous system hasbeen partially unraveled, the function of PMAT remains poorly characterized. In vitro, PMATtransports preferentially dopamine and serotonin and its expression is widespread in the brain,encompassing monoamine nuclei but also projection regions. In this study, we determined theprecise neuronal specificity of PMAT in several highly-expressing regions. We show that it isfound mostly in PV+ GABAergic neurons of basal forebrain and basal ganglia, in allcholinergic interneurons of the striatum and in some cholinergic neurons of basal forebraincomplex. These systems, highly regulated by monoamines, are important for locomotion,motivation, learning and wakefulness. Our result show that PMAT is located at a strategicposition to control the aminergic modulation of these integrated functions.To investigate the implication of PMAT in these regions, we used the Cre-lox technology, avalued and widely used approach for the study of gene function in vivo, injecting an adenoassociatedvirus expressing Cre recombinase in substantia nigra (SN) of mice in which PMATgene was floxed. In this study, we could not assess PMAT function in this SN but found thatAAV-CRE expression in this region produces major toxic effects. We showed that AAV-Creinjection in this region engenders a massive decrease of neuronal populations in both parscompacta and reticulata, leading to DA depletion in the nigrostriatal pathway. This wasassociated with a drastic behavioral phenotype with increased basal locomotor activity and lossof locomotor response to cocaine. Several hallmarks of Cre toxicity were found in SN of AAVCreinjected mice, including an increase of the DNA break markers. These observationsunderscore the need for careful control of Cre toxicity in the brain and reassessment of previous studies.To study the role of PMAT, we also generated PMAT knock out mice (PMAT-/-). Behavioralstudies that we just started have revealed significant impairments of locomotor activity in a newenvironment and anxiety level, supporting a possible disruption of monoaminergic systems inthese mice. On-going studies aim to explore other behaviors and search for eventualneurochemical changes provoked by PMAT invalidation. These experiments should providesome cues to understand which monoamines and circuits may be affected, that can beinvestigated functionnally and more specifically in a second step
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Quinn, T. G. "Characterisation of the vesicular monoamine transporters 1 and 2." Thesis, Queen's University Belfast, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368550.
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Lee, Na-Ra. "DISCOVERY OF NOVEL PHARMACOTHERAPEUTICS FOR SUBSTANCE USE DISORDERS." UKnowledge, 2019. https://uknowledge.uky.edu/pharmacy_etds/104.
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Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding pathway commonly activated by opioids and cocaine.
With respect to METH, it induces release of dopamine (DA) in neuronal terminals by interacting with the vesicular monoamine transporter-2 (VMAT2) and DA transporter (DAT). VMAT2 inhibitors have been found by our research group to decrease METH-evoked DA release, METH-induced hyperlocomotion, and METH self-administration in rats. However, these VMAT2 inhibitors lacked selectivity and tolerance developed to these pharmacologic effects after repeated administration, thereby limiting their potential as pharmacotherapeutics for METH use disorders. In the current study, analogs from a novel scaffold were found to selectively inhibit VMAT2 and were evaluated using neurochemical and behavioral pharmacological approaches. R- and S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610 and GZ-11608, respectively) exhibited 94- to 3450-fold selectivity for VMAT2 over human-ether-a-go-go (hERG) channel, DAT, serotonin transporter, and nicotinic acetylcholine receptors. GZ-11608 competitively and concentration-dependently inhibited METH-evoked DA release via VMAT2. Also, GZ-11610 (56-300 mg/kg, oral) and GZ-11608 (300 mg/kg, oral; 10-30 mg/kg, s.c.) reduced METH-induced hyperlocomotor activity in METH-sensitized rats. Furthermore, GZ-11608 (1-30 mg/kg, s.c.) inhibited METH self-administration, cue- and METH-induced reinstatement in a dose-dependent manner, and 30 mg/kg (s.c.), 10 mg/kg (s.c.), and 17 mg/kg (s.c.) produced significant effect, respectively. Importantly, the GZ-11608-induced decrease in METH self-administration was not surmounted by increasing the amount of METH available. GZ-11608 did not substitute for METH and did not serve as a reinforcer in rats self-administering METH and drug naïve rats, respectively. Thus, these VMAT2 inhibitors incorporating a new scaffold are novel leads for new pharmacotherapeutics to treat METH use disorders.
Substances with high abuse potential including opioids and cocaine elevate extracellular DA concentration in the nucleus accumbens, and this mechanism has long been considered to underly substance-induced reward. DA in the nucleus accumbens originates from DA neuron cell bodies located in the ventral tegmental area in the midbrain. Interestingly, M5 muscarinic acetylcholine receptors (mAChRs) are proteins that are highly expressed on ventral tegmental area DA neurons. Also, studies investigating M5 mAChRs knockout mice showed reduced responding for cocaine in cocaine self-administration and decreased time spent in cocaine-paired and morphine-paired place preference studies. Pharmacological inhibition of M5 mAChRs function via microinfusing mAChR antagonists exhibiting no selectivity among M1-M5 mAChRs subtypes into the ventral tegmental area where expression of M5 mAChRs are dominant, reduced morphine-induced hyperlocomotion and cocaine seeking behaviors in rats. These studies support therapeutic potential of M5 mAChRs selectivity antagonists in opioids and cocaine use disorders. Thus, in the current study, affinity of a series of pethidine and quinuclidinyl N-phenylcarbamate analogs for M5 mAChRs was evaluated using in vitro and ex vivo neuropharmacological assays. Among the pethidine analogs, compound 6a showed the highest binding affinity at M5 (Ki = 0.38 µM), but also high affinity at M1 and M3 mAChRs (0.67 and 0.37 µM, respectively). Among the quinuclidinyl N-phenylcarbamate analogs, compound 13c exhibited the highest affinity at M5 (Ki = 1.8 nM), but also high affinity at M1, M2, M3 and M4 mAChRs (Ki = 1.6, 13, 2.6, 2.2 nM, respectively). Also, 13c acted as an agonist of mAChRs on oxotremorine-induced DA release from rat striatal slices. In addition, compound 13b was found exhibiting the highest selectivity (17-fold) at M3 over M2 mAChRs, suggesting potential of 13b as a chronic obstructive pulmonary disease therapeutics. Taken together, these novel analogs serve as leads for further discovery of subtype-selective M5 mAChR antagonists that may have potential as therapeutics for substance use disorders, as well as for chronic obstructive pulmonary disease.
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DESNOS, CLAIRE. "Regulation de l'expression du transporteur vesiculaire des monoamines." Paris 6, 1992. http://www.theses.fr/1992PA066452.
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La stimulation prolongee des cellules chromaffines provoque une augmentation de l'expression de certains enzymes de biosynthese des catecholamines et constituants des granules de secretion. Afin d'etudier cette induction trans-synaptique in vitro il est possible de stimuler de facon prolongee les cellules chromaffines bovines en culture en les depolarisant dans un milieu riche en potassium. Nous nous sommes interesses a l'expression d'une proteine de la membrane granulaire, le transporteur vesiculaire des monoamines, responsable de l'accumulation des catecholamines dans les granules de secretion. Le transporteur vesiculaire des monoamines est dose en utilisant un ligand specifique, la (#3h) dihydrotetrabenazine. Nos resultats indiquent qu'une entree de calcium dans les cellules chromaffines provoque une induction specifique de l'expression de transporteur, probablement par activation de sa neosynthese. Nous avons egalement observe, en collaboration avec m. Weber, qu'il existait une regulation du transporteur vesiculaire des monoamines dans les neurones sympathiques de ganglion cervical superieur de rat nouveau-ne en milieu depolarisant. Par la suite, notre objectif a ete de mieux comprendre les consequences d'une secretion soutenue et notamment de localiser sur quel type de vesicules se situait le transporteur induit. L'etude de la localisation subcellulaire montre que dans ces conditions de stimulation prolongee, les cellules chromaffines restent capables de secreter et accumulent des precurseurs de granules dont la composition membranaire et matricielle est modifiee
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Nguyen, Vy. "Analyzing Interactions Between Methcathinone Analogs and the Human Monoamine Transporters." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/6004.
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Psychostimulants elicit their psychological and behavioral effects through interactions with the monoamine transporters. These compounds are classified as either substrates or reuptake inhibitors, depending on their mechanism of action, and have varying potencies at the three human monoamine transporters, hDAT, hSERT, and hNET. Substrates and reuptake inhibitors also have distinct electrophysiological signatures: reuptake inhibitors cause hyperpolarization in HEK293 cells stably expressing the monoamine transporters, whereas substrate transport mediates a depolarizing current. Recent studies have shown that substrate-mediated depolarization is sufficient to activate L-type calcium channels, a characteristic which has been used to develop a novel calcium assay which uses calcium signals to measure monoamine transporter activity. In the present study, the calcium assay is used to assess the activity of a series of methcathinone analogs at hSERT and hNET from a structure-activity relationship standpoint. All compounds were found to be significantly weaker at SERT as compared to hDAT, which suggests higher potential abuse liability. SERT appears to be stereospecific with regard to methcathinone analogs and requires a substituent in the S position for drug activity. All compounds were found to be twice as potent at hNET as compared to hDAT. Given the functional relationship between hDAT and L-type calcium channel Cav1.2, this study also sought to characterize the physical interaction between the two proteins. Using a high-resolution technique known as FRET, it was determined that hDAT and Cav1.2 do not colocalize to a significant extent and thus are unlikely to directly interact to form a complex.
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Bedet, Cécile. "Caractérisation de modifications post-traductionnelles des transporteurs vésiculaires de neuromédiateurs : étude d'une phosphorylation du transporteur des acides aminés inhibiteurs." Paris 6, 2002. http://www.theses.fr/2002PA066028.
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Blackmore, Colin Giles. "Modulation of intravesicular pH and progastrin processing by vesicular monoamine transporters." Thesis, University of Liverpool, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366674.
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Branger, Caroline. "Développement de molécules pour l'exploration des transporteurs des monoamines." Tours, 1995. http://www.theses.fr/1995TOUR3305.
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Henkes, Liliane. "Klonierung und funktionelle Charakterisierung des extraneuronalen Monoamin-Transporters (EMT) des Hausschweins." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=980580293.
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Lizarraga-Zazueta, Lucina Eridna. "The Role Of Sertonin And Vesicular Monoamine Transporters In The Adverse Responses To Methylenedioxymethamphetamine." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/332686.
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3,4-(±)-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely abused amphetamine derivative with potent stimulant properties. The neuropharmacological effects of MDMA are biphasic in nature. MDMA initially causes synaptic monoamine release, primarily of serotonin (5-HT), producing hyperthermia and hyperactivity (5-HT syndrome). Conversely, the long-term effects of MDMA manifest as a prolonged depletion in 5-HT, and structural damage to serotonergic nerve terminals. Monoamine transporter systems at the plasma membrane and storage vesicles of 5-HT neurons have been implicated in MDMA toxicity. Nonetheless, many mechanistic questions remain regarding the precise role of uptake transporters in MDMA neurotoxicity. The present study was designed to address the importance of the serotonin reuptake transporter (SERT) and the vesicular monoamine transporter 2 (VMAT2) to the physiological, behavioral and neurotoxic responses to MDMA. SERT functions as a primary regulator of 5-HT homeostasis, mediating the reuptake of 5-HT from the synaptic space following its release during neurotransmission. SERT is a molecular target site for MDMA and many antidepressant agents such as the selective serotonin reuptake inhibitor (SSRI) class. Pharmacological inhibition of SERT protects against MDMA-induced serotonergic neurotoxicity. Thus, the effects of MDMA are in part mediated by an ability to interact with and inhibit SERT. Using a SERT-knockout (SERT-KO) rat model, we determined that SERT deficiency modulated the acute toxicities of MDMA, such as hyperthermia and hyperactivity, whilst completely preventing long-term depletions in tissue 5-HT levels, indicating the abolishment of neurotoxicity. Disruption of vesicular monoamine storage via interaction with VMAT2 has also been implicated in MDMA neurotoxicity. VMAT2 participates in the transport of monoamine neurotransmitters, in particular 5-HT and dopamine (DA), into intra-neuronal storage vesicles. As such, VMAT2 is critical in maintaining neuronal health by preventing neurotransmitter oxidation within the cytosol. Pharmacological inhibition of VMAT2 with Ro4-1284 reduced MDMA-induced hyperactivity and averted hyperthermia along with persistent serotonergic deficits. Overall, our results corroborate the hypothesis that SERT and VMAT2 are critical to the in vivo effects of MDMA. Furthermore, given that VMAT2 inhibition diminished the behavioral response to MDMA in rats, pharmacological manipulation of this transporter could be used in the treatment of MDMA abuse and overdose.
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Sagné, Corinne. "Etude du transporteur vesiculaire des monoamines : purification et caracterisation de domaines fonctionnels." Paris 6, 1997. http://www.theses.fr/1997PA066173.
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Dans les neurones monoaminergiques et certaines cellules endocrines, les monoamines sont accumulees dans des organites specialises, permettant leur liberation par exocytose lors d'une stimulation de ces cellules. L'accumulation est due a un antiport proton/monoamine dont est responsable le transporteur vesiculaire des monoamines (vmat), qui utilise le gradient electrochimique de protons transmembranaire cree par une atpase translocatrice de protons. Le transporteur est inhibe selectivement par la reserpine, la tetrabenazine et la ketanserine. Nous nous sommes attaches a caracteriser la structure de vmat. Tout d'abord, nous avons mis au point une technique de purification originale, par agregation selective, de l'isoforme vmat2, majoritaire dans les granules de la medullo-surrenale bovine. Cette methode est susceptible d'etre appliquee a d'autres proteines membranaires. L'etude de l'agregation nous a egalement permis de proposer qu'il existe des structures secondaires extremement stables dans vmat2 qui ne peuvent etre denaturees que par l'acide trifluoroacetique anhydre. Ensuite, nous avons localise un domaine de liaison de la ketanserine sur la sequence primaire de vmat2 a l'aide d'un derive photoactivable, l'azik. En combinant le sequencage de peptides derives du transporteur purifie a la mutagenese dirigee d'un site de proteolyse de vmat2, nous avons montre que l'azik se fixe sur son domaine n-terminal, precisement entre les residus 2 et 55 (sur 518 acides amines). Enfin, nous avons initie une etude experimentale de la topologie de vmat2 par traduction in vitro en utilisant des sites de glycosylation comme rapporteurs de topologie. D'autre part, la mutagenese des extremites n- et c-terminales de bvmat2 semble indiquer qu'elles ne participent pas a l'activite de transport.
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Balasse, Laure. "Etude de transporteurs atypiques des monoamines : la famille des transporteurs de cations organiques (OCTs) et PMAT." Paris 6, 2009. http://www.theses.fr/2009PA066337.
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Les transporteurs de cations organiques (OCT) et PMAT (Plasma Membrane Monoamine Transporter) sont des transporteurs des monoamines à faible affinité. Une étude anatomique fine combinant hybridation in situ et immunohistochimie nous a permis de montrer que, dans le cerveau de rat, PMAT est exprimé principalement dans les corps cellulaires et les neurites des neurones des zones de projections des voies aminergiques, ce qui suggère un rôle dans la recapture au niveau post-synaptique. L’étude anatomique d’OCT2 montre que ce transporteur est fortement exprimé dans les régions limbiques. Les souris mutées pour OCT2 présentent des modifications de la neurotransmission aminergique, une réponse au stress altérée, un comportement de type « dépressif », ainsi que des modifications de la sensibilité à des antidépresseurs sélectifs de la noradrénaline ou la sérotonine. Ce travail met en évidence un nouvel acteur dans les comportements liés à l’humeur et la sensibilité aux antidépresseurs.
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Shalabi, Abdelrahman R. "Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters." VCU Scholars Compass, 2017. https://scholarscompass.vcu.edu/etd/5176.
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The khat plant, catha edulis, has been abused for some time in the Middle East and the African horn for its short-term stimulant effects. However, it was not until 1975 when cathinone, β-ketoamphetamine, was identified as the major stimulant component of khat. Structural analogues of cathinone, synthetic cathinones, are new psychoactive substances available on the clandestine market of numerous countries including the USA. Abuse of these new illicit stimulants is a worldwide growing health concern which necessitates the investigation of the pharmacological properties of these new drugs of abuse. The abuse liabilities of these compounds seem to be related to the three major monoamine transporters (MATs): the dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively). Synthetic cathinones act as either releasing agents by stimulating the release of the presynaptic neuronal content of neurotransmitters, or as reuptake inhibitors by inhibiting normal physiological reuptake of neurotransmitters from the synaptic cleft. Bupropion (DAT/NET reuptake inhibitor) is clinically prescribed for the treatment of depression and smoking cessation, whereas its closely related cousin, cathinone (DAT/NET releasing agent), is a drug of abuse. Deconstruction of bupropion (i.e., a stepwise conversion – or structural transition – of bupropion to cathinone) and investigation of the actions of the deconstructed analogues at the three major MATs showed that the steric bulk at the terminal amine controls the molecular mechanisms of these compounds at MATs (i.e. reuptake inhibition versus substrate-induced release). This study also concluded that bupropion is abused, because it is a cathinone derivative. Methcathinone (MCAT), N-methylcathinone, (DAT/NET releasing agent) is a recreational street drug and a US Schedule I substance; however, new MCAT analogues are continually appearing on the clandestine market to circumvent prosecution under the Controlled Substance Analog Enforcement Act. We investigated the actions and structure-activity relationships of a series of 3-substituted MCAT analogues at MATs and their quantitative structure-activity relationships to determine the physicochemical properties of the 3-position substituents important for the releasing actions of these compounds. This study indicated that the steric bulk of the 3-position substituents controls the selectivity of these compounds at MATs.
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Vialou, Vincent Gautron Sophie. "Rôle des transporteurs de monoamines à faible affinité dans le système nerveux central." Créteil : Université de Paris-Val-de-Marne, 2007. http://doxa.scd.univ-paris12.fr:8080/theses-npd/th0394102.pdf.
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Thèse de doctorat : Neurosciences : Paris 12 : 2005.<br>Version électronique uniquement consultable au sein de l'Université Paris 12 (Intranet). Titre provenant de l'écran-titre. Bibliogr. : 295 réf.
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Vialou, Vincent. "Rôle des transporteurs de monoamines à faible affinité dans le système nerveux central." Paris 12, 2005. https://athena.u-pec.fr/primo-explore/search?query=any,exact,990003941020204611&vid=upec.
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Dans le cerveau, le principal contrôle de l'intensité et de la durée de la neurotransmission monoaminergique est assuré par les transporteurs situés dans la membrane plasmique des neurones. En plus des transporteurs à haute affinité (DAT, SERT et NET), le cerveau exprime des transporteurs à faible affinité, les transporteurs de cations organiques (OCT1, OCT2 et OCT3) et PMAT (plasma membrane monoamine transporter). J'ai pu démontrer pour la première fois l'implication d'OCT3 dans des fonctions physiologiques dans le cerveau, en particulier dans l'activation de l'organe subfornical et dans la régulation du comportement d'ingestion d'eau et de sel. L'étude comparative de la distribution des 3 OCTs montre un profil d'expression spécifique pour chaque forme suggérant une spécialisation fonctionnelle. Enfin, j'ai réalisé une étude détaillée de la distribution de l'ARNm de PMAT dans le cerveau de rat et montré qu'il était très fortement exprimant dans des régions spécifiques du cerveau<br>Intensity and duration of monoamine signaling are regulated by transporters located on plasma membrane. In addition to high-affinity transporters (i. E. DAT, SERT and NET), the brain expresses low-affinity monoamine transporters to regulate extracellular monoamine levels, particulary the organic cation transporters (OCT) family and PMAT (plasma membrane monoamine transporters). Using OCT3 KO mice, I demonstrated for the first time a physiological role for OCT3 in CNS function, in the activation of circumventricular organs and the regulation of salt-intake behavior. I also showed that OCT3 is implicated in monoamine homeostasis and in psychosimulant action. I did a comparative study of the brain distribution of the 3 members of the OCT family (OCT1, 2 and 3) and showed distinct patterns for each form, suggesting different roles in brain function. Finally, I made an extensive anatomical study of a transporter first described in 2004, PMAT, which is broadly expressed in the brain
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Neiens, Patrick [Verfasser], and Klaus T. [Akademischer Betreuer] Wanner. "Simultaneous multiple MS binding assays targeting the monoamine transporters hDAT, hNET, and hSERT / Patrick Neiens ; Betreuer: Klaus T. Wanner." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1151818437/34.
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Turpin, Frédéric. "Contribution au développement de marqueurs technétiés pour l'exploration des transporteurs des monoamines dans le système nerveux central." Grenoble 1, 2002. http://www.theses.fr/2002GRE10009.
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Notre travail porte sur la synthèse de radiopharmaceutiques permettant l'exploration scintigraphique des transporteurs des monoamines par tomographie d'émission monophotonique (SPET). Des modifications de la densité et de la fonction de ces transporteurs sont observées lors de maladies neurodégénératives et psychiatriques (Parkinson, dépression, schizophrénie). Le but est d'établir un diagnostic précoce et d'évaluer l'efficacité des traitements mis en place lors de ces maladies. Pour réaliser ces études, il est nécessaire de développer des radiopharmaceutiques, émetteurs de rayonnement y, spécifiques de ces transporteurs. Dans le cadre d'un projet européen EUREKA (Projet EU 1836), notre étude à conduit à l'élaboration de trois nouveaux traceurs technétiés dérivés du tropane portant un système complexant de type oxocyclam. Les marquages au 99mTc ont été réalisés. Les premiers tests biologiques effectués sur ces composés ont révélé une faible fixation au transporteur de la dopamine et un passage difficile de la barrière hématoencéphalique. Des modifications structurales de ces composés doivent donc être apportées pour améliorer leurs propriétés biologiques. Lors de ces travaux, une collaboration s'est établie avec un laboratoire de l'Université de Yale pour étudier un mécanisme de réarrangement du cycle tropane observé lors de la synthèse d'un intermédiaire précurseur: le 2β-méthanesulfonyloxyméthyl3β-p-tolyltropane. Enfin, nous avons débuté l'étude d'une synthèse d'un nouveau type de dérivés du tropane dans l'objectif d'aborder une autre approche de marquage. Nous avons imaginé pour cela d'inclure un chélate fort du 99mTc dans le cycle tropane. Cette approche implique la construction complète du cycle tropane avec la présence de fonctions permettant l'insertion du système complexant. La synthèse de nouveaux dérivés du tropane a été réalisée et les structures originales obtenues ont ouvert de nouvelles et nombreuses perspectives<br>This work investigates the synthesis of radiolabeled tracers, based on tropane derivatives, allowing scintigraphic exploration of monoamine transporters by single-photon emission tomography (SPET). Alterations of the density and function of these transporters have been implicated in neurodegenerative and psychiatric diseases (Parkinson, depression, schizophrenia). Imaging the density of such transporters with radiolabeled tracers would be of great interest to diagnose patients at early stages of the disorder and to monitor its progression. Therefore, many efforts have been carried out to synthesize specific probes, labeled with y emitters. As part of an european EUREKA program (project EU 1836), our study led to the elaboration of three new Tc-99m-Iabeled tropane derivatives with an oxocyclam chelating unit. The radiolabeling and preliminary in vivo biological evaluation of these ligands have been achieved. These compoùnds showed a low initial brain uptake and sorne difficulties to cross the blood-brain barrier. Several structural modifications of these compounds should be done to improve the biological properties. During this work, a collaboration has been established with a team from Yale University to study the rearrangement mechanism of the tropane skeleton observed in the 2pmethanesulfonyloxymethyl3p-tolyltropane precursor. Finally, we have started the synthesis of new class of tropane derivatives in purpose to develop another labeling approach. Therefore, we have devised to include 99m- Tc complex in the tropane skeleton. This approach implies the synthesis of tropane moiety with functional groups allowing the chelating unit insertion. Synthesis of new tropane derivatives has been achieved and these compounds open up many new future prospects
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LEBRAND, CECILE. "Role de la serotonine et des transporteurs des monoamines dans le developpement du systeme thalamocortical chez les rongeurs." Paris 6, 1999. http://www.theses.fr/1999PA066285.
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La serotonine (5-ht) semble jouer un role fondamental dans le developpement des cartes sensorielles corticales. Pour comprendre le role de la serotonine dans le developpement du cortex, nous avons examine de plus pres, chez les rongeurs, les relations cellulaires existant entre les afferences serotoninergiques et les afferentes thalamocorticales pendant le developpement. Nous avons pu demontrer, que la serotonine s'accumule dans les terminaisons thalamocorticales pendant une phase transitoire de leur developpement. Nous avons pu montrer egalement que les messagers et les proteines du transport membranaire de la 5-ht ainsi que du transporteur vesiculaire des monoamines s'expriment transitoirement dans les noyaux thalamiques sensoriels du thalamus dorsal. Cette decouverte d'une expression conjointe du transporteur membranaire de la serotonine (sert) et du transporteur vesiculaire des monoamines (vmat2) dans des neurones glutamatergiques du thalamus qui ne synthetisent pas l'amine etait tout a fait nouvelle. La suite de mon travail de these a ete d'etudier precisemment le decours temporel de ces expressions transitoires de transporteurs (sert, vmat2) ainsi que leur localisation precise. Nous avons realise une cartographie de l'expression des genes vmat2, sert dans la region du forebrain. Nous avons pu comparer les resultats de cette etude, avec les resultats de localisation de sites de recapture ectopique de 5-ht visualises facilement chez les souris maoa-deficientes. Ce travail de localisation nous a permis de mettre en evidence que ces expressions transitoires ne sont pas le seul fait des neurones thalamiques sensoriels, mais concernant la plupart des neurones de relais des differentes modalites sensorielles. Ces etudes chez les rongeurs, pendant la periode embryonnaire et post-natale permet aujourd'hui d'envisager plus precisemment les differents roles que pourrait jouer la serotonine au cours du developpement. La serotonine dans ce systeme pourrait avoir des effets trophiques et jouer un role dans la mise en place de projection specifiques et organisees topographiquement.
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Apsunde, Tushar D. "Synthesis and Biological Evaluation of N-heterocycles for Activity on Monoamine Transporters and Exploration of Iridium Chemistry for Synthesis of Medicinally Important Molecules." ScholarWorks@UNO, 2014. http://scholarworks.uno.edu/td/1862.
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The focus of these studies was directed towards the synthesis of novel N-heterocyclic compounds and pharmacological evaluation of these compounds for activity at monoamine transporters. A series of novel piperidine and pyrrolidine analogues were prepared from commercially available starting material with a three and four step synthetic method, respectively. A variety of substituents on the aromatic ring were incorporated to achieve a diverse library of compounds. The preliminary binding studies of piperidine molecules showed strong affinity towards serotonin transporters and moderate affinity towards dopamine transporters. The focus of further studies was directed towards utilization of iridium catalysis for the development of new synthetic methods for biologically important molecules. This research has led to the development of a new synthetic strategy for the construction of nicotine and its analogues. In addition, the iridium catalysis was also used for alkylation of amides with primary and secondary alcohols under microwave conditions.
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Bacq, Alexandre. "Rôle du transporteur de cations organiques 2 dans la clairance des monoamines dans le cerveau et les comportements liés à l'humeur." Paris 6, 2012. http://www.theses.fr/2012PA066604.
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La neurotransmission monoaminergique est principalement contrôlée par la recapture à l’aide de transporteurs à haute affinité, qui sont les cibles de nombreux antidépresseurs. Au cours de ma thèse, je me suis intéressé au rôle d’un transporteur à faible affinité des monoamines, le transporteur de cations organiques 2 (OCT2). OCT2 est fortement exprimé dans les régions limbiques, et est retrouvé dans de nombreuses régions régulant la réponse au stress et l’axe hypothalamo-hypophyso-surrénalien dans le cerveau ainsi que dans les glandes surrénales. Dans ces régions, OCT2 participe à la clairance de la sérotonine (5-HT) et de la noradrénaline (NE), en complément des transporteurs à haute affinité. Nous avons montré qu’OCT2 joue un rôle significatif dans les comportements liés à l’humeur, comme l’anxiété et le désespoir comportemental. De plus, dans un modèle de dépression chronique, nous avons montré qu’OCT2 est requis pour l’action à long terme des antidépresseurs. OCT2 joue également un rôle important dans la réponse au stress. J’ai montré en effet que les souris OCT2-/- présentent une augmentation considérable (150%) de la sécrétion de corticostérone plasmatique en réponse à un stress aigu, sans suractivité des glandes surrénales. Réciproquement, le transport de 5-HT et de NE ex vivo médié par les OCTs n’est pas altéré par la corticostérone. Ces expériences indiquent que l’activité d’OCT2 dans le cerveau contrôle la réponse hormonale au stress, sans pour autant interagir directement avec la corticostérone. Ce travail a permis de démontrer pour la première fois un rôle d’OCT2 dans la clairance des monoamines dans le cerveau et les fonctions centrales régulant l’humeur<br>Monoaminergic neurotransmission is primarily controlled by high-affinity reuptake transporters, which are targets of several antidepressants. During my PhD thesis, I studied the role of a low-affinity reuptake transporter, the organic cation transporter 2 (OCT2). I showed that OCT2 is highly enriched in limbic regions, and is also found in several regions regulating the response to stress and the hypothalamo-pituitary-adrenal axis in the brain and in adrenal glands. In these regions, OCT2 is involved in serotonin (5-HT) and norepinephrine (NE) clearance, in complement with high-affinity transporters. We showed that OCT2 plays a significant role in mood-related behaviors, such as anxiety and behavioral despair. Moreover, in a chronic depression-like model, we showed that OCT2 is required for the correct long-term effect of antidepressants. OCT2 also plays an important role in response to stress. Indeed, I showed that OCT2-/- mice present a significant corticosterone secretion increase (150%) in response to an acute stress, without overactivity of adrenal glands. Reciprocally, 5-HT and NE ex vivo OCT2-mediated uptake is not altered by corticosterone. These experiments show that brain OCT2 activity controls the hormonal response to stress, without interacting directly with corticosterone. This work demonstrates for the first time a role of OCT2 in brain monoamines clearance and central functions regulating mood
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Courtet, Philippe. "Génétique moléculaire des conduites suicidaires." Montpellier 1, 2000. http://www.theses.fr/2000MON1T025.
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Darchen, François. "Etude de deux proteines associees aux granules chromaffines de la glande medullo-surrenale : le transporteur vesiculaire des monoamines et la proteine g rab3." Paris 6, 1991. http://www.theses.fr/1991PA066086.
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Cette these porte sur les proprietes de la membrane d'un type de vesicules de secretion, les granules chromaffines de la medullo-surrenale. La premiere partie concerne le transporteur vesiculaire des monoamines biogenes (catecholamines et serotonine) et l'application des lignads de ce transporteur a l'etude des neurones monoaminergiques. Nous avons caracterise de nouveaux substrats de ce transporteur comme le mpp#+ (une toxine specifique des neurones dopaminergiques), et un nouvel inhibiteur, la ketanserine, consideree jusqu'alors comme antagoniste specifique des recepteurs serotoninergiques s2. De plus, grace a une approche de pharmacologie moleculaire, un modele fonctionnel du transporteur a ete propose, qui postule l'existence de deux etats conformationnels oscillant lors du cycle catalytique. Enfin, les ligands de ce transporteur ont ete utilises pour visualiser, par autoradiographie, les regions riches en vesicules synaptiques monoaminergiques, ou encore pour quantifier la neurodegenerescence au cours de la maladie de parkinson. Le second aspect de ce travail concerne la proteine g rab3, une proteine g homologue du protooncogene ras. Nous avons localise cette proteine dans les cellules chromaffines, et notamment, sur les granules chromaffines. Le role de rab3 dans la regulation de la secretion est suspecte
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Masri, Fadi. "Synthèse de dérivés fonctionnalisés du 8-méthyl-8-azabicyclo[3. 2. 1]octane : vers de nouveaux marqueurs technétiés des transporteurs des monoamines." Université Joseph Fourier (Grenoble), 2003. http://www.theses.fr/2003GRE10029.
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Razy-Krajka, Florian. "Etude des systèmes monoaminergiques de l'ascidie Ciona intestinalis : De la différenciation au comportement : hypothèses d'homologies." Paris 11, 2010. http://www.theses.fr/2010PA11T005.
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Urtikova-Pavlioutenkova, Nataliya. "Régulation du développement des neurones sérotoninergiques par la sérotonine et ses recepteurs : étude de souris génétiquement modifiées." Paris 6, 2008. http://www.theses.fr/2008PA066375.
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La sérotonine (5-HT) joue un rôle important dans le développement du SNC, y compris dans celui de son propre système. Nous avons cherché à préciser in vivo le rôle des éléments-clés du phénotype sérotoninergique dans le développement des neurones 5-HT chez des souris génétiquement dépourvues de l’un ou de l’autre de ces éléments : récepteurs 5-HT1A ou 5-HT1B, transporteur de la 5-HT (5-HTT) et monoamine-oxydase de type A (souris Tg8). Les résultats obtenus par immunocytochimie au cours du développement périnatal montrent que l’absence d’un des élément-clés provoque toujours une modification du nombre des neurones dans les noyaux antérieurs du raphé, mais seulement chez les souris 5-HTT-/- dans les noyaux postérieurs. Elle provoque également des modifications de la taille des neurones et du taux de 5-HT intracellulaire. La 5-HT exerce donc bien in vivo un contrôle inhibiteur sur le développement de ses neurones, qui passe par l’activation des autorécepteurs, en particulier 5 HT1A. Ce contrôle est différent dans les noyaux antérieurs par rapport aux noyaux postérieurs du raphé.
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Vilpoux, Catherine. "Contribution à l'étude du délai d'action des antidépresseurs : effets de traitements chroniques par des antidépresseurs sur le transporteur vésiculaire des monoamines, la tyrosine hydroxylase, les récepteurs opioïdes mu et delta et le récepteur ORL1 de la nociceptine chez le rat." Rouen, 2001. http://www.theses.fr/2001ROUES016.
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Les antidépresseurs présentent un délai d'efficacité de deux à trois semaines, qui correspondrait à la mise en place d'un ensemble de mécanismes adaptatifs neuronaux. Un traitement chronique par la paroxétine, inhibiteur sélectif de la recapture de la sérotonine, ne modifie pas la densité du transporteur vésiculaire des monoamines (VMAT2) et de son ARN messager dans le cerveau de rat. L'immunoréactivité de la tyrosine hydroxylase diminue transitoirement dans le locus coeruleus au 14 ème jour de traitement par la paroxétine et revient au niveau des témoins après 21 jours. Cette régulation est commune à plusieurs antidépresseurs et révèlerait les interactions entre les systèmes à sérotonine et à noradrénaline (NA). Après des traitements de courte durée par la paroxétine (4 et 7 jours), la densité de liaison de la 3H-naloxone (déplaçable par le DAGO) aux récepteurs est augmentée dans des régions limbiques et corticales. Après 21 jours, cette densité est diminuée dans le thalamus. La réboxétine, inhibiteur sélectif de la recapture de la NA et le moclobémide, inhibiteur réversible de la monoamine oxydase de type A modifient la densité de sites de liaison de la 3H-naloxone (sensible au DAGO) dans des régions cérébrales différentes. Bien qu'il n'existe pas de trait commun aux trois antidépresseurs, ces régulations apparaissent dans des régions impliquées dans la physiopathologie dépressive. Une étude parallèle concernant les récepteurs montre des profils de réponse différents selon l'antidépresseur étudié. La liaison de la 3H-nociceptine augmente dans le raphé dorsal au cours d'un traitement chronique par la paroxétine. Au 4ème jour, l'augmentation de cette densité s'accompagne de l'augmentation du couplage du récepteur
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Schonn, Jean-Sébastien. "Mécanismes de la sécrétion régulée des hormones et des neurotransmetteurs ; rôle des GTPases Rab3 et Rab27." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2003. http://tel.archives-ouvertes.fr/tel-00011576.
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Les bases moléculaires de la sécrétion hormonale et de la libération de neurotransmetteurs dépendantes du calcium sont très semblables. Durant ma thèse, je me suis intéressé à divers aspects du cycle des granules de sécrétion dans des modèles cellulaires neuroendocriniens. J'ai en particulier étudié la contribution des transporteurs plasmiques de neuromédiateurs à la taille du quantum de sécrétion. Nous avons démontré que la surexpression de SERT (le transporteur plasmique de recapture de la sérotonine) au sein de la lignée neuroendocrine PC12 induit une augmentation de la taille des quanta sécrétés, et que le contrôle du remplissage vésiculaire était cinétique plutôt que thermodynamique. Ces observations ont permis de développer une méthode de mesure de l'activité sécrétrice d'une sous-population transfectée des cellules PC12. Cette technique permet de quantifier l'effet d'une protéine co-transfectée avec SERT sur l'activité sécrétrice.<br /><br />Une autre partie de mon travail concerne les petites GTPases Rab. Ces protéines régulent de nombreuses étapes du trafic cellulaire. Rab3 joue un rôle dans le contrôle d'étapes tardives de la neurotransmission/sécrétion d'hormones. Nos résultats, basés sur des analyses électrochimiques et biochimiques, suggèrent que Rab3 contrôlerait l'étape d'amorçage de la fusion.<br /><br />Plus récemment, notre attention s'est portée sur Rab27, une Rab proche de la famille Rab3, ainsi que sur MyRIP (Myosin and Rab Interacting Protein). Nous avons montré que MyRIP est un ligand de Rab27 et que ces deux protéines sont associées aux granules de sécrétion. MyRIP interagit aussi avec les myosines 7a/5a et avec l'actine. Ainsi, Rab27 et MyRIP lient les granules au cytosquelette d'actine et contrôlent leur mobilité au voisinage de la membrane plasmique.<br /><br />Nos études sur Rab3 et Rab27 ont permis de mieux comprendre les mécanismes moléculaires des processus impliquant ces GTPases, et illustrent la diversité des modes d'action de ces protéines.
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Schmitt, Mathieu. "Modulation de l’expression et de la fonction des protéines dopaminergiques présynaptiques par les statines : Application potentielle pour une intervention thérapeutique dans la maladie de Parkinson." Thesis, Bordeaux, 2015. http://www.theses.fr/2015BORD0187/document.
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La maladie de Parkinson (MP) est caractérisée par une perte progressive des terminaisons présynaptiques dopaminergiques et reste actuellement incurable. Néanmoins, dans les études épidémiologiques, il a été montré que l’utilisation des statines, médicaments hypocholestérolémiants, diminue le risque de développer une MP. Les statines sont également capables d'inhiber les effets neurodégénératifs dans les modèles précliniques in-vitro et in-vivo de la MP. Cependant, les mécanismes moléculaires à l’origine de ces effets neuroprotecteurs ne sont pas encore complétement élucidés. Ainsi, nous avons étudié les effets potentiels des statines sur l'expression des marqueurs synaptiques et sur le transport de la dopamine. Dans nos études, les statines induisent la croissance des neurites dans les cellules dopaminergiques et déclenchent une augmentation de l’expression des protéines synaptiques dopaminergiques telles que le transporteur vésiculaire des monoamines (VMAT2) et le transporteur de la dopamine. Les statines induisent une diminution de la recapture de la dopamine cellulaire et des changements d’affinités aux niveaux des sites de liaison des inhibiteurs sélectifs du VMAT2. L’activation du facteur de transcription nucléaire protéine-1 se liant à l'élément de régulation des stérols (SREBP-1), cholestérol-dépendent, serait l’élément inducteur de la surexpression des marqueurs dopaminergiques présynaptiques induite par les statines. En outre, ces résultats soutiennent un potentiel thérapeutique neuroprotecteur et/ou neurorestaurateur des statines précédemment proposées dans la MP et permettent de mettre en évidence de nouvelles cibles thérapeutiques comme le facteur SREBP<br>Parkinson disease (PD) is characterized by a progressive loss of dopaminergic presynaptic terminals and remains incurable. However in epidemiological studies, it has been shown that the use of statins, which are hypocholesterolemic drugs, diminishes the risk to develop a PD. Statins are able to inhibit the neurodegenerative effects in in-vitro and in-vivo models of PD. However, the molecular mechanisms driving neuroprotective effects are not yet fully understood. Consequently, we investigated the potential effects of statins on the synaptic expression and dopamine transport function in the dopaminergic system. In our studies, statins enhance the neurite outgrowth in the dopaminergic cells and trigger an increase in the expression levels of presynaptic dopaminergic proteins such as vesicular monoamine transporter 2 (VMAT2) and dopamine transporter. Statins induce a reduction of dopamine cellular uptake and modulate the binding-affinity of the specific inhibitors for VMAT2. The activation of the nuclear transcriptional factor sterol regulatory element-binding protein 1 (SREBP-1), cholesterol-dependent, could be the key element of the overexpression of dopaminergic presynaptic markers induced by the statins. Furthermore, these findings highlight the therapeutic neuroprotective and/or neurorestorative potentials of statins previously proposed in PD and allow to bring out new potential therapeutic targets such as SREBP factor
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Hsieh, Hao-Yu, and 謝皓宇. "Synthetic Study of Monoamine Transporter Inhibitor." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/usw6yz.
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博士<br>國立臺灣大學<br>藥學研究所<br>107<br>Monoamine neurotransmitters are important regulatory molecules that control emotion, cognition, and memory in human brain. The structure is usually a monoamine with two carbon chains attached to the end of the aromatic ring. Dopamine, serotonin, and norepinephrine are common in humans. The most common way to regulate these monoamine neurotransmitters is by monoamine transporters. The monoamine transporters commonly found in nerves are dopamine transporter (DAT), serotonin transporter (SERT), norepinephrine transporter (NET), and vesicular monoamine transporter type 2 (VMAT2). The role of the first three is to transport monoamine neurotransmitters from the synaptic space to presynaptic neurons, the last one transport monoamine neurotransmitters from the cytoplasm to synaptic vesicles. This has a very important regulatory effect on monoamine neurotransmitters. VMAT2 has been shown to cause many clinical neurological diseases, including drug addiction, mood disorders and stress, as well as Parkinson''s Disease (PD) and Alzheimer''s disease (AD). However, only Parkinson''s disease and Alzheimer''s disease are currently associated with VMAT2, but the detailed relationship is not clear. Tetrabenazine is currently the only drug approved by the US FDA for the treatment of Huntington''s disease. It has a very high affinity for VMAT2, and its specific configuration of the metabolite (+)-DTBZ has an affinity for VMAT2 of 0.97 nM. How to get (+)-TBZ is an important issue. A selective serotonin reuptake inhibitor (SSRI) is used as a method of inhibiting serotonin transporters. If it has a chlorine atom on the para position of the main structure of diphenylthioaniline, it can enhance the inhibitory effect of SSRI on SERT and enhance its selectivity. However, if the structure of diphenylthioaniline is chlorinated at the para position of the amine by the currently known chlorination reaction method. In our laboratory, when the nitro group was reduced by stannous chloride, a side reaction was found to be a chlorine atom attached to the amine group after the reduction. Therefore, based on this, an amine-based chlorination method on diphenylthioaniline was developed.
In this study, (+)-TBZ was successfully synthesized by asymmetric synthesis and its application was explored. The optimal conditions for one-pot reduction chlorination were also found under various experimental conditions.
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Sievert, Michael Kenneth. "Identification of drug binding sites on the vesicular monoamine transporter." 1996. http://catalog.hathitrust.org/api/volumes/oclc/36465623.html.
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Thesis (Ph. D.)--University of Wisconsin--Madison, 1996.<br>Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 227-243).
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Lin, Hung Ming, and 林宏銘. "Evaluation of New Derivatives of TBZ Targeting Vesicular Monoamine Transporter 2." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/36733981090671336272.
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碩士<br>長庚大學<br>醫學影像暨放射科學系<br>99<br>The release of neurotransmitters by cerebral nerve cells plays a key mechanism in the transmission of nerve signals. The second type of vesicular monoamine transporter (VMAT2), a vesicle membrane protein, is responsible for the storage and the release of monoamine neurotransmitter through the vesicles in nerve cells. Since the presence of VMAT2 in monoamine nerve cells, some neurodegenerative diseases, such as Parkinease`s disease, may be diagnosed by quantitative detection of VMAT2 distribution in cerebral neurons. In addition, VMAT2 also distributes in the pancreatic islet cells, quantifation of VMAT2 distribution in the pancrease may be helpful to study pancreatic cell function and for diabetes diagnosis. For imaging VMAT2 with PET, several radiolabeled tetrabenazine (TBZ) derivatives, such as C-11-TBZ, C-11-dihydrotetrabenazine (DTBZ), F-18-FE-DTBZ and F-18-FP-DTBZ, were recently developed. Among these known TBZ analogs, an isopropyl group attached to the carbon No. 3 of TBZ/DTBZ backbone is common. The objective of this study was to evaluate if TBZ derivatives with straight-chain alkyl group on the carbon No. 3 possess specific binding affinity to VMAT2. A series of straight-chain alkyl derivatives, including TBZ-M, TBZ-E and TBZ-B were prepared and the competition of these derivatives against F-18-FP-(+)-DTBZ were evaluated in the rat striatum homogenates ( VMAT2-enriched region ). The results showed that the binding of three straight-chain alkyl derivatives of TBZ prepared bound poorly to VMAT2 sites in the striatum homogeneous (Ki values were greater than 10,000 nM ), far inferior to the isopropyl bond derivative, FP-TBZ ( Ki value of 0.44 nM ).
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Manepalli, Sankar. "Structure Based Ligand Design for Monoamine Transporters and Mitogen Activated Kinase 5." 2012. http://digital.library.duq.edu/u?/etd,154098.
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Depression is a major psychological disorder that affects a person's mental and physical abilities. The National Institute of Mental Health (NIMH) classified it as a serious medical illness. It causes huge economic, as well as financial impact on the people, and it is also becoming a major public health issue. Antidepressant drugs are prescribed to mitigate the suffering caused by this disorder. Different generations of antidepressants have been developed with dissimilar mechanisms of action. According to the Center for Disease Control, the usage of antidepressants has skyrocketed by 400 percent increase over 2005- 2008 survey period. This dramatic rise in usage indicates that these are the most prescribed drugs in the US. Even with the FDA mandated "black box" warning of increased suicidal thoughts upon use of selected antidepressants, these drugs are still being used at a higher rate.
<br>All classes of antidepressants are plagued by side effects with mainly sexual dysfunction common among them. To avoid the adverse effects, an emphasis is to discover novel structural drug scaffolds that can be further developed as a new generation of antidepressants. The importance of this research is to discover structurally novel antidepressants by performing in silico virtual screening (VS) of chemical databases using the serotonin transporter (SERT). In the absence of a SERT crystal structure, a homology model was developed. The homology model was utilized to develop the first structure-based pharmacophore for the extracellular facing secondary ligand binding pocket. The pharmacophore captured the necessary drug-SERT interaction pattern for SERT inhibitory action. This pharmacophore was employed as one of the filters for VS of candidate ligands. The ten compounds identified were purchased and tested pharmacologically. Out of the ten hits, three structurally novel ligands were identified as lead compounds. Two of these compounds exhibited selectivity towards SERT; the remaining lead compound was selective towards the dopamine transporter and displayed cocaine inhibition. The two SERT selective compounds will provide new opportunities in the development of novel therapeutics to treat depression.
<br>For dopamine transporter (DAT), the study was based on recently developed structurally diverse photo probes. In an effort to better understand the binding profile similarities among these different scaffolds, the photo probes were docked into DAT. The finger print analysis of the interaction pattern of docked poses was performed to identify the inhibitor-binding sites.
<br>For mitogen activated protein kinase 5 (MEK5), given the lack of structural information, a homology model of MEK5 was developed to guide the rational design of inhibitors. Docking of known MEK5 inhibitors into the homology model was performed to understand the inhibitory interaction profile. Several series of analogues were designed utilizing the generated interaction profile.<br>Bayer School of Natural and Environmental Sciences<br>Chemistry and Biochemistry<br>PhD<br>Dissertation
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Thiriot, David Schreiner. "Engineering the human vesicle monoamine transporter to study structure, function, and ligand binding sites." 2001. http://www.library.wisc.edu/databases/connect/dissertations.html.
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Karpowicz, Richard. "I. Advanced Fluorescent False Neurotransmitters for the Study of Monoamine Transporter Activity and Synaptic Transmission." Thesis, 2013. https://doi.org/10.7916/D8ST7P9D.
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This thesis details two projects at the interface of chemistry and neuroscience. Part I focuses on the development and characterization of fluorescent optical tracers of monoamine neurotransmitters for use in the study of monoamine transporter activity and distribution, as well as synaptic transmission in the brain. The second section details early studies concerning experimental therapeutics recently identified by our group to induce the synthesis and release of Glial Derived Neurotrophic Factor (GDNF) from a model astroglial cell line. Part I consists of Chapters 1-5. Chapter 1 provides a brief introduction to the relationship between chemistry and neuroscience, while explaining the motivation and background behind the development and study of Fluorescent False Neurotransmitters (FFNs). Chapter 2 discusses the characterization of new fluorescent substrates for the Vesicular Monoamine Transporter 2 (VMAT2) for applications in high throughput screening of VMAT activity and inhibition, as well as for imaging aminergic synaptic transmission in brain tissue. Chapter 3 describes the discovery of fluorescent probes FFN201 and AGH093 as dual substrates for the norepinephrine transporter (NET) and VMAT, with potential applications in the imaging of noradrenergic modulation of cortical signaling networks. NG54, a FFN with substrate activity at each of the monoamine transporters was also identified, and represents a new structural class of FFNs. In Chapter 4, APP+, a known fluorescent substrate for the monoamine transporters, is evaluated as a potential tracer of monoamines in the brain. It has been determined that while this molecule may have utility as a marker for monoaminergic neurons, APP+ is not an appropriate FFN due to high background labeling of mitochondria and other intracellular structures. Chapter 5 discusses the discovery of fluorescent substrates of the Organic Cation Transporter 3 (OCT3) and Plasma Membrane Monoamine Transporter (PMAT). Mounting evidence suggests that these transporters play a significant role in clearing extracellular space of monoamines and are likely involved in neurological disease. As such, fluorescent substrates of OCT3 or PMAT would be useful as imaging agents in the brain, as well as for the development of fluorescence-based quantitative inhibition assays. Part II of this thesis (Chapter 6) discusses N-arylethyl isoquinuclidines as releasers of glial cell line-derived neurotrophic factor (GDNF) from a model glial cell line. Initial characterization of GDNF release and its dependence on protein synthesis and MAPK/ERK signaling is described. Preliminary studies indicate that at least two experimental compounds described herein modulate fibroblast growth factor receptor (FGFR) signaling.
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Chao, Ko Ting, and 趙可婷. "Biodistribution and Radiation Dosimetry of the Vesicular Monoamine Transporter Type 2 Ligand [18F]-AV133 in rats." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/61550784275088519232.
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碩士<br>長庚大學<br>醫學影像暨放射科學系<br>98<br>英文摘要
Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. 18F-labeled derivatives of dihydrotetrabenazine (DTBZ) will improve the VMAT2 image in clinical setting instead of 11C-labeled derivatives. To further facilitate its future utilization in clinical trials. In the present study, we investigated the biodistribution and radiation dosimetry of 18F-FP-(+)-DTBZ or 18F-AV-133 using animal PET.
Five male Wistar rats were used in the biodistribution study. Six-hour dynamic whole-body animal PET/CT images were acquired immediately after intravenous injection of 25.7 ± 3.09 MBq 18F-AV-133. The co-registrated PET/CT images were displayed and analyzed using the PMOD image analysis workstation. Volume of interests including brain, lungs, heart, liver, stomach, pancreas, intestine, kidneys, bladder, testes, red bone marrow and whole body were manually delineated on the fused PET/CT images. The animal biodistribution data expressed as the percentage of injected dose (%ID) was extrapolated to model human organs (i.e., Standard Man) according to each organ weight. The OLINDA/EXM application was used to determine the effective doses (EDs) for individual organ. The standard uptake value ratio (SUVR) of region striatum and brainstem to cerebellum were also been evaluated in another dynamic PET study.
The high-absorbed doses were found in the upper large intestine wall, small intestine, liver and pancreas. The critical organ was the upper large intestine wall which received 53.8±2.28 μGy/MBq. The effective dose equivalent and effective dose were 24.9±0.5 μSv/MBq and 20.6±0.5 μSv/MBq, respectively. These data are similar to those reported in human, which were 36.5±2.8 μSv/MBq and 27.8±2.5 μSv/MBq, respectively, and comparable to other 18F-labeled radiopharmaceuticals reported in the literatures. SUVR of striatum and brainstem to cerebellum reached the plateau 8.04±1.3 around 105 minutes and 4.68±1.1 around 85 minutes after injection, respectively.
18F-AV-133 demonstrated appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in rats. The results showed that small-animal PET presents an opportunity for providing radiation dose estimates with statistical and logistical advantages.
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Hsin, Tsao Hsin, and 曹馨心. "Binding of 9-fluoropropyl-(+)-dihydrotetrabenazine [FP-(+)-DTBZ] to the vesicular monoamine transporter type 2 (VMAT2) in rats." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/16092201684111759922.
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碩士<br>長庚大學<br>醫學物理暨影像科學研究所<br>97<br>C-11 or F-18 labeled tetrabenazine derivatives targeting vesicular monoamine transporters (VMAT2), a potential biomarker for beta cell mass (BCM), have shown some promising results. In the present study we examined the binding characteristics of F-18-FP-(+)-DTBZ, a potential PET tracer for BCM imaging, in rat pancreas and rat brain, respectively.
Exocrine and islet cells were isolated from Sprague-Dawley rats. Membrane homogenates prepared from pancreatic exocrine and islet cells as well as from brain striatum and hypothalamus regions were used for in vitro binding studies. In vitro and ex vivo autoradiography studies with F-18-FP-(+)-DTBZ were performed on brain and pancreas sections. Islet beta cells were confirmed via immunohistochemistry with anti-insulin antibody.
Excellent binding affinities of F-18-FP-(+)-DTBZ were observed in rat striatum and hypothalamus homogenates with Kd values of 0.19 and 0.25 nM, respectively (Bmax= 45.0 and 5.0 fmol/mg protein). Islet cell homogenates, however, showed two saturable binding sites (site A: Kd = 6.76 nM, Bmax = 60 fmol/mg protein; site B: Kd = 241 nM, Bmax =1,500 fmol/mg protein). Similar B sites were also observed in exocrine cells (Kd = 209 nM). In vitro autoradiography of F-18-FP-(+)-DTBZ using frozen sections of rat pancreas in optimum conditions showed labeling of islets, as evidenced by co-localization with anti-insulin antibody. Ex vivo VMAT2 pancreatic autoradiography in the rat however was not successful, in contrast to the excellent ex vivo autoradiography of VMAT2 binding sites in the brain.
F-18-FP-(+)-DTBZ is an excellent imaging agent for mapping VMAT2 sites in rat brain and specifically binds islet cells in vitro and post-mortem. Additional optimization may be required to achieve ex vivo islet beta cell labeling in rats.