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Hatcher-Solis, Candice N. "PHARMACOLOGICAL IMPLICATIONS OF ADENOSINE 2A RECEPTOR- DOPAMINE TYPE 2 RECEPTOR HETEROMERIZATION." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4458.
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G protein-coupled receptors (GPCRs) are heptahelical, transmembrane proteins that mediate a plethora of physiological functions by binding ligands and releasing G proteins that interact with downstream effectors. GPCRs signal as monomers, complexes of the same receptor subtype (homomers), or complexes of different receptor subtypes (heteromers). Recently, heteromeric GPCR complexes have become attractive targets for drug development since they exhibit distinct signaling and cell-specific localization from their homomeric counterparts. Yet, the effect of heteromerization on the pharmacology of many GPCR homomers remains unknown. Therefore, we have undertaken the task to examine the effect of heteromerization on Gs signaling through the adenosine 2A receptor (A2AR) and Gi signaling through the dopamine type 2 receptor (D2R) since the A2AR-D2R heteromer is an emerging therapeutic target for Parkinson’s disease (PD). We examined the effect of heteromerization on A2AR and D2R homomeric signaling using electrophysiology and the Xenopus laevis oocyte heterologous expression system. G protein-coupled inwardly rectifying potassium channels (GIRKs) were used as reporters for Gi signaling because activation leads to direct Gbeta-gamma (Gβγ)-mediated stimulation of the GIRK current. We also coupled GIRK channels to Gs signaling by overexpressing Gαs and signaling throughGαsβγ. Our electrophysiological assay is innovative because it allows us to optimize the conditions of heteromerization and directly observe GPCR signaling at the G protein level. Our data demonstrate that heteromer formation alone decreases dopamine-elicited Gi signaling through the D2R and CGS-21680-elicited Gs signaling through the A2AR. Furthermore, this reciprocal antagonism was predominately due to changes in efficacy versus potency. We also examined crosstalk observing that applying agonists or antagonists to the adjacent receptor further modulate this inhibition with the combination of agonists and antagonists relieving inhibition. Mutating the A2AR-D2R heteromer interface abrogated all of the aforementioned ligand-induced effects on G protein signaling through the A2AR-D2R heteromer. We are currently aiming to validate our results from the oocyte experiments with an in vivo model. Our data further elucidate the effect of various ligands on G protein signaling through the A2AR- D2R heteromer, which may facilitate future studies that examine A2AR-D2R heteromer signaling.
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ZANINOVICH, OREL ANTHONY. "THE CLONING OF AN INDR-TYPE DOPAMINE RECEPTOR IN MANDUCA SEXTA." Thesis, The University of Arizona, 2008. http://hdl.handle.net/10150/192256.
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Mann, Miranda Jane. "A neuropsychological investigation of dopamine receptor 4 differences among attention deficit hyperactivity disorder-combined type and control children /." Digital version accessible at:, 2000. http://wwwlib.umi.com/cr/utexas/main.
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Gorji, Hassan. "Role of adenylyl cyclase type 5 in the regulation of the dopamine D3 receptor phosphorylation." Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/27364.
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Adenylyl cyclase type 5 (AC5) is expressed in the brain where the highest density of the dopamine D3 receptor (D3R) has been found. The D3R-mediated Gi/o protein activation leads to a specific inhibition of AC5. Therefore, as AC5 is the main signalosome partner of D3R, I hypothesize that D3R phosphorylation is differentially regulated in cells expressing AC5. In HEK293 cells expressing D3R alone, D3R undergo dopamine-induced phosphorylation. Interestingly, in cells co-expressing AC5 and D3R, D3R undergoes a Galphai-dependent dephosphorylation upon dopamine exposure while retaining its ability to be phosphorylated in a Src-dependent manner under basal conditions. In cells co-expressing D3R and AC5, dopamine-induced D3R dephosphorylation and Gi/o mediated inhibition of cAMP production are specifically blocked by pharmacological inhibitors of the serine/threonine phosphatase PP2B and tyrosine phosphatases. Overall, our results suggest a novel paradigm in G protein-coupled receptor signaling whereby AC5 serves as a potential scaffolding complex containing phosphatases regulating the D3R phosphorylation status.
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Maier, Annette Louise. "Comparative regional ontogeny of dopamine D₁ receptor binding and mRNA expression in pre- and postnatal rat brain /." Zürich, 1994. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=10902.
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Etchepare, Laetitia. "Role of glutamate N-Methyl-D-Aspartate receptor surface trafficking in the firing pattern of midbrain dopaminergic neurons." Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0849/document.
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Les neurones dopaminergiques (DA) mésencéphaliques jouent un rôle prépondérant dans de nombreuses fonctions cérébrales telles que la motivation, mais ils sont également impliques dans l’émergence de pathologies telles que la maladie de Parkinson et l’addiction aux drogues. Ces processus ayant en commun de modifier l’activité de décharge des neurones DA mésencéphaliques, il est d’une importance primordiale de comprendre les mécanismes sous-tendant cette activité. Parmi les différents canaux ioniques et récepteurs impliques dans la génération de l’activité de décharge des neurones DA, les récepteurs au glutamate de type N-Methyl-D-Aspartate (NMDAR) et les canaux potassiques calcium-dépendants SK régulent fortement le patron de décharge, et interagissent fonctionnellement dans divers types neuronaux incluant les neurones DA. Cependant, les mécanismes mis en jeu dans cette régulation restent méconnus. Le couplage fonctionnel des NMDAR et des canaux SK dépendant notamment de leur distribution membranaire relative, nous avons émis l’hypothèse que la diffusion latérale des NMDAR, processus qui régule la localisation de surface du récepteur, pouvait jouer un rôle dans le patron de décharge des neurones DA via la modulation de la fonction des canaux SK. Nous avons tout d’abord montre que les NMDAR membranaires étaient mobiles dans les neurones DA en culture. L’altération de leur trafic de surface par immobilisation avec des anticorps anti-NMDAR modifie profondément la régularité du patron de décharge des neurones DA issus de tranches aigües de mésencéphale, alors que le blocage pharmacologique des NMDAR est sans effet. De plus, j’ai mis en évidence qu’un bloqueur des canaux SK, l’apamine, qui induit un changement similaire de la regularite du patron de décharge en condition contrôle, etait moins efficace lorsque la mobilité latérale des NMDAR etait alteree. Ainsi, ces résultats démontrent que la dynamique de surface des NMDAR module le patron de décharge des neurones DA en régulant la fonction des canaux SKMidbrain dopaminergic (DA) neurons play several key functions in the brain such as the processing of salient information but are also associated with the emergence of pathologies including Parkinson’s disease and drug addiction. Because these processes have in common to modify the firing activity of midbrain DA neurons, it is of crucial importance to understand the mechanisms underlying this activity. Among the various ions channels and receptors involved in the generation of the firing activity of midbrain DA neurons, glutamate N-methyl-D-aspartate receptors (NMDAR) and calciumdependent potassium SK channels strongly modulate the firing pattern and functionally interact in several neuronal types including DA neurons. However, the mechanisms by which they regulate the firing pattern are poorly understood. Since the functional coupling between NMDAR and SK channels depends on their relative membrane distribution, we hypothesized that the lateral diffusion of NMDAR, which regulates the surface localization of the receptor, could play a role in the firing pattern of midbrain DA neurons through the modulation of SK channel function. We showed first that membrane NMDAR was highly mobile in cultured DA neurons. Alteration of its surface trafficking by a crosslink with NMDAR antibodies profoundly modified the regularity of the firing pattern of DA neurons in midbrain slices, whereas pharmacological blockade of NMDAR did not affect it. Furthermore, a SK channel blocker, which induces a similar change in the firing regularity in control conditions, was less effective when NMDAR surface trafficking was altered. Taken together, these results demonstrate that NMDAR surface dynamics modulate the firing pattern of midbrain DA neurons by regulating SK channel function
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Roberts-Crowley, Mandy L. "Modulation of Cav1.3 L-Type Calcium Channels by Arachidonic Acid and Muscarinic M1 Receptors: A Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/348.
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Membrane excitability, gene expression, and neurotransmitter release are all controlled by voltage-gated L-type Ca2+ (L- )channels. In turn, Ca2+ channels are highly regulated by signal transduction cascades initiated by G protein-coupled receptor (GPCR) activation. In medium spiny neurons of the striatum, both the muscarinic M1 receptors (M1R) and dopaminergic D2 receptors (D2R) specifically inhibit the Cav1.3 L-channel.
In Chapters III and IV, the pathways downstream of M1Rs and D2Rs are examined to determine whether an overlap or intersection in inhibition of Cav1.3 occurs by these two receptors. Transient transfection of Cav1.3 channels in HEK 293 cells, stably transfected with the M1R, and in ST14A cells were used as model systems. While a further characterization of ST14A cells determined that they exhibit a striatal profile, D2Rs or M1Rs did not inhibit Cav1.3. Lack of current inhibition may be due to the finding of no detectable expression of phospholipase Cβ-1 protein in ST14A cells.
Ca2+ channels are multiprotein complexes comprised of α1, β, and α2δ subunits. While the actions of arachidonic acid (AA) have been shown to mimic M1R inhibition of L-current in superior cervical ganglion neurons, the precise identity of the L-channel in these neurons -either Cav1.2 or Cav1.3 or both- is not known. The transfected model systems allowed for the analysis of whole-cells currents with different β subunit combinations as well as the study of only Cav1.3 channels. In Chapter III, I show that activation of M1Rs with the agonist Oxo-M inhibited Cav1.3 channels coexpressed with either β1b, β2a, β3, or β4 subunits. Surprisingly, the magnitude of Cav1.3, β2a currents was inhibited less than Cav1.3 currents with other β subunits. In Chapter V, AA is shown to mimic the profile of M1R stimulation on Cav1.3 currents. The magnitude of Cav1.3, β2a currents was inhibited less than Cav1.3 currents with other β subunits by AA. This discovery points to a novel role for accessory β subunits in altering the magnitude of AA inhibition and kinetic changes of Cav1.3.
Arachidonic acid (AA) inhibits Ca2+ channels by an unknown mechanism at an unknown site. In Chapter V, I found that Cavl.3 inhibition by AA was state-dependent and most likely stabilizes a closed channel conformation. The finding that the Ca2+ channel accessory β subunit alters the magnitude of AA inhibition and kinetic changes of Cav1.3 suggests that AA could alter processes which rely on L-channels such as Ca2+-dependent gene expression, secretion and membrane excitability.
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Lucas, Guillaume. "Etude in vivo des modalités d'intervention de la sérotonine et des récepteurs sérotoninergiques de type 5-HT/2A/2C, 5-HT3 et 5-HT4 dans le contrôle de la transmission dopaminergique nigro-striée et mésoaccumbale chez le rat." Bordeaux 2, 1999. http://www.theses.fr/1999BOR28692.
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Hegron, Alan. "Implication des récepteurs de la mélatonine dans les troubles neurologiques et le diabète de type 2 et identification de régions clés du récepteur MT1 responsables de sa sélectivité fonctionnelle." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS555/document.
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La mélatonine est une neurohormone produite principalement par la glande pinéale de manière circadienne et agissant par l’activation de deux récepteurs couplés aux protéines G (RCPGs) appelés MT1 et MT2. La mélatonine régule de nombreuses fonctions physiologiques importantes. La régulation des niveaux de dopamine (DA) et de glucose en font partie mais nous ne savons pas clairement comment la mélatonine les régule.Les niveaux de DA extracellulaire sont principalement régulés par son transporteur (DAT) responsable de sa recapture dans les neurones présynaptiques afin de prévenir d’une hyperactivation des récepteurs dopaminergiques. Par conséquent, nous avons vérifié le rôle de DAT dans la régulation du système dopaminergique par le système mélatoninergique. Nous avons montré qu’en interagissant avec la forme immature non-glycosylée de DAT, MT1 et MT2 le retiennent dans le réticulum endoplasmique régulant ainsi son expression à la surface cellulaire et donc la recapture de la DA. De la même manière, les souris déficientes en MT1 ou MT2 ont montré une augmentation de la recapture de la DA dans les synaptosomes de striatum et une baisse de l’hypermotilité induite par l’amphétamine. Dans ce projet nous avons ainsi révélé un nouveau lien entre les systèmes mélatoninergiques et dopaminergiques basé sur la formation de complexes moléculaires entre les récepteurs de la mélatonine et DAT.Afin de mieux comprendre le rôle de la mélatonine dans la régulation des niveaux de glucose, nous avons ensuite étudié l’implication de variants génétiques de MT2 dans le développement du diabète de type 2 (DT2). Des études antérieures avaient montré que des variants naturels défectueux fonctionnellement étaient associés à un risque de développer le DT2. Afin de déterminer plus précisément les propriétés défectueuses en lien avec le DT2, nous avons mesuré l’activation spontanée et celle induite par la mélatonine de 40 variants MT2. Nous avons ainsi montré que des défauts d’activation des protéines Gαi et Gαz induite par la mélatonine et de recrutement spontané de la βarrestine-2 sont significativement reliés à un risque de développer le DT2. Les résultats expérimentaux corrélaient avec les prédictions de l’analyse sur le score d’évolution. Ce travail permettra de nouvelles avancées dans la recherche de traitements personnalisés pour les personnes portants les mutations sur MT2 afin qu’il retrouve une réponse non défectueuse.Le séquençage de 9393 personnes a permis l’identification de 32 variants naturels MT1. Le récepteur MT1 sauvage et les variants ont ainsi été caractérisés grâce aux techniques de transfert d’énergie par résonnance de bioluminescence (BRET). Nous avons montré que MT1 active les protéines Gαi/o, Gα12 et Gα15 et recrute la βarrestine-2. L’analyse des résultats par factorisation matricielle non linéaire a révélé l’existence de 5 clusters caractérisés par différents profils de signalisation. La modélisation 3D par homologie de MT1 a permis de déterminer l’impact de chaque variant sur l’activation du récepteur et ses interactions avec les protéines G et la βarrestine-2. Ce projet a ainsi permis de démontrer que des variants naturels sont très intéressant afin de comprendre les mécanismes d’action des RCPGs. En résumé, ce travail contribue à la compréhension des fonctions des récepteurs à la mélatonine et souligne leur importance dans la régulation du système dopaminergique et de l’homéostasie glucidique. Nos résultats offrent de nouvelles perspectives dans la recherche de nouveaux traitements personnalisés pour les patients souffrant d’un dérèglement du système dopaminergique ou de DT2Melatonin is a neurohormone mainly released from the pineal gland in a circadian manner acting through two G protein-coupled receptors (GPCRs) called MT1 and MT2. Melatonin regulates many important physiological functions. Regulation of dopamine (DA) and glucose levels are two of them but how they do this is not clear.Extracellular DA levels are mainly regulated by its transporter (DAT) which mediates DA re-uptake into presynaptic nerve termini to prevent DA receptor hyperactivation in the presynaptic cleft. Consequently, we verified the role of DAT in the regulation of the DA system by melatonin. We showed that MT1 and MT2, by interacting with the immature non-glycosylated form of DAT retain DAT in the endoplasmic reticulum thus regulating DAT cell surface expression and DA reuptake. Consistently, mice with targeted deletion of MT1 and MT2 show markedly enhanced DA uptake in striatal synaptosomes and decreased amphetamine-induced locomotor activity. Collectively, we revealed here a molecular link between the melatonin and DA systems, which is based on the formation of a molecular complex between melatonin receptors and DAT.To better understand the role of melatonin on the regulation of glucose levels, we studied the involvement of genetic variants of MT2 in the development of type 2 diabetes (T2D). Previous studies showed that natural loss-of-function variants of MT2 associate with T2D risk. To determine more precisely the defective properties linked to T2D risk we monitored spontaneous and melatonin-induced activation of different signaling pathways by 40 MT2 variants. We show that defects in melatonin-induced Gαi and Gαz activation and spontaneous βarrestin-2 recruitment are most significantly associated to T2D risk. Experimental results correlated well with those predicted by evolutionary lineage analysis. This work will help to propose personalized treatments for MT2 variant carriers to recover their defective responses.Sequencing of 9393 individuals resulted in the identification of 32 natural MT1 variants. MT1 wild-type and variants were functionally characterized in bioluminescence resonance energy transfer (BRET) assays. We showed that MT1 activates Gαi/o, Gα12 and Gα15 proteins and recruits βarrestin-2. Analyzes of results by non-linear matrix factorization revealed the existence of 5 clusters characterized by different signaling profiles. Computational homology modeling of the 3D model of MT1 helped to determine the impact of each variant on receptor activation and interaction with G proteins and βarrestin-2. Collectively, our data illustrate that natural variants are powerful tools to understand the molecular basis of GPCR function. Overall, this work contributes to our understanding of the function of melatonin receptors and highlights their importance in the regulation of the DA system and glucose homeostasis. Our results will open new, personalized therapeutic options for patient suffering from a defective DA system or T2D
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Thirtamara, Rajamani Keerthi Krishnan. "Animal Models of Drug Addiction and Autism Spectrum Disorders." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1386011455.
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Domingo, Rodriguez Laura 1992. "Neurobiological mechanisms involved in the loss of control over food intake." Doctoral thesis, Universitat Pompeu Fabra, 2020. http://hdl.handle.net/10803/668410.
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The easy access to palatable foods is a major contributing factor for compulsive eating and development of food addiction, a disorder closely linked to obesity and binge eating disorder. The concept of food addiction is still controversial but a validated tool for diagnosis, the Yale food addiction scale (YFAS 2.0), is widely accepted. However, the complex multifactorial nature of this disorder and the unknown neurobiological mechanistic correlation explain the current lack of effective treatments. In this thesis, we used a food addiction mouse model to elucidate the crucial role of the glutamatergic cortico‐striatal pathways modulated by the endocannabinoid and the dopamine systems as a critical mechanism for the loss of inhibitory control for palatable food seeking. This result was supported by electrophysiological recordings, genome‐wide RNA and DNA methylome sequencing, chemogenetic interference and adenoviral gene delivery, giving an understanding of the food addiction construct at genetic, epigenetic, cellular, circuit and behavioral level. This thesis unravels a new neurobiological mechanism underlying resilience and vulnerability to develop food addiction, which is expected to pave ways for novel interventions to battle compulsive eating behavior and other related disorders.El fàcil accés a aliments altament saborosos és un factor important que contribueix a la ingesta compulsiva i al desenvolupament de l’addicció al menjar. Aquest trastorn està molt vinculat a l’obesitat i al trastorn per afartament. El concepte d’addicció al menjar és controvertit, però l’aparició d’una eina diagnòstica valida, el Yale food addiction scale (YFAS 2.0), ha sigut àmpliament acceptada. Tot i això, la naturalesa complexa i multifactorial d’aquest trastorn i la desconeguda correlació neurobiològica expliquen la manca actual de tractaments efectius. En aquesta tesi, hem utilitzat un model d’addicció al menjar en ratolins per descobrir el paper crucial de les vies cortico‐estriatals glutamatergiques modulades pels sistemes endocannabinoid i dopaminèrgic com a mecanisme clau per a la pèrdua del control inhibitori en la cerca d’aliments saborosos. Aquest resultat, amb el suport d’estudis electrofisiològics, seqüenciació d’ARN i d’ADN de tot el genoma i tècniques de “chemogenetics” ens donen una comprensió del trastorn a nivell genètic, epigenètic, cel·lular, de circuit i de comportament. Aquesta tesi revela un nou mecanisme neurobiològic subjacent a la resiliència i a la vulnerabilitat a desenvolupar addicció al menjar. S’espera que obri noves vies eficients d’intervenció per combatre el comportament d’ingesta compulsiva i altres trastorns relacionats.
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Benac, Nathan. "Molecular mechanisms underlying the surface organization of the NMDA receptors during development." Electronic Thesis or Diss., Bordeaux, 2024. http://www.theses.fr/2024BORD0185.
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Comprendre comment les neurones se développent pour former le schéma organisé des connexions synaptiques reste une question centrale en neurosciences. La grande majorité des synapses excitatrices se forment tôt au cours du développement pendant une fenêtre de synaptogenèse. Les récepteurs N-méthyl-D-aspartate (NMDAR) sont depuis longtemps considérés comme un candidat important pour stimuler la synaptogenèse, car les données in vivo et in vitro montrent un rôle clé des NMDARs pendant cette phase. De plus, le fait que les NMDARs se trouvent dans les synapses « silencieuses », immatures sur le plan développemental, et parmi les premiers récepteurs à s'accumuler et s’agréger au site des synapses naissantes conduit à l'hypothèse que l'agrégation des NMDARs est un point de départ dans la formation des synapses. Cependant, les mécanismes moléculaires précoces sous-tendant l'agrégation des NMDARs en assemblages pro-synaptogéniques restent peu connus. De précédents travaux montrant que les NMDARs peuvent interagir directement avec d'autres protéines de surface, y compris des récepteurs, ont favorisé la possibilité que les interactions protéine-protéine (PPI) à la surface des neurones représentent un moyen puissant pour agréger les récepteurs. En utilisant une combinaison d'imagerie en direct et de microscopie super-résolution, nous avons observé que l'interaction entre les D1R-GluN1-NMDARs était favorisée dans les neurones immatures, pendant la phase de synaptogenèse. Nous avons montré que l'interaction D1R-GluN1-NMDAR façonne directement l'organisation des NMDARs, permettant leur agrégation fonctionnelle et la synaptogenèse. En effet, empêcher l'interaction dans les neurones immatures, et non dans les neurones matures, a altéré la formation des synapses excitatrices. Nous nous sommes ensuite concentrés sur les mécanismes de régulation intracellulaire et extracellulaire de l'interaction. Nous avons démontré un rôle des récepteurs métabotropes du glutamate (mGluR) et de la caséine kinase 1 (CK1) dans la promotion de l'interaction entre les D1Rs et les GluN1-NMDARs. D’autre part, le fait que l'acide hyaluronique (HA), l'un des principaux composants de la matrice extracellulaire (ECM), soit enrichi tôt dans le cerveau immature et régule la diffusion de surface des macromolécules ouvre l'hypothèse que l'ECM régule la capacité des NMDARs à interagir avec d'autres macromolécules de surface, y compris le D1R. Pourtant, les approches classiques se sont principalement concentrées sur la dégradation de l'ECM. Ici, nous avons visé à augmenter le contenu de l'ECM en HA en surexprimant à la fois la forme sauvage de la hyaluronane synthase de type synthase 2 de rat (HAS2) ou une forme portant les deux mutations ponctuelles présentes chez le rat-taupe nu (NMR; N178S et N301S) qui est connu pour produire de l'HA de très haut poids moléculaire (vHMW-HA). Nous avons observé que l'augmentation de la matrice entravait le développement des neurones et modifiait à la fois l'organisation et le trafic de surface des NMDARs. Ces résultats valident notre stratégie et ouvrent de nouvelles voies pour enquêter sur le rôle de l'ECM dans le développement neuronalUnderstanding how neurons develop to form the organized pattern of synaptic connections remains a central question in neuroscience. The vast majority of excitatory synapses are formed early in development during a synaptogenesis window. N-methyl-D-aspartate receptors (NMDAR) have long been a strong candidate to drive synaptogenesis as both in vivo and in vitro data show a key role for NMDARs during that phase. Furthermore, the facts that NMDARs are found in the developmentally immature “silent” synapses and among the first receptors to accumulate at the site of nascent synapses together lead to the assumption that NMDAR’s clustering is a nucleation point. Yet, the mechanisms underpinning the early clustering of NMDARs into synaptogenic assemblies remain enigmatic. Evidences that NMDARs can directly interact with other surface proteins, including receptors, has promoted the possibility that surface protein-protein interaction (PPI) represents a potent way to cluster receptors. Using a combination of live imaging and super-resolution microscopy, we observed that the interaction between D1R-GluN1-NMDARs were promoted in immature neurons, during the synaptogenesis phase. We showed that the D1R-GluN1-NMDAR interaction directly shapes the organization of NMDARs, allowing their functional clustering and synaptogenesis. Indeed, preventing the interaction in immature neurons, and not in mature neurons, altered the formation of excitatory post-synapses. We then focused on the intracellular and extracellular regulatory mechanisms of the interaction. We demonstrated a role of metabotropic glutamate receptors (mGluR) and casein kinase 1 (CK1) in promoting the interaction between D1Rs and GluN1-NMDARs. On the other hand, both the fact that the hyaluronic acid (HA), one of the main components of the extracellular matrix (ECM), is enriched early in the immature brain and regulates the surface diffusion of macromolecules opens the hypothesis that the ECM regulates the ability of NMDARs to interact with other surface macromolecules, including D1R. Yet, classical approaches have mainly focused on degrading the ECM. Herein, we aimed at increasing the ECM content in HA by over-expressing both the wild-type form of the rat hyaluronan synthase 2 (HAS2) or one bearing the two point-mutations present in the naked mole rat (NMR; N178S and N301S) which produces very high molecular weight HA (vHMW-HA). We observed that increasing the matrix impaired the development of the neuron and modified both the surface organization and trafficking of NMDARs. These findings validate our strategy, and open new paths for investigating the role of the ECM on neuronal development
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Sugamori, Kim S. "The dopamine D1C receptor, expansion and origin of the dopamine D1 receptor family." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0001/NQ41320.pdf.
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Torvinen, Maria. "Adenosine receptor/dopamine receptor interactions : molecular and biochemical aspects /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-298-1/.
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Middleton, Lisa Sue. "Nicotine receptor modulation of dopamine transporters." Lexington, Ky. : [University of Kentucky Libraries], 2005. http://lib.uky.edu/ETD/ukyphsc2006d00383/Middleton.pdf.
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Thesis (Ph. D.)--University of Kentucky, 2005.Title from document title page (viewed on March 2, 2006). Document formatted into pages; contains vii, 264 p. : ill. Includes abstract and vita. Includes bibliographical references (p. 196-260).
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Middleton, Lisa Sue. "NICOTINIC RECEPTOR MODULATION OF DOPAMINE TRANSPORTERS." UKnowledge, 2006. http://uknowledge.uky.edu/gradschool_diss/412.
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The current project examined the ability of nicotine to modulate dopamine transporter (DAT) function. Initial experiments determined the dose-response for nicotine to modulate dopamine (DA) clearance in rat striatum and medial prefrontal cortex (MPFC) using in vivo voltammetry and determined if this effect was mediated by nicotinic receptors (nAChRs). In both striatum and MPFC, nicotine increased DA clearance in a mecamylamine-sensitive manner, indicating nAChR-mediation. The effect of acute nornicotine on DAT function was also determined. In contrast to nicotine, nornicotine in a dose-related manner decreased striatal DA clearance in a mecamylamine-sensitive manner, indicating nAChR mediation. To determine if tolerance developed to the nicotine effect nicotine, separate groups of rats were injected once daily for 5 days with nicotine or saline. DA clearance in striatum and MPFC was determined 24 hrs after the last injection. Nicotine increased DA clearance only 10-15% in the group repeatedly administered nicotine, demonstrating that tolerance developed. To determine if nicotine altered striatal DAT efficiency, following nicotine injection, DAT density and maximal velocity of [3H]DA uptake was determined using [3H]GBR12935 binding and saturation analysis of [3H]DA uptake in rat striatum, respectively. Nicotine did not alter the Bmax or Kd of maximal binding of [3H]GBR12935 binding. However, an increase in Vmax was observed at 10 and 40 min following nicotine injection, suggesting that nicotine increases DAT efficiency. To determine if systemic nicotine enhanced DAT function via an action at nAChRs on striatal DA terminals, [3H]DA uptake was determined in striatum in vitro in the absence or presence of nicotine in the buffer. Nicotine did not alter the Vmax for [3H]DA uptake in vitro, suggesting that the nicotine-induced increase in DAT function observed in vivo is mediated by nAChRs on DA cell bodies or another site which indirectly alters DAT function. To determine if the increase in DAT efficiency was due to increased surface expression of striatal DAT, biotinylation and Western blot analyses were performed. Nicotine did not alter striatal DAT, suggesting that the nicotine-induced increase in DA clearance in vivo and DAT efficiency in vitro is not the result of increased trafficking of this protein to the cell surface.
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Genn, Rachel F. "Dopamine receptor subtypes and ingestive behaviour." Thesis, Durham University, 1999. http://etheses.dur.ac.uk/4303/.
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Both centrally and systemically administered dopamine agonists and antagonists decrease ingestive behaviour. The aim of this thesis was to examine whether drugs acting at different receptor subtypes decreased intake in different ways. A microstructural analysis was used to examine dopaminergic drug effects on licking behaviour. A dopamine D3 receptor agonist, 7-OH-DPAT, a dopamine D2 receptor antagonist raclopride and a mixed dopamine D2/D3 agonist quinpirole were compared in this paradigm. These drugs reduced the number of licks by differentially decreasing parameters which are thought to reflect the palatability of the stimulus such as mean bout duration of licking and the initial rate of licking. Follow-up experiments were conducted to further examine the possibility that motor deficits were underlying decreases in licking parameters. The effects of raclopride and 7-OH-DPAT were compared to the effects of a dopamine Dl antagonist SCH- 23390 and were analysed using a brief contact licking test. Again, the behavioural expression of anorexia induced by these drugs seemed to rely on a differential decrease in mean bout duration. Results also revealed that the three drugs used differed in the extent to which they produced a motoric deficit Attempts to block the effects of 7-OH-DPAT on licking (wameters were made by using the putative D3 receptor antagonists PNU-99194A and amisulpride. In addition, the effects of these drugs alone on licking behaviour were examined PNU-99194A failed to block the effects of 7-OH-DPAT and was relatively ineffective in producing changes in licking behaviour when administered alone. Amisulpride blocked the effects of 7-OH-DPAT only at high doses and when injected alone produced an increase in intake through an increase in mean bout duration of licking. Results from Chapters 4,5 and 6 suggested that 7-OH-DPAT was having an effect on palatability. Therefore, Chapter 7 presents an experiment which examines the effect of 7-OH-DPAT on the licking behaviour of rats which encounter a devaluation of reward (successive negative contrast). 7-OH-DPAT reduced successive negative contrast leading to the proposal that D3 receptors may mediate relative as well as absolute reinforcer value. These results bear important implications for understanding the role of dopamine receptor subtypes in components of food reward and appetitive behaviour in general and may well have implications for the treatment of eating disorders.
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Rimondini-Giorgini, Roberto. "Behavioural and biochemical pharmacology of adenosine/dopamine receptor/receptor interaction /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3617-X/.
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Kim, Douglas S. "Dopamine and adenosine receptor function in adult and developing dopamine-deficient mice /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/5063.
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Knapp, Mark. "Development of dopamine receptor-expressing adenoviral vectors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0001/MQ28801.pdf.
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D'Souza, Ursula M. "Structure of the Dâ†2 dopamine receptor." Thesis, University of Kent, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259680.
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Salmi, Peter. "Clozapine as a dopamine D1 receptor agonist /." Stockolm : Universitet Stockholms, 1998. http://catalogue.bnf.fr/ark:/12148/cb401175060.
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Satchell, Rupert. "Signalling and regulation of the D1 dopamine receptor." Thesis, University of Leicester, 2013. http://hdl.handle.net/2381/38068.
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Signalling, desensitization and allosteric modulation have been investigated in cell-lines endogenously or recombinantly expressing human D1 dopamine receptors. Each of the D1 dopamine receptor agonists studied (dopamine, SKF 38393, SKF 81297, SKF 82958, SKF 83822, SKF 83959, dihydrexidine and rotigotine) concentration-dependently increased cAMP accumulation in SK-N-MC human neuroblastoma cells endogenously expressing the D1 dopamine receptor. However, D1 receptor stimulation failed to evoke a Ca2+ response. Agonist pre-treatment of SK-N-MC cells induced acute desensitization, characterized by significant reductions in maximal cAMP responses to dopamine re-challenge. The putative D1 dopamine receptor positive allosteric modulators, GSK1542480A and GSK2113779A, failed to stimulate cAMP accumulation in SK-N-MC cells when applied alone, but both compounds potentiated dopamine-stimulated cAMP responses and enhanced dopamine displacement of [3H]SCH 23390 binding in HEK-D1 membranes. These data reveal that these novel compounds modulate positively the affinity of dopamine at the D1 dopamine receptor. Quantitative automated image analysis of bimolecular fluorescence complementation (BiFC) demonstrated that D1 dopamine receptor agonists promote recruitment of β-arrestin1 and β-arrestin2 to the D1 receptor. Furthermore, GSK1542480A and GSK2113779A potentiated dopamine-induced β-arrestin2 recruitment. Comparisons between agonist-stimulated BiFC and cAMP responses revealed that SKF 81297, SKF 82958, SKF 83822 and SKF 83959 exhibited bias towards β-arrestin2 recruitment. These studies extend our knowledge of the orthosteric and allosteric pharmacology of the D1 dopamine receptor, provide new insights into the regulation of this subtype and hint at the potential of such agents to bias the receptor between G protein-dependent and –independent signalling.
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Oldenhof, John. "SH3 binding domains in the dopamine D4 receptor." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0017/NQ45764.pdf.
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謝志恒 and Chi-hang Tse. "Molecular cloning of the goldfish dopamine D2 receptor." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1998. http://hub.hku.hk/bib/B42128511.
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Tse, Chi-hang. "Molecular cloning of the goldfish dopamine D2 receptor." Click to view the E-thesis via HKUTO, 1998. http://sunzi.lib.hku.hk/hkuto/record/B42128511.
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Karper, Patrick Eugene. "Role of the Dopamine D₁-like receptor in amphetamine-induced behavioral sensitization: A study using Dopamine D₁A-receptor deficient mice." CSUSB ScholarWorks, 2000. https://scholarworks.lib.csusb.edu/etd-project/1682.
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The ability of the indirect dopamine agonist, amphetamine, to produce behavioral sensitization was assessed in adult D₁A-deficient and wild-type mice. It was originally predicted that : 1) dopamine (DA) D₁-like receptors are necessary for the occurrence of short- and long-term amphetamine-induced behavioral sensitization, 2) DA D₁-like receptors are necessary for environmental conditioning factors associated with amphetamine-induced behavioral sensitiazation, and 3) DA D₅ receptors are required for amphetamine-induced behavioral sensitization. Locomotor activity and sterotyped sniffing were assessed in each of three experiments.
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Sheppard, Ashley Brianna. "Sex Differences in Nicotine-Conditioned Hyperactivity in a Model of Dopamine D2 Receptor Priming: Roles of Dopamine D2 and D3 Receptor Subtypes." Digital Commons @ East Tennessee State University, 2008. https://dc.etsu.edu/etd/1978.
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The aim of this investigation was to determine the effect of a nicotine-conditioned context on locomotor hyperactivity in an animal model of D2-priming, and whether conditioned hyperactivity could be blocked by the D2 antagonist eticlopride or the D3 antagonist nafadotride. D2-primed male rats showed enhanced nicotine sensitization as evidenced by statistically significant differences in horizontal activity. D2-primed female rats administered nicotine demonstrated an increased hypoactive response after initial sensitization and increased stereotypy. Eticlopride and nafadotride blocked sensitization to nicotine in both D2-primed and non D2-primed males and females. Eticlopride blocked conditioned hyperactivity in females but not in males. D2-primed female rats administered nicotine demonstrated significantly higher conditioned-hyperactivity as compared to non D2-primed females and controls, and this increase was more effectively blocked by nafadotride as compared to eticlopride. These results suggest differential roles of the dopamine D2 and D3 receptors in both adolescent nicotine sensitization and conditioned activating effects of nicotine.
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Kotowski, Sarah. "Regulation of dopamine signaling by D1 receptor membrane trafficking." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390053.
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Ray, Avi Andrew. "SH3 binding domains in the dopamine D¦3 receptor." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0018/MQ45843.pdf.
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Zawarynski, Paul. "Dopamine D2 receptor monomers, dimers and higher order oligomers." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0025/MQ40852.pdf.
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Terasmaa, Anton. "Dopamine D2 receptor G protein coupling and its regulation /." Stockholm, 2003. http://diss.kib.ki.se/2004/91-7349-788-6/.
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Pesek, Erin Fae Newland M. Christopher. "The role of dopamine receptor subtypes in reinforced variability." Auburn, Ala, 2008. http://repo.lib.auburn.edu/EtdRoot/2008/SUMMER/Psychology/Thesis/Pesek_Erin_41.pdf.
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Shaikh, Sanober. "Molecular genetic studies of dopamine receptor genes in schizophrenia." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243332.
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Kostrzewa, Richard M., John P. Kostrzewa, Russell W. Brown, Przemyslaw Nowak, and University of Silesia Ryszard Brus Medical. "Dopamine Receptor Supersensitivity: Development, Mechanisms, Presentation, and Clinical Applicability." Digital Commons @ East Tennessee State University, 2008. https://doi.org/10.1007/BF03033804.
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The process of receptor supersensitivity (RSS) has a long history and is an epiphenomenon of neuronal denervation. Dopamine (DA) RSS (DARSS) similarly occurs after DA denervation, and this process is invoked in neuropsychiatric and neurodegenerative disorders. From studies largely over the past 25 years, much has been learned regarding DARSS. For example, overt D1 DARSS occurs after perinatal destruction of nigrostriatal DA fibers. However, following perinatal destruction of DA innervation, the most-prominent behavioral effects of a D1 agonist are observed after a series of D1 agonist treatments--a process known as priming of D1 DA receptors. Moreover, perinatal lesioning of DA fibers produces prominent serotonin (5-HT) RSS, and in fact 5-HT RSS appears to modulate D1 DA RSS. In rodents, receptor supersensitization by these means appears to be irreversible. In contrast to the observed D1 DARSS, D2 DARSS apparently does not occur after perinatal DA denervation. Also, while repeated D1 agonist treatment of intact rats has no observable effect, repeated D2 agonist treatments, during or after the ontogenetic phase, produces prominent life-long D2 RSS. The process may have an association with substance abuse. Therefore, production of D1 and D2 DARSS occurs by different means and under different circumstances, and in association with perhaps different neuronal phenotypes, and with greater incidence in either intact (D2) or DA-lesioned counterparts (D1). The physiological consequence of RSS are multiple.
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Marcott, Pamela F. "Mechanisms of dopamine D2-receptor activation across the striatum." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1502719812531202.
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Gallagher, Edward Jude. "Targeted disruption of the neurotensin receptor gene." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241741.
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Xiang, Lianbin, Katalin Szebeni, Attila Szebeni, Violetta Klimek, Craig A. Stockmeier, Beata Karolewicz, John Kalbfleisch, and Gregory A. Ordway. "Dopamine Receptor Gene Expression in Human Amygdaloid Nuclei: Elevated D4 Receptor mRNA in Major Depression." Digital Commons @ East Tennessee State University, 2008. https://dc.etsu.edu/etsu-works/8608.
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Previous findings from this laboratory demonstrating changes in dopamine (DA) transporter and D2 receptors in the amygdaloid complex of subjects with major depression indicate that disruption of dopamine neurotransmission to the amygdala may contribute to behavioral symptoms associated with depression. Quantitative real-time RT-PCR was used to investigate the regional distribution of gene expression of DA receptors in the human amygdala. In addition, relative levels of mRNA of DA receptors in the basal amygdaloid nucleus were measured postmortem in subjects with major depression and normal control subjects. All five subtypes of DA receptor mRNA were detected in all amygdaloid subnuclei, although D1, D2, and D4 receptor mRNAs were more abundant than D3 and D5 mRNAs by an order of magnitude. The highest level of D1 mRNA was found in the central nucleus, whereas D2 mRNA was the most abundant in the basal nucleus. Levels of D4 mRNA were highest in the basal and central nuclei. In the basal nucleus, amounts of D4, but not D1 or D2, mRNAs were significantly higher in subjects with major depression as compared to control subjects. These findings demonstrate that the D1, D2 and D4 receptors are the major subtypes of DA receptors in the human amygdala. Elevated DA receptor gene expression in depressive subjects further implicates altered dopaminergic transmission in the amygdala in depression.
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Tumova, Katerina. "Uncovering the molecular interplays of dopamine D1-like receptor activation." Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/26347.
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D1-like dopaminergic receptor family consists of two heptahelical G protein-coupled receptors (GPCRs), termed D1A (or D1) and D1B (or D5). In this study, we have used a functional complementation of chimeric D1-like receptors to address the molecular interplay between the third extracellular loop (EL3) and the cytoplasmic tail (CT) in coordinating the functional properties of D1-like receptors expressed in transfected human embryonic kidney 293 (HEK 293) cells. Our results indicate that ED and CT participate in interfering intramolecular interactions that regulate the total functional receptor number and the agonist-mediated G protein coupling properties of the D1-like receptors in HEK 293 cells. In contrast, the agonist-independent activity of the D1-like receptors appears to be regulated solely by the sequences of the CT. In addition, we have identified the proximal region of CT, known as the fourth intracellular loop (IL4), as the pivotal domain underlying the CT-induced properties of the D1-like receptors. Overall, our study provides an insight into the molecular basis of D1-like receptor activation with possible implications for entire field of GPCR signaling.
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Kruse, Maria Sol. "Plasticity of the dopamine 1 receptor and its signaling pathway /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-652-9/.
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Johnson, Christopher Norbert. "The design and synthesis of subtype-selective dopamine receptor antagonists." Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266875.
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Costanza, Rino Michelangelo. "Dopamine receptor subtype involvement in the behavioural effects of cocaine." Thesis, University of Birmingham, 2000. http://etheses.bham.ac.uk//id/eprint/5890/.
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The relationship between the behavioural effects of cocaine and the increase in dopamine caused by its blockade of dopamine re-uptake has been a major focus of research interest. However, little is known regarding the involvement of recently cloned dopamine D2-like receptor subtypes (D2, D3 and D4) in different cocaine induced behaviours. The purpose of the work described in this thesis was to use a series of behavioural tests to assess dopamine receptor subtype involvement in cocaine's effects. In the first series of experiments, we tested the effects of antagonists selective for receptors within the D2-like subfamily on the discriminative stimulus effects of cocaine (10 mg/kg), and compared them with the effects of a Dl-like receptor antagonist. A separate group of rats were trained to discriminate a low dose of cocaine (3 mg/kg). Neither U-99194A (a D3 antagonist) nor L-745,870 (a D4 antagonist) substituted for cocaine, and neither drug shifted the dose-response function for cocaine at the higher training dose. On the other hand, pre-treatment with SCH 39166 (a selective Dl-like antagonist) produced significant dose-related rightward shifts in the cocaine generalisation curve, indicating effective antagonism. Three other centrally-acting D2-like antagonists (L-741,626; haloperidol and raclopride) produced rightward shifts in the dose-response function for cocaine at both training doses. The D2-like antagonists, however, produced dissimilar effects on cocaine-induced hypophagia and hyperactivity in the rat. The D3 and D4 antagonists (which produced minimal effects on feeding and motor behaviours on their own) failed to alter any of the behavioural effects induced by cocaine. The D21D3 antagonist, raclopride, produced only a marginal attenuation of cocaine-induced hyperactivity and rearing, but a marked attenuation of cocaine-induced decreases in grooming. On the other-hand, a Dl-like antagonist potently reversed cocaine-induced hypophagia, hyperactivity and rearing, but failed to affect grooming behaviour. While drug discrimination studies suggests negligible involvement of D3 and D4 receptors in cocaine's effects, an important role for Dl-like and D2 receptors was observed. In contrast, it seems that the Dl-like subfamily may play a more prominent role than the D2-like subfamily in cocaine-induced hypophagia and motor hyperactivity, although cocaine-induced inhibition of grooming appears to be specifically a D2-mediated effect.
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Kant, Andrew Charles Mailman Richard B. "Functional selectivity at the D1 dopamine receptor studies using SKF83959 /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,2006.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Master of Science in the Curriculum in Toxicology." Discipline: Toxicology; Department/School: Medicine.
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Stott, Lisa Alice. "Determination of agonist intrinsic efficacies at the dopamine D2 receptor." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/39305/.
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G protein coupled receptor agonists can be described by two parameters; affinity (ability to bind a receptor) and efficacy (ability to activate a receptor once bound). While affinity is now an accessible parameter through binding studies, agonist efficacies have historically been difficult to determine. This is due to the significant system dependence of agonist responses and is particularly true of traditional maximal response and potency measurements. The Black and Leff operational model determines agonist affinity and efficacy estimations directly from functional data. Its measure of efficacy (τ) offers improvement over maximal response determinations but remains a system dependent parameter. More recently, the Slack and Hall operational model has been described. This model uses receptor constitutive activity to estimate the system contribution to agonist responses to derive system independent measures of intrinsic agonist efficacy. This thesis explores the use of operational models in the analysis of agonist functional responses at the dopamine D2 receptor. This receptor is an important therapeutic target in the treatment of schizophrenia and Parkinson’s disease, and has well documented receptor constitutive activity. Maximal responses and potencies in two representative functional assays, CRE-SPAP reporter gene and receptor internalisation, were determined for a panel of ligands at the D2L receptor. In the receptor internalisation assay, agonist maximal responses and potencies were decreased, consistent with an assay of reduced receptor reserve. Applying the Black and Leff operational model to the responses of four representative agonists, in the absence and presence of the irreversible antagonist phenoxybenzamine, yielded affinity and efficacy estimations consistent with the known pharmacology of the compounds. However, experiments did not provide evidence for the receptor constitutive activity necessary to apply the Slack and Hall operational model. As such, site-directed mutagenesis was performed to generate a constitutively active D2L receptor. T6.34R mutation increased agonist potencies and relative maximal responses consistent with a receptor more likely to adopt the active state; however, potencies of the ergo-derived compounds were selectively decreased. Mutagenesis of three key binding site serine residues examined the mode of agonist binding in both wild type (WT) and T6.34R backgrounds. Each serine mutation had differential effects on the responses of structurally distinct agonists, suggesting agonists engage specific serine residues; while S5.42 and S5.46 were required for catechol agonist responses, S5.46 was essential for the responses of the ergo-derived compounds, bromocriptine and dihydroergocristine. It was unknown whether these specific modes of binding would generate functionally similar active conformations. Generally, the differences between the effects on CRE-SPAP reporter gene and receptor internalisation assay responses were sufficiently explained by differences in receptor reserve. However, there were differential effects of serine mutations on WT and T6.34R D2L receptors, particularly the opposing effect of S5.42A on quinpirole potencies in the CRE-SPAP reporter gene assay. This suggests that WT and T6.34R D2L receptors adopt different conformations. Finally, we have described a method to determine agonist affinity and efficacy from [35S]-GTPγS binding assays using operational models, which does not rely on irreversible antagonist treatments. Buffer Na+ substitution revealed consistent constitutive activation of the D2S receptor, but not of the D2L or D2L T6.34R receptors. Agonist responses at the D2S receptor, in the presence and absence of buffer Na+, were analysed with the Black and Leff and Slack and Hall operational models respectively, generating agonist affinity and efficacy estimations. A novel operational model, written specifically for the analysis of [35S]-GTPγS binding assays, was also examined. This model provided similar affinity derivations to the Black and Leff operational model but provided a τ value that may have reduced system dependency. Although there may be compromises in the associated experimental conditions and which receptors can be investigated, the Slack and Hall operational model can be applied to constitutively active systems to provide system independent measures of agonist intrinsic efficacy.
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Etter, Guillaume. "Role of retinoid X receptor gamma and dopamine receptor D2 in hippocampal and memory functions." Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ055.
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Dans ce travail de thèse, j'ai cherché à comprendre les mécanismes de contrôle des fonctions mnésiques par Rxrγ ainsi que l’implication potentielle de la signalisation dopaminergique dans ces mécanismes. Dans ce cadre, j'ai focalisé mon étude sur les fonctions hippocampiques à différent niveaux. J'ai cherché (1) à identifier les populations cellulaires de l'hippocampe exprimant Rxrγ en utilisant des techniques histologiques(immunohistochimie, hybridation in situ) afin de pouvoir (2) étudier les fonctions électrophysiologiques de ces cellules en utilisant la technique du patch-clamp. Pour comprendre le rôle de Rxrγ dans le contrôle des fonctions autonomes de ces cellules et les conséquences sur le réseau neuronal environnant, j’ai étudié les effets de la perte de fonction chez les souris Rxrγ/.Étant donné que différentes sous régions de l'hippocampe sont impliquées dans différents processus mnésiques, et que notamment le gyrus denté a été associé au processus de pattern separation (Leutgeb et al., 2007), j'ai également (3) cherché à préciser les fonctions mnésiques qui dépendent de l'activité de Rxrγ en réalisant des analyses comportementales chez les souris Rxrγ/. Etant donné que Rxrγ possède une activité transcriptionnelle, entre autre sur le gène du récepteur D2 à la dopamine (Drd2) (Samad et al., 1997), j'ai également (4) étudié la signalisation dopaminergique dans l’hippocampe chez les souris sauvages et les mutants nuls Rxrγ/. Enfin, afin de démontrer la spécificité neuroanatomique et homéostatique du contrôle exercé par Rxrγ sur la mémoire,j’ai procédé à (5) l’inactivation spécifique de Rxrγ dans les hippocampes de souris floxées pour ce gène, au moyen d’un virus AAV exprimant la recombinase CreThe present thesis work is an attempt to understand the mechanisms of Rxrγ control of memory functions, as well as the potential involvement of dopaminergic signaling in these mecanisms. In this context, I focused my research on hippocampal functions at several distinct levels. The first part of my work (1) aimed at defining the hippocampal cell populations expressing Rxrγ using various histological techniques (immunohistochemistry, in situhybridization) in order to (2) study the electrophysiological functions of these cells using invitro patch-clamp.To identify the role of Rxrγ in the control of cell autonomous functions, as well as the consequences on the surrounding network, I have studied the effects of its loss of function in Rxrγ/mice.As the different subregions of the hippocampus are implicated indistinct aspects of learning and memory, and in particular the dentate gyrus being associated with pattern separation (Leutgeb et al., 2007), I have also tried to dissect the mnemonic processes that rely on Rxrγ activity by performing behavioral analyses of Rxrγ/mice. Considering the transcriptional activities of Rxrγ on Drd2, I have also (4) studied dopaminergic signaling in the hippocampus of wild type and Rxrγ null mutant mice. Finally, to demonstrate the neuroanatomical and homeostatic specificity of Rxrγ control on memory, I performed (5) specific inactivations of Rxrγ in hippocampi of conditional mutant mice that possessed floxed Rxrγ, using AAV vectors expressing recombinase Cre
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Voicu, Cristian, and n/a. "Electrophysiological effects in the rat basal ganglia following systemic adenosine A2A receptor stimulation and dopamine D2 receptor blockade." University of Otago. Department of Physiology, 2008. http://adt.otago.ac.nz./public/adt-NZDU20080811.155439.
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The difficulty with movement initiation, or akinesia, is a cardinal symptom of Parkinson�s disease (PD) and the loss of dopaminergic cells, affecting the function of the basal ganglia, the thalamus and the motor cortex, has long been documented. From a broader perspective, it has been proposed that akinesia is caused by impaired function in different brain areas, inside and outside the basal ganglia, operating as a �behavioural arrest control system� (Klemm, 2001). Several neurotransmitters seem to modulate the activity of this system and, contrasting the well-known effects of dopamine, the involvement of adenosine has only recently emerged, particularly via A2A receptors. Adenosine plays an opposite role to dopamine in the brain: adenosine stimulation at A2A receptors inhibits movement (Ferre et al., 1991a; Hauber and Munkle, 1995; Rimondini et al., 1997), whereas A2A antagonists seem to promote movement (Kanda et al., 2000; Bara-Jimenez et al., 2003; Pinna et al., 2005). Although specific adenosine A2A and dopamine D2 receptors are known to antagonistically interact (Ferre et al., 1997; Fuxe et al., 1998; Ferre et al., 2001), little is known of the involvement of A2A receptors in regulating neural activity in the basal ganglia, a crucial point for the future use of A2A antagonists as adjuvant therapy in Parkinson�s disease. In fact, although it is generally accepted that akinesia results from altered function in the cortico-basal ganglia-cortical loop, as confirmed in several studies reporting changes in basal ganglia activity following dopamine depletion (Blandini et al., 2000; Bevan et al., 2002; Boraud et al., 2002), no study to date has systematically investigated electrophysiological changes in the basal ganglia during akinesia induced by adenosine receptor stimulation.
Starting from a common behavioural effect, this study tries to bridge this gap by investigating and comparing, in two basal ganglia structures, the neural substrate of akinesia after acute dopamine D2 receptor blockade and adenosine A2A receptor stimulation. The external segment of the globus pallidus (GP, or simply globus pallidus in the rat) and the substantia nigra pars reticulata (SNr) were chosen as the recording sites because both nuclei are included into the �behavioural arrest control system� and seem to express somewhat complementary functions, as a respective key integrative station and main output of the basal ganglia. Dopamine function was manipulated by acute decrease in availability of dopamine binding sites in the brain, through specific dopamine D2 receptor blockade with systemic injections (1.0 and 1.5 mg/kg) of raclopride(3,5-dichloro-N-[(1-ethylpyrrolidin-2-y)methyl]-2-hydroxy-6-methoxy-benzamide), resulting in akinesia. Conversely, movement was inhibited by specific adenosine A2A receptor stimulation with systemic injections (2.5 and 5.0 mg/kg) of the drug CGS21680 (sodium-2-p-carboxyethylphenylamino-5-N-carboxamidoadenosine). In both situations, behaviour was assessed through specific akinesia tests. Single neuron activity before injection and changes in the firing frequency and firing pattern occurring after injection have been analysed and compared for each cell recorded from GP and SNr, during periods of behavioural rest. Synchronised firing between cell pairs has also been assessed. However, the small number of cell pairs showing correlated firing in each structure after systemic injection of drugs was not statistically relevant for further analysis and interpretation of synchronised firing during drug induced akinesia. In our experiments, both drugs inhibited movement, albeit somewhat differently, with lack of rigidity and �flat� body position after adenosine stimulation. Dopamine blockade decreased mean firing rate and dramatically altered the firing pattern in both investigated structures, generally increasing burst activity (increased percentage of spikes in bursts, mean number of bursts, mean number of spikes per burst, mean intra-burst firing frequency) and decreasing regularity of firing (increased coefficient of variation of the inter-spike intervals). Increased burst activity in the rat basal ganglia in an acute model of parkinsonian akinesia, following systemic raclopride injections, confirmed the importance of changes in the firing pattern in PD. The only electrophysiological effect of systemic A2A stimulation was decreased mean firing rate in the GP, a weak effect that could not propagate towards output stations of the basal ganglia. The lack of changes in the firing pattern, at both input and output levels of the basal ganglia, suggests a correlation with the lack of rigidity in adenosine-stimulation-induced akinesia.
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Al-Ali, Asmaa M. H. "Understanding the role of dopamine D4 receptor regulation of mesolimbic dopamine function in a rat model of schizophrenia." Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/43047.
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The project concentrated on characterising the effect of D4 receptor activation in the context of an animal model relevant to schizophrenia (phencyclidine pretreatment) and elucidating the mechanisms involved. Behavioural studies measured selective attention to motivational stimuli, through measurement of latent inhibition of conditioned learning (LI), and episodic memory measured by novel object recognition (NOR), behaviours which are dysfunctional in schizophrenia. Subchronic PCP pre-treatment for five days disrupted LI and induced behavioural deficits in NOR, replicating previous findings using seven days pre-treatment. A412997 reversed deficit in NOR but not in LI. However, the neural the mechanisms these processes are as yet unclear. A better understanding of the physiology of cortical-limbic circuits is important in elucidating the neurophysiological mechanisms underlying dopamine-mediated processes which are vital for normal behaviour, and which may be abnormal in schizophrenia. The project examined the neuropharmacology underlying these behavioural processes, both in normal animals, and in animals pretreated with phencyclidine. Focusing on the role of D4 receptors. To achieve these aims fast-scan cyclic voltammetry was used to measure electrically stimulated dopamine release in nucleus accumbens, in rat brain slices in vitro. The selective dopamine receptor agonist A412997 caused a decrease in electrically stimulated dopamine release which was abolished in animals pretreated with PCP. This inhibitory effect of A412997 was blocked by D4 specific antagonist L-741,742. Gene expression of dopamine D4 receptors, as well as in other dopamine receptors (D1, D2, D3, D5) in response to sub-chronically pre-treated with PCP was significantly changed in different regions of rat brain, as well as these pre-treatment as modelling relevant to schizophrenia produced changes on the basal level of dopamine and its metabolites in the same brain areas. Taken together with behavioural data this demonstrated changes in D4-receptor mediated regulation of accumbal dopamine function after PCP pretreatment, suggesting a role for these receptors in schizophrenia.
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Jaworski, Jason Noel. "Effect of dopamine D2/D3 receptor antagonist sulpiride on changes in mesolimbic dopamine produced by amphetamine and ethanol /." Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3008360.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.Title from electronic title page (viewed Oct. 10, 2007). " ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Division of Medicinal Chemistry & Natural Products." Discipline: Medicinal Chemistry and Natural Products; Department/School: Pharmacy. On title page "2L" appears as subscript.