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1
Hilditch, A. "Pharmacological characterisation of peripheral dopamine receptors". Thesis, Open University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.352607.
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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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Obray, J. Daniel. "Peripheral Dopamine 2 Receptors Both Modulate Central Dopamine Release and Adopt in a Similar Manner to that of Central Dopamine 2 Receptors". BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/8983.
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Alcohol use disorder is a debilitating disorder affecting nearly 5% of people in the United States. Despite the prevalence of alcohol use disorder few affected individuals seek treatment and of those who do many will relapse. This highlights a need to develop new treatments for alcohol use disorder that are both more accessible and more effective. This dissertation characterizes a novel pathway involved in ethanol enhancement of dopamine levels in the nucleus accumbens as well as investigating alterations in dopamine 2 receptor expression and function following an acute dose of ethanol. This was done by using microdialysis to measure dopamine levels in the nucleus accumbens, single-unit recordings of dopamine neurons in the ventral tegmental area to measure dopamine neuron activity and place conditioning to measure the rewarding properties of the intravenous dopamine and ethanol. It was found that activation of peripheral dopamine 2 receptors by intravenous dopamine enhanced dopamine levels in the nucleus accumbens and dopamine neuron firing rate in the ventral tegmental area. Additionally, intravenous dopamine produced a modest conditioned place preference. Domperidone, a peripheral dopamine 2 receptor antagonist blocked each of these effects. Further, domperidone blocked ethanol enhancement of dopamine release in the nucleus accumbens and bidirectionally modulated the sedating effects of ethanol depending on the dose of ethanol administered. The involvement of peripheral dopamine 2 receptors in ethanol reward could not be ascertained in these studies as domperidone produced a weak conditioned place aversion. Finally, acute ethanol was found to enhance dopamine 2 receptor expression in the nucleus accumbens and medial prefrontal cortex while also enhancing dopamine 2 receptor expression on NK and B cells. Additionally, ethanol was found to reduce desensitization of dopamine 2 receptors in the ventral tegmental area. These results demonstrate that activation of peripheral dopamine 2 receptors can enhance dopamine levels in the nucleus accumbens and that this effect has relevance in understanding the effects of ethanol on dopamine release in the mesolimbic pathway. These results also provide evidence for transient upregulation of dopamine 2 receptors in the brain and on leukocytes suggesting that dopamine 2 receptor levels on leukocytes may be a useful biomarker for central dopamine function.
4
Evans, Anthony Mark. "Dopamine receptors of the cockroach salivary gland". Thesis, University of Edinburgh, 1990. http://hdl.handle.net/1842/27986.
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A study has been made of the secretory response and the electrical reponse (a hyperpolarization followed by a depolarization) mediated by dopamine receptors of the cockroach (Nauphoeta cinerea Olivier) salivary gland in-vitro. Although domperidone did not inhibit the electrical response to dopamine, three other actions were observed: one, post-synaptic, led to the potentiation of the hyperpolarization; this action was shared by (±)sulpiride. A separate post-synaptic action resulted in the inhibition of the depolarizing phase of the response. Finally a pre-synaptic action led to the abolition of the response to nerve stimulation.Effects of the calmodulin antagonists W7 and calmidazolium. In an attempt to investigate the role of calmodulin in stimulus-secretion coupling with the salivary gland, the actions of two calmodulin antagonists, W7 and calmidazolium, were studied. In high concentrations, but within the range in which they are known to inhibit calmodulin, W7 and calmidazolium were found to inhibit dopamine-induced secretion and hyperpolarize the acinar cells. The hyperpolarization was not inhibited by SGH23390, and resulted from an increase in cytosolic free calcium, released from the same source as that accessed by dopamine. Lower concentrations of these two antagonists caused submaximal secretion and potentiated dopamine-induced hyperpolarizations. An interpretation of these results is that calmodulin promotes secretion, and exerts a negative control on cytosolic free calcium by an independent process which can be selectively inhibited.
5
Hollis, Clare M. "Central and peripheral Dâ†1 dopamine receptors". Thesis, University of Kent, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292301.
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Clark, Kenneth Lyle. "Pharmacology of renal dopamine and angiotensin receptors". Thesis, Open University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293275.
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Dopamine and angiotensin II (Ang II) are naturally occurring molecules with profound but contrasting effects in the kidney. This study aimed to increase knowledge of the pharmacology and physiology of renal dopamine and angiotensin receptors. Little evidence was found to the presence of dopamine DA1 receptors, mediating dilatation, or angiotensin receptors, mediating constriction, in canine isolated main branch, interlobar, or arcuate renal artery rings. However, in anaesthetised dogs, renal vascular angiotensin and dopamine receptors were clearly demonstrated, suggesting that they are located primarily on renal resistance vessels. In anaesthetised dogs, intra-renal artery (i.r.a.) infusion of the selective dopamine DA1 agonist, fenoldopam, caused local dose-related vasodilatation, and a diuresis which appeared to be due to reduced tubular reabsorption. No evidence was found to suggest that subtypes of renal vascular and tubular dopamine DA1 receptors occur, since the renal vasodilator and diuretic responses to fenoldopam were blocked to a similar extent by the DA1 receptor antagonist, SCH 23390. The inhibitory effect of fenoldopam on renal tubular sodium reabsorption, and its vasodepressor activity were enhanced when angiotensin converting enzyme was inhibited. Thus, these effects may normally be limited by fenoldopam-induced renin release. Attempts to characterise renal tubular dopamine receptors in anaesthetised cats were unfruitful. Renal dopamine DA1 receptors could not be demonstrated in this species, and in contrast to literature reports, the diuretic response to intravenous infusions of dopamine seemed to be mediated by -adrenoceptors. In the renal and mesenteric vascular beds of anaesthetised cats, comparisons were made of the vasoconstrictor potency of Ang II relative to Ang III, and of the antagonist potency (versus Ang II) of the peptide antagonists, lle^7-Ang III and saralasin, and the novel, non-peptide angiotensin AT_1 receptor antagonist, DuP 753. The results suggest that angiotensin receptors in the renal vascular bed share similar broad characteristics to those in the mesenteric. Using lle^7-Ang III, DuP 753, and the non-peptide angiotensin AT_2 receptor ligand, PD 123,177, renal angiotensin receptor pharmacology was further studied in anaesthetised dogs. Tonic effects of endogenous Ang II on renal haemodynamic/tubular function, blood pressure, and aldosterone release appeared to be mediated by angiotensin AT_1 receptors. Similarly, AT_1 receptors appeared to mediate the effects of exogenous Ang II infusions (i.r.a.) on renal haemodynamic and tubular function. However, evidence was found suggesting the presence of subtypes of angiotensin AT_1 receptors on the renal arterioles. Moreover, the AT_2 ligand, PD 123,177 caused some inhibition of renal vasoconstrictor responses to high doses of Ang II, possibly indicating further heterogeneity of renal vascular angiotensin receptors. These findings, and their potential implications, are critically discussed.
7
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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8
Tong, Huaxia. "Modulation of NMDA receptor activity by dopamine receptors in the rat striatum". Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445880/.
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NMDA receptors are of particular importance in the control of synaptic strength and integration of synaptic activity. Dopamine receptor modulation of NMDA receptors in the striatum may influence the efficacy of synaptic transmission in the cortico-striatal pathway (Calabresi et al., 2000c Centonze et al., 2003) and if so, this modulation will be lost in Parkinson's disease. This change may be an important factor in the changes in the basal ganglia neural network that occur in Parkinson's Disease. In this thesis I have studied dopamine D1 and D2 receptor modulation of NMDA receptors in medium spiny neurons of 7-21 day old rat striatum. The dopamine D1 receptor agonist, SKF-82958, significantly decreased rat striatal NMDA receptor currents in patch-clamp whole-cell recordings from 7 day old rats. This inhibition was not abolished by application of a G protein inhibitor (GDP-p-S) or irreversible activator (GTP-y-S) suggesting a G protein-independent mechanism. In addition, intracellular application of protein tyrosine kinase inhibitors (lavendustin A or PP2) abolished D1 inhibition of NMDA currents. Functional NR2A receptors were absent in 7 day old rat striatum according to my experiments. Single-channel recordings showed that direct D1 receptor inhibition of NMDA receptors can not be observed in isolated membrane patches, which may indicate that D1 inhibition in whole-cell recordings is mediated by a change in NMDA receptor trafficking. Consistent with this hypothesis, intracellular application of a dynamin inhibitory peptide (QVPSRPNRAP) abolished D1 inhibition of NMDA receptor currents. I therefore conclude that a tyrosine kinase-dependent alteration of NMDA receptor trafficking underlies D1 dopamine receptor-mediated down-regulation of NMDA receptor currents in the striatum. The D2 class dopamine receptor agonist, quinpirole, significantly inhibited the NMDAR responses at 1 uM, but at a lower concentration (40 nM) there was no significant effect in 7 day old rat striatum. Replacement of GTP with GDP-P-S in the pipette solution abolished the inhibition induced by 1 uM quinpirole suggesting a G protein-dependent mechanism underlies the D2 family dopamine receptor modulation of NMDA receptors in the striatum.
9
Heusner, Carrie L. "Genetic analysis of striatal glutamate-dopamine interactions /". Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/9212.
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Oak, James N. "Characterization of epitope-tagged dopamine D¦4 receptors". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0001/MQ45554.pdf.
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Harper, Laura. "A[2A subscript] adenosine receptors, dopamine and reward". Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408638.
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12
Maguire-Robinson, Nicola Jane. "Expression and analysis of Dâ†2 dopamine receptors". Thesis, University of Kent, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311283.
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Wallace, Raye Ann. "The interaction of structural analogs of dopamine, chlorpromazine and sulpiride with striatal dopamine receptors /". The Ohio State University, 1987. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487586889186522.
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Castro, Diogo Sampaio e. "Functional studies on the orphan receptor Nurr1 and related retinoid receptors /". Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4608-6/.
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15
Worrall, S. "The purification of D2̲ dopamine receptors from bovine striatum". Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.377448.
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Abbott, W. M. "Immunological studies and partial purification of brain dopamine receptors". Thesis, University of Nottingham, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371990.
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Borcherding, Dana. "Human Adipocytes: Dopamine Receptors and the Regulation of Prolactin". University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1289945037.
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Kalani, M. Yashar S. Gray Harry B. "Structure and function studies of the human dopamine receptors /". Diss., Pasadena, Calif. : California Institute of Technology, 2004. http://resolver.caltech.edu/CaltechETD:etd-05042004-203854.
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Nkemdirim, Arinzechukwu Okere. "Effect of Melatonin and Dopamine in Site Specific Phosphorylation of Phosducin in Intact Retina". BYU ScholarsArchive, 2005. https://scholarsarchive.byu.edu/etd/758.
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Phosducin (Pdc) is a 28 kDa binding partner for the G protein beta gamma subunit dimer (G-beta-gamma) found abundantly in the photoreceptor cells of the retina and pineal gland. In the retina, light-dependent changes in cAMP and Ca2+ control the phosphorylation of Pdc at serine 73 and 54, respectively, which in turn controls the binding of Pdc to G protein beta gamma subunit dimer . G protein beta gamma subunit dimer binding has been proposed to facilitate light-driven transport of G protein beta gamma subunit dimer from the site of phototransduction in the outer segment of the photoreceptor cell to the inner segment, thereby decreasing light sensitivity and contributing to the process of light adaptation. Dopamine and melatonin are neuromodulators whose concentrations in the retina vary reciprocally during the circadian cycle, with dopamine high during the day and melatonin high during the night. Together, they control numerous aspects of light and dark adaptation in the retina. In this study, we have investigated the possible roles of dopamine and melatonin in regulating Pdc phosphorylation. Using phosphorylation-site specific antibodies to serines 54 and 73, we show that dopamine decreases the phosphorylation of both sites. This decrease is blocked by D4 receptor antagonists and pertussis toxin, indicating that dopamine causes a decrease in photoreceptor cell cAMP and Ca2+ concentration via the D4 receptor coupled to the Gi protein. Conversely, melatonin increases the phosphorylation of both S54 and S73, most likely via the inhibition of dopamine synthesis. These results demonstrate that dopamine and melatonin control the phosphorylation state of phosducin by changing the concentration of cAMP and Ca2+ in photoreceptor cells, and they suggest that dopamine and melatonin may contribute to the light-induced movement of the photoreceptor G protein by regulating Pdc phosphorylation.
20
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.
21
謝志恒 i 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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22
Sánchez, Soto Marta. "Noncanonical Neurotransmitter Activation of Catecholamine Receptors". Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/400298.
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From the D2‐like receptors (D2,D3, D4), only D4 receptor (D4R) has been described as “promiscuous” since it can be activated both by dopamine (DA) and norepinephrine (NE) and function as a noradrenergic receptor in the brain. However, there is no evidence for the other D2‐like receptors. In addition, D4R has a large number of polymorphisms, one of the variants, D4.7, has been associated with several neuropsychiatric disorders. The first aim of this thesis was to study the possible activation of D2‐like recptors (including the three main D4 variants, D2 short, D2 long and D3) by radiolabeled ligand binding and BRET‐based functional assays. Our results indicate that first, NE binds and activates D2‐like receptors and second, there are no differences in the signaling of D4R variants. In addition, the potency of DA and NE depends not only on the receptor but also on the G protein subtype.
The catecholamine NE is implicated in important brain functions and it binds to three receptor families. The α2A receptor (α2AR) is expressed in many brain regions and is particularly enriched in the striatum together with α2C (α2CR). The low levels of NE in the striatum led us to question what is the role of α2R there and hypothesize whether DA could provide the endogenous neurotransmitter of α2R in the striatum. Therefore, the second aim of this thesis was to study the activation of α2AR and α2CR by DA and dopaminergic ligands through radiolabeled binding experiments, activation of different subtypes of G protein and adenylyl cyclase inhibition. Surprisingly, the potencies of α2AR and α2CR for DA are very similar or even higher than for some D2‐like receptors. Thus, we can hypothesize that the DA in the striatum should reach enough concentration to activate α2AR and α2CR. In addition, these receptors are also targets for compounds previously described as D2‐like agonists. Particularly striking is the ability of the D3R and D4R agonists, 7‐OH‐PIPAT and RO‐105824 to bind and activate with high affinity α2AR i α2CR. Similar to the previous part, the efficacy and potency of ligands depends on the receptor and the G protein subtype.
Finally, is its well accepted that G protein‐coupled receptors (GPCRs) form homo‐, heteromers and high order oligomers. Since we had shown that DA and NE bind and activate D2‐like receptors and α2R, we wanted to study the activation of G protein mediated by the complexes formed by D4R variants, D4.4R and D4.7R, and D2R or α2R. In order to do that we used CODA‐RET (complemented donor‐acceptor resonance energy transfer) a technique that allows the study of the function of a signaling complex formed by two defined GPCRs and a subunit of the heterotrimeric G protein. Our results indicate that, although they physically interact, D4.7R is not implicated in the G protein activation when is forming complexes with D2R or α2AR. Also, there are no differences in the potency or efficacy of the endogenous neurotransmitters DA and NE with D4.4R and D4.7R monomers or homodimers, but the association with D2R or 2AR discloses differences between the two D4R variants. Finally, we found important differences in the potency and efficacy dopaminergic ligands for the different receptor complexes that could be important for some neuropsychiatric diseases.Dels receptors D2‐like de dopamina (D2, D3, D4) només el D4 (D4R) s’ha descrit com a “promiscu” ja que pot ser activat tant per dopamina (DA) com per noradrenalina (NE); en canvi, no hi ha evidències de que això sigui cert per la resta de receptors D2‐like. A més, el D4R és un receptor molt polimòrfic i una de les seves variants, la D4.7, s’ha associat a desordres psiquiàtrics. El primer objectiu va ser estudiar la possible activació dels receptors D2‐like (D2S, D2L, D3 i les tres variants més prevalents de D4) per NE mitjançant estudis d’unió de radiolligands i assajos funcionals de BRET. Els resultats mostren que primer, la NE s’uneix i activa els receptors D2‐like i segon, no hi ha diferències en la senyalització de les variants de D4R. El receptor α2A (α2AR) adrenèrgic s’expressa en moltes zones cerebrals i està particularment enriquit a l’estriat junt amb el receptor α2C (α2CR). Els baixos nivells de NE a l’estriat donen peu a la possibilitat de que la DA sigui el neurotransmissor endogen de α2AR i α2CR. Per tant, el segon objectiu de la tesi va ser estudiar l’activació de α2AR i α2CR per DA i lligands dopaminèrgics mitjançant estudis d’unió de radiolligands, activació de diferent proteïnes G i inhibició d’adenilat ciclasa. Sorprenentment les potències de α2AR i α2CR per la DA són molt similars o inclús més altes que per alguns receptors D2‐ like. Per tant és probable que els nivells de DA a l’estriat siguin suficients per activar α2R. A més, aquests receptors també són activats per compostos prèviament descrits com agonistes dels receptors D2‐like com ara el 7‐OH‐PIPAT (D3R) i el RO‐105824 (D4R). A més, tant l’eficàcia com la potència dels lligands depèn del receptor i del subtipus de proteïna G. Per últim, els GPCRs poden formar dímers, heteròmers o entitats superiors. A la tercera part vam voler comparar l’activació de proteïna G per DA i NE mitjançant complexes entre dues de les variants de D4R, D4.4R i D4.7R amb D2R i α2AR. Els resultats indiquen que hi ha diferències en l’activació dels diferents complexes que podria tenir importància en malalties com RLS i Parkinson. A més, donen suport a la teoria de que les diferències entre les variants de D4R es troben en la seva interacció amb altres receptors.
23
Baxter, Andrew Douglas. "Enantioselective synthesis of aminotetralins : novel synthetic applications of amino acids". Thesis, University of East Anglia, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359328.
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Casadó, Anguera Verònica. "Allosteric interactions between catecholamine receptors and other G protein-coupled receptors: Pharmacological and functional characterization". Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/586262.
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Catecholamines, including dopamine (DA) and norepinephrine (NE), are widely distributed in the body and constitute a class of conventional neurotransmitters and hormones that occupy key positions in the regulation of physiological processes and in the development of neurological, psychiatric, endocrine and cardiovascular diseases. There is a linkage between a variety of genes related to DA (e.g. D4 receptor) and NE (e.g. α2A-adrenoceptor) and the vulnerability for developing attention deficit hyperactivity disorder (ADHD), which is characterized by pervasive symptoms of inattention, impulsivity and/or hyperactivity. In addition, adenosine, acting on adenosine receptors (AR), is a modulator of other receptors such as D1-like and D2-like DA receptors (DR). DA and adenosine receptor complexes are involved in the control of the direct and indirect pathway of motor control in basal ganglia, in which adrenergic receptors are also involved.
NE, DA and adenosine receptors belong to the GPCR family, also known as seven transmembrane domain receptors. GPCRs have an enormous biomedical importance. It is estimated that about 35% of approved drugs target GPCRs. Thus, is not surprising that lots of models have been developed in order to explain the pharmacological behavior of these receptors. A large number of GPCRs have been described to form homodimers, heterodimers and higher order oligomers with different pharmacological and functional properties than of its individual components.
The aim of this Thesis has been to study and characterize the molecular interactions at pharmacological and functional level of heterodimers between catecholamine receptors and between catecholamine and adenosine receptors involved in several neurological pathologies related to imbalances in attention, impulsivity and motor control.
For simplicity, for pharmacologically characterize GPCRs, most of the developed models consider them as monomeric entities. Thus, it is not surprising that, when working with receptor dimers but using monomeric models, some parameters obtained may be erroneous. Then, first of all, we went deeper into the study of allosteric interactions within GPCRs using the dimer receptor model, which considers GPCRs as dimers.
Along our study, we have given further evidences that homodimers are the GPCR predominant species, and that allosteric interactions between orthosteric ligands of the different protomers of a GPCR heteromer, have important implications in the field of catecholamine receptor pharmacology. A paradigmatic example of complex allosteric interactions is the A2AR-A2AR-D2R-D2R-Gs-Gi-AC5 heteromer. Moreover, since bivalent ligands are the best example of oligomer selective-ligands that can interact simultaneously with GPCR dimers with high affinity and subtype selectivity, we have developed a precise strategy for developing them. Using computational tools that considered the TM interfaces, distances between orthosteric binding sites and the mode of interaction of the pharmacophore units, we have higher success in affinity results. In particular, the obtained GPCR bivalent ligand had a picomolar binding affinity for the dopamine D2 receptor (D2R) homodimer. However, to obtain oligomer-selective bivalent ligands, the selected pharmacophores must be highly specific. This is not always easy to find. As an example, we have demonstrated that catecholamine receptors constitute a “functional” family of GPCRs. Specifically, in this study we have shown that DA and synthetic DA receptor ligands are able to bind to α2Rs and activate the same signaling pathways as NE. In addition, we have demonstrated the existence of functional D4R-D2SR in vitro and, for the first time, functional D4R-α2AR heteromers in vitro and in rodent brain tissues not only with the D4.4R but also with the D4.7R variant, prevalent in ADHD. Significant different properties of these heteromers were D4R variant-dependent. Finally, given that D2R, D4R and α2AR, are involved in the pathophysiology of ADHD, we suggest that D4R-D2R and α2AR-D4R heteromers could be target for the therapeutic treatment of such neurological disorders.Les catecolamines dopamina (DA) i norepinefrina (NE) tenen una funció clau en la regulació de processos fisiològics i en el desenvolupament de diverses patologies. Existeix una correlació entre gens relacionats amb la DA (com el receptor D4) i amb la NE (com el receptor α2A) i la vulnerabilitat per desenvolupar el trastorn per dèficit d’atenció i hiperactivitat (TDAH). A més, l’adenosina, actuant sobre els receptors d’adenosina (AR), és un modulador dels receptors de DA tipus D1 i D2, que controlen el moviment als ganglis basals, on també es troben implicats els adrenoreceptors. Els receptors de NE, DA i adenosina pertanyen a la família dels GPCR, que té una gran importància biomèdica, essent diana d’un 35% dels fàrmacs aprovats. És conegut que els GPCRs formen homodimers, heterodimers i oligòmers més complexos amb noves propietats farmacològiques i funcionals. En aquesta Tesi hem caracteritzat les interaccions moleculars entre receptors de catecolamines i entre receptors de catecolamines i d’adenosina, involucrats en patologies neurològiques relacionades amb l’atenció, la impulsivitat i el control motor. Concretament, hem donat evidències que els homodimers de GPCRs són les espècies predominants a l’organisme i que les interaccions alostèriques entre lligands ortostèrics dins un heteròmer tenen importants implicacions farmacològiques. També hem generat un protocol de síntesis de lligands bivalents molt eficient. Aquests lligands permeten actuar sobre un oligòmer concret, minimitzant els efectes secundaris en comparació amb fàrmacs dirigits a monomèrs. Hem demostrat que els receptors de catecolamines constitueixen una mateixa família funcional donada la promiscuïtat entre els seus lligands. Finalment, hem descrit l’existència de complexos entre els receptors D4 i D2S i entre D4 i α2A, trobant diferències funcionals segons la variant del receptor D4 involucrada. Donat que els receptors D2R, D4R i α2AR estan involucrats en el TDAH, aquests heteròmers poden ser una nova diana terapèutica per a aquesta patologia.
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Sickler, Thaís de Paula. "Análise da expressão da filamina A nos tumores hipofisários e suas implicações clínicas e terapêuticas". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-08052018-083923/.
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A filamina A (FLNA) é uma proteína de citoesqueleto com diversas funções, dentre as quais estão motilidade celular e ancoragem de receptores de membrana. A alteração de sua expressão foi anteriormente descrita em diversos tipos de neoplasia. Em tumores hipofisários, demonstrou-se que sua expressão se correlacionou à expressão de receptores de dopamina tipo 2 (DRD2) em prolactinomas, e com a sinalização intracelular do receptor de somatostatina tipo 2 (SSTR2) após ativação por agonista, em somatotropinomas. Neste estudo, avalariam-se a expressão da FLNA, DRD2, SSTR2 e SSTR5 em diversos tumores hipofisários: prolactinomas, somatotropinomas, corticotropinomas e adenomas clinicamente não funcionantes (ACNF). Avaliou-se também a correlação entre a expressão da FLNA e resposta aos tratamentos medicamentosos, com agonista dopaminérgico (AD) ou com ligantes do receptor de somatostatina (LRS), e entre FLNA e as características de invasividade e/ou agressividade tumorais. Houve correlação entre a expressão de FLNA e a expressão de DRD2 e, entre FLNA e a resposta ao AD, nos ACNFs. Nos corticotropinomas, houve correlação entre a expressão da FLNA e critérios de invasividade tumoral. Portanto, o papel da FLNA nos tumores hipofisários pode depender do tipo celular implicado. Além disso, o envolvimento da FLNA nos mecanismos de resistência aos medicamentos utilizados nos tumores hipofisários, AD ou LRS, não deve estar relacionado apenas à sua ação na ancoragem e reciclagem dos receptores DRD2 e SSTRs, mas também à sua ação na motilidade celular, propiciando caratecterísticas de invasividadeFilamin A (FLNA) is a cytoskeletal protein with a variety of functions, including cell motility and membrane receptor anchorage. Changes in FLNA expression has already been described in several types of neoplasia. In pituitary tumors, its expression has been shown to correlate with the expression of dopamine type 2 receptors (DRD2) in prolactinomas and with intracellular somatostatin type 2 receptor (SSTR2) signaling after agonist activation in somatotropinomas. The expression of FLNA, DRD2, SSTR2 and SSTR5 in different pituitary tumors: prolactinomas, somatotrophinomas, corticotrophinomas and clinically nonfunctioning adenomas (CNFA) were evaluated. We also correlate FLNA expression to sensibility to drug treatments with dopamin agonists (DA) or somatostatin receptor ligands (SRL), and to tumor invasiveness and/or aggressiveness. Positive correlation between FLNA expression and DRD2 expression and between FLNA and DA response were found in CNFA. In corticotrophinomas, there was correlation between FLNA expression and tumor invasiveness. Therefore, the role of FLNA in pituitary tumors seems to depend on the cell type involved. Additionally, FLNA involvement in the mechanisms of drug (DA or SRL) resistance in pituitary tumors could not be related only to its action in the anchoring and recycling of DRD2 and SSTR receptors, but also to its action on cellular motility and invasiveness
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SANTOS, Anderson Felipe da Silva. "Expressão tecidual dos receptores dopaminérgicos D1 no Núcleo Accumbens e estriado de ratas desnutridas". Universidade Federal de Pernambuco, 2015. https://repositorio.ufpe.br/handle/123456789/16607.
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A desnutrição durante o período perinatal tem sido associada a aumento da compulsão alimentar, preferência por alimentos palatáveis e risco de desenvolvimento de obesidade na vida adulta. O apetite é controlado por vários sistemas fisiológicos, dentre os quais o sistema neural de recompensa. A dopamina é um conhecido neurotransmissor deste sistema, estando envolvida nas relações de prazer proporcionado por alimentos e drogas, agindo através da ligação em receptores neuronais, de duas classes: D1-like e D2-like. O objetivo deste trabalho foi avaliar a expressão dos receptores dopaminérgicos D1 no Núcleo Accumbens e estriado, áreas relacionadas ao comportamento alimentar, em ratas desnutridas. Dois grupos experimentais foram formados: grupo-controle (CF - fêmeas gestadas por mães normonutridas durante a gestação e lactação) e grupo-desnutrido (DF - fêmeas gestadas por mães que receberam dieta hipoprotéíca no período perinatal). Os animais passaram a receber dieta-padrão de laboratório após o desmame e tiveram o peso avaliado em diferentes momentos da vida. No 120º dia, foram sacrificadas e submetidas à perfusão, para retirada dos encéfalos. Após os cortes dos cérebros em micrótomo de congelamento, procedeu-se a Imunohistoquímica para contagem de neurônios marcados para DRD1. As imagens foram obtidas através de câmera acoplada ao microscópio óptico e a morfometria realizada no software livre ImageJ. Os dados estatísticos foram expressos em média±desvio-padrão, sendo analisados no software livre GraphPad Prism 5. Os animais desnutridos apresentaram menor peso em relação aos normonutridos desde o nascimento até o sacrifício. Não foi encontrada diferença significativa entre os grupos na expressão de DRD1 nas áreas cerebrais analisadas (Estriado: CF: 230,0 ± 86,40, n=4; DF: 225,50 ± 89,90, n=4; Núcleo Accumbens: CF: 109,80 ± 41,40, n=4; DF: 128,0 ± 49,50, n=5; test t de Student, p<0,05). Estes dados sugerem que a expressão dos receptores D1 está diretamente relacionada à quantidade de dopamina liberada na fenda sináptica, quantidade essa que é maior na apresentação de alimentos novos e palatáveis.
Malnutrition during the perinatal period has been linked to increased binge eating, preference for palatable foods and risk of obesity developing in adulthood. Appetite is controlled by several physiological systems, including the neural reward system. Dopamine is a neurotransmitter in this system and it is involved in relations of pleasure provided by foods and drugs, acting through its binding to neuronal receptors of two classes: D1-like and D2-like. The goal of this study was to evaluate the expression of dopamine D1 receptors in the striatum and Nucleus Accumbens, areas related to feeding behavior, in malnourished rats. Two experimental groups were formed: the control group (CF - rats coming from normonutridas mothers during pregnancy and lactation) and group-malnourished (DF - coming rats of mothers who received low protein diet during the perinatal period). The animals began to receive standard laboratory diet after weaning and had the weight assessed at different times of life. In 120 days, they were sacrificed and submitted to perfusion, to remove the brains. After the cuts of the brains in freezing microtome, it proceeded to Immunohistochemistry for counting neurons marked for DRD1. The images were obtained through camera coupled to an optical microscope and morphometry performed on the Free Software ImageJ. Statistical data were expressed as mean ± standard deviation and analyzed the free software GraphPad Prism 5. Malnourished animals showed lower weight compared to well-nourished from birth to the sacrifice. There was no significant difference between groups in the expression of DRD1 the analyzed brain areas (Striatum: CF: 230.0 ± 86.40, n = 4; DF: 225.50 ± 89.90, n = 4; Nucleus Accumbens: CF: 109.80 ± 41.40, n = 4; DF: 128.0 ± 49.50, n = 5; Student's t test, p <0.05). These data suggest that the expression of D1 receptors is directly related to the amount of dopamine released in the synaptic cleft, which amount is higher in presenting new and palatable food.
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Kostrzewa, Richard M., John P. Kostrzewa, Russell W. Brown, Przemyslaw Nowak i 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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Ng, Gordon Y. K. "Biochemical and pharmacological studies on dopamine D1 and D2L receptors". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ35444.pdf.
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Lane, Jonathan R. D. "The G protein-coupling specificity of D2-like dopamine receptors". Thesis, University of Glasgow, 2007. http://theses.gla.ac.uk/30/.
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The G-protein coupling specificity of D2-like dopamine receptors was investigated using both receptor-G protein fusions and membranes of cells in which pertussis toxin-resistant mutants of individual Gi-family G proteins could be expressed in an inducible fashion. A range of ligands displayed agonism at the long isoform of the human dopamine D2 receptor. However, varying degrees of efficacy were observed for individual ligands as monitored by their capacity to load [35S] GTPγS onto each of Gi1, Gi2, Gi3 and Go1. By contrast, S-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine (S-(-)-3PPP) was a partial agonist when Go1 was the target G protein but an antagonist/inverse agonist at Gi1, Gi2, Gi3. In ligand binding assays dopamine identified both high and low affinity states at each of the dopamine D2 receptor-G protein fusion proteins and the high affinity state was eliminated by guanine nucleotide. S-(-)-3PPP bound to an apparent single state of the constructs where the D2 receptor was fused to Gi1, Gi2 or Gi3. However, it bound to distinct high and low affinity states of the D2 receptor-Go1 fusion with the high affinity state being eliminated by guanine nucleotide. Similarly, although dopamine identified guanine nucleotide-sensitive high affinity states of the D2 receptor when expression of pertussis toxin-resistant forms of either Gi2 or Go1 was induced, S-(-)-3PPP identified a high affinity site only in the presence of Go1. These results demonstrate S-(-)-3PPP to be a protean agonist at the D2l receptor and may explain in vivo actions of this ligand. Furthermore, in agreement with previous studies, the ability of the dopamine D2l receptor to couple promiscuously to Gαi1-3, and Gαo1 was demonstrated. However, despite high homology between dopamine D2l and D3 receptors, the G protein-coupling specificity of the D3 receptor has not been well characterised. Again using both receptor-G protein fusions and membranes of cells in which pertussis toxin-resistant mutants of individual Gi-family G proteins could be expressed in an inducible fashion, we confirmed the selective coupling of the D3 receptor to Gαo1. A range of ligands displayed agonism at the D2l receptor and the D3 receptor when coupled to Gαo1. As a general trend, agonists, including dopamine, displayed a higher potency at the D3 receptor. This perhaps reflects the role of D3 as an autoreceptor. Of particular interest was the demonstration that S-(-)-3PPP has both a higher efficacy and potency at the D3 receptor when coupled to Gαo1. The investigations into dopamine receptor-G protein coupling highlighted the utility of the [35S]GTPγS binding assay as a method of directly measuring receptor catalysed nucleotide exchange on the α subunit of G proteins. However, the expense associated with the use of radiolabels makes this assay less attractive, particularly for high-throughput screening programmes. In an attempt to develop a non-radioactive assay equivalent to the [35S] GTPγS assay an immunisation programme was initiated to generate antibodies selective against the active (GTP bound) conformation of G proteins. 4 way primary screening of 1632 hybridomas generated from mice immunized with GTPS-loaded Gi1 and isolated using an automated robotic colony picker, identified 3 antibodies that interacted with the constitutively active Q204L but neither the constitutively inactive G203A nor wild type form of Gi1. This profile extended to other closely related Gi-family G proteins but not to the less closely related Gs and Gq/G11 families. Each of these antibodies was, however, also able to identify wild type, GDP-bound Gi- family G proteins in the presence of AlF4- which mimics the presence of the terminal phosphate of GTP and hence generates an active conformation of the G protein. Stimulation of cells co-expressing a wild type Gisubunit and the dopamine D2 receptor with the agonist ligand nor-apomorphine also allowed these conformation selective antibodies to bind the G protein. Such reagents allow the development of label- free assays for G protein-coupled receptor-mediated activation of Gi- family G proteins.
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Gutierrez, Arnold. "The role of dopamine receptors in methamphetamine-induced cognitive deficits". University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1521189209471948.
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Castelo-Branco, Gonçalo de Sá e. Sousa de. "Wnt signalling in the development of ventral midbrain dopaminergic neurons /". Stockholm, 2004. http://diss.kib.ki.se/2005/91-7140-176-8/.
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Gravel, Paul. "Positron emission tomography of extra-striatal dopamine release". Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112625.
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Altered dopamine (DA) neurotransmission is implicated in neurological and psychiatric disorders. Positron Emission Tomography (PET) imaging of DA release has mainly been restricted to striatal areas, rich in D2/D 3 receptors, owing to the moderate affinity of the radioligands used. To measure extra-striatal DA release, where D2/D3 receptor concentrations are much smaller, an approach using a high affinity radioligand, such as [18F]Fallypride, is required. The aim of the present study was to investigate in healthy volunteers the suitability of [ 18F]Fallypride to measure variations in D2/D3 receptor occupancy, as a function of amphetamine-induced DA release, in extra-striatal regions. Six healthy male volunteers underwent two 18F-Fallypride PET sessions, following the double-blind oral administration of 0.3 mg/kg of d-amphetamine (Dexedrine) or placebo (lactose), counter-balanced for order. Following amphetamine administration, D2/D3 receptor occupancy of 18F-Fallypride was significantly reduced in striatum, but also in extra-striatal regions, including substantia nigra, amygdala, thalamus, hippocampus, and cortical areas.
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Rodvelt, Kelli Renee. "Acute & subchronic NMDA receptor blockade alters nicotine-evoked dopamine release". Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/5060.
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Thesis (M.A.)--University of Missouri-Columbia, 2007.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on April 10, 2009) Includes bibliographical references.
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Leonard, M. N. "Studies on the potential heterogeneity of D2̲ dopamine receptors from bovine and rat brain". Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381474.
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Mason, Sarah. "Post-mortem neuropharmacological studies of human and rat brain relating to schizophrenia and antipsychotic drug action". Thesis, University of Sheffield, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364237.
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Hara, Yuko. "Dopamine-dependent plasticity and subcellular locations of dopamine D1 receptors : in relation to glutamate NMDA receptors and endogenous opioids in the nucleus accumbens, implications for schizophrenia /". Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1528441261&sid=22&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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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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Gardner, B. "Elucidating the mechanisms of agonist action at Dâ†2 dopamine receptors". Thesis, University of Kent, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283973.
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Marston, Deborah Louise. "Expression and characterisation of dopamine Dâ†2â†S and olfactory receptors". Thesis, University of Reading, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339980.
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Avalos, Melva Nidia. "Partial agonist interactions with dopamine in clonal cell lines expressing recombinant receptors : towards a molecular model of antipsychotic drug action /". Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.
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Karasinska, Joanna Monika. "Functional interactions of D1 and D3 dopamine receptors, generation and behavioural assessment of mice lacking both receptors". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0023/MQ50451.pdf.
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Romanholi, Daniella de Jesus Patrick Carminatti. "Efeito da administração de octreotide, cabergolina e a associação de ambos nos níveis de ACTH e cortisol em pacientes com doença de Cushing: correlação da resposta clínica com a expressão tumoral dos receptores de dopamina (DRD2) e de somatostatina (SSTR2 e SSTR5)". Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-21092010-095750/.
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Introdução: A doença de Cushing apresenta elevada morbimortalidade. Seu tratamento de escolha é a cirurgia transesfenoidal que possui resultados satisfatórios em cerca de 70% dos casos. Na doença persistente ou recorrente, reabordagem cirúrgica, radioterapia e adrenalectomia bilateral podem ser realizadas, porém, essas opções apresentam como desvantagens o desenvolvimento de hipopituitarismo e a dependência de terapia de reposição. Até o momento, nenhuma droga tem se mostrado eficaz no tratamento do corticotrofinoma. Os esquemas terapêuticos mais eficazes são os inibidores da esteroidogênese que não atuam no tumor hipofisário. Objetivos: avaliar o efeito do octreotide e da cabergolina administrados isoladamente e em associação nas concentrações urinárias de cortisol e plasmáticas de ACTH em pacientes com corticotrofinomas; correlacionar esse efeito com a expressão tumoral dos receptores SSTR2, SSTR5 e DRD2; correlacionar a expressão tumoral desses receptores através de RT-PCR quantitativa e imunohistoquímica; avaliar se o uso prévio dessas drogas altera a expressão desses receptores. Casuística e Métodos: grupo controle composto por 11 pacientes (10 mulheres e 1 homem) entre 21 e 43 anos sem tratamento prévio à neurocirurgia e um grupo tratado formado por 11 pacientes (2 homens e 9 mulheres) entre 22 e 53 anos que receberam o seguinte tratamento antes da cirurgia: coleta de três amostras de cortisol urinário e ACTH plasmático, seguida da introdução de octreotide 100 g, subcutâneo, 8/8h durante 30 dias e nova coleta de três amostras de cortisol urinário e ACTH plasmático. Em seguida, iniciou-se a cabergolina 0,5 mg via oral 3 vezes na semana durante 30 dias com nova coleta de três amostras de cortisol urinário e ACTH plasmático. A seguir, o octreotide era associado por mais 30 dias com nova coleta de três amostras de cortisol urinário e ACTH plasmático. Resultados: Os valores de cortisol urinário apresentaram queda significante após o uso de cabergolina isolada (P = 0,016) e em associação ao octreotide (P = 0,012). A eficácia do tratamento combinado não foi maior que a da cabergolina isolada. Os valores de ACTH plasmático não revelaram diferença significante durante o tratamento e não se correlacionaram com os valores de cortisol. A média de expressão do mRNA do gene DRD2 foi maior no grupo tratado (1,170 ± 0,417) quando comparada ao grupo controle (0,776 ± 0,252) (P = 0,036). Houve dissociação entre os conteúdos de mRNA e da proteína desse receptor. Não foi possível analisar a expressão do mRNA do gene SSTR5, pois o tratamento das amostras com DNAse causou degradação do RNA. A imunorreatividade para SSTR5 esteve presente em todos os pacientes e não foi alterada pelo tratamento prévio. Não houve diferença estatística na expressão do gene SSTR2 entre os grupos controle (1,253 ± 0,511) e tratado (1,267 ± 0,386) bem como diferença significante da imunoexpressão do SSTR2 entre os grupos. Houve correlação entre os conteúdos de mRNA e da proteína desse receptor (P = 0,021). Não houve correlação entre a expressão dos receptores analisados e a resposta ao octreotide e à cabergolina isoladamente ou em associação. Conclusões: a cabergolina isolada representa opção terapêutica na doença de Cushing persistente ou recorrente. A associação de octreotide na dose estudada por 30 dias não foi mais eficiente em reduzir o cortisol urinário. A resposta a essas drogas não está relacionada à expressão dos receptores SSTR2, SSTR5 e DRD2Introduction: The Cushings disease presents high morbimortality. Its treatment of choice is transsphenoidal surgery which has satisfactory results in about 70% of cases. In persistent or recurrent disease, a second transsphenoidal surgery, radiotherapy and bilateral adrenalectomy can be carried through, however, these options present disadvantages as development of hypopituitarism and lifelong dependence on hormone replacement therapy. Presently, no drug has shown efficacy in corticotrophinomas treatment. The most efficient agents are the inhibitors of steroidogenesis which have no effect at pituitary tumor. Objectives: To evaluate isolated octreotide and cabergoline effects and their association on plasma ACTH and urinary cortisol in Cushings disease patients, to correlate this effect with tumoral expression of SSTR2, SSTR5 and DRD2 receptors; to correlate tumoral expression of these receptors by quantitative RT-PCR and immunohistochemistry; to evaluate whether these drugs modifies these receptors expression. Patients and methods: control group with 11 patients (10 women and 1 man) between 21 and 43 years who underwent pituitary surgery with no prior treatment and a treated group with 11 patients (2 men and 9 women) between 22 and 53 years that received the following treatment before surgery: : after three baseline urinary cortisol samples and one plasma ACTH sample, patients received octreotide 100 g, subcutaneous 8/8h for 30 days collecting three urinary cortisol samples and one plasma ACTH. After that, cabergoline was introduced 0,5 mg 3x/week for 30 days collecting three urinary cortisol samples and one plasma ACTH sample. Then, octreotide was associated to cabergoline for another 30 days followed by three urinary cortisol and one plasma ACTH sample. Results: Urinary cortisol concentrations significantly decreased after isolated and combined cabergoline use (P = 0,016 and P = 0,012, respectively). Combined treatment efficacy was not greater than isolated cabergoline administration. Plasma ACTH did not change statistically during treatment and did not correlate with urinary cortisol. The average of DRD2 gene expression was higher in control group (0,776 ± 0,252) in relation to treated group (1,170 ± 0,417) (P = 0,036). It had dissociation between mRNA and protein contents of this receptor. SSTR5 gene mRNA expression was not analyzed due to RNA degradation after DNAse tissue treatment. SSTR5 immunoreactivity was present in all patients and it was not modified by previous treatment. No statistic difference was observed between SSTR2 gene expression in control group (1,253 ± 0.511) and in treated group (1,267 ± 0,386). There was no significant difference in SSTR2 immunoexpression between groups. It had correlation between the mRNA and protein contents of this receptor (P = 0.021). No significant relationship was found between hormonal response to isolated and combined therapy and receptors mRNA expression levels. Conclusions: cabergoline represents therapeutical option in persistent or recurrent Cushings disease. Octreotide-cabergoline association in the studied dosage and for the period of 30 days was not more efficient in eliciting urinary cortisol reduction. The responsiveness to these drugs did not correlate to SSTR2 and DRD2 mRNA expression
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Andersson, Daniel. "Dopamine and the regulation of movements : significance of nigral and striatal dopamine release in normal, hemiparkinsonian and dyskinetic rats /". Göteborg : Dept. of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, 2009. http://hdl.handle.net/2077/19327.
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Sousa, Kyle Matthew. "Nuclear receptor and Wnt function in developing dopaminergic neurons /". Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-105-0/.
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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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Zhang, Boyang. "Functional and Structural Insights into the First and Second Intracellular Domains for D1-Class Dopaminergic Receptors". Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35932.
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Previous studies have shown that the subtype-specific pharmacological properties of D1-class receptors (D1R and D5R) can be attributed to their third intracellular domain and C-terminal tail. However, the importance of their first and second intracellular domains (IC1 and IC2) has yet to be explored. Using mutagenesis and bioinformatics, we examine the functional and structural roles of Ser/Thr spanning IC1 and IC2—most of which are conserved not only among D1-class receptors but also among other GPCRs. Mutant receptors of human D1-class receptors (hD1R and hD5R) were constructed whereby all Ser and Thr were mutated to the respective Ala and Val in the IC1 region (termed ST1 mutant receptors) and in the IC2 region (termed ST2 mutant receptors). We found that hD1-ST2 and hD5-ST2 exhibited contrasting properties of agonist affinity, constitutive activity, and dopamine potency. On the other hand, both ST2 mutants underwent internalization as wild-type but displayed weakened desensitization abilities. Homology models, which have been refined under membrane simulations, illustrate that the conserved Ser3.55 and Thr3.65 utilize their side chains to anchor the loop regions of IC2 to cytoplasmic helices. We also found multiple functional alterations in the hD1-ST1 and hD5-ST2, but in a subtype-similar manner. Mutating the conserved Thr2.39 recapitulated the ablated basal activity and drastic decrease in dopamine potency previously witnessed in the hD1-ST1. Based on the recurring theme observed in crystal structures, the side-chain of Thr2.39 may help to position IC2 to have proper contacts with the G protein. Mutating the conserved Ser2.45 was found to be solely responsible for the elevated Emax (maximal response) of the hD1-ST1. Using single point mutagenesis, we further found that breaking the potential molecular interactions of Ser2.45 in hD1R (i.e. with Asn3.42 and Trp4.50) mimicked its elevated Emax. This elevated Emax was not found to be caused by altered abilities to undergo agonist-induced desensitization or internalization relative to hD1R. Overall, our work highlights the important functional and structural roles of IC1 and IC2 that needs to be accounted for in our current canonical models of GPCR signalling. Given the conserved nature of these Ser/Thr, our work may also be pertinent towards understanding the roles of IC1 and IC2 for other GPCRs.
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Gong, Li. "Co-sensitization of Dopamine and Serotonin Receptors Occurs in the Absence of a Change in the Dopamine D1 Receptor Complex After a Neonatal 6-ohda Lesion". Digital Commons @ East Tennessee State University, 1993. https://dc.etsu.edu/etd/2686.
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To test whether SKF 38393 could ontogenetically sensitize dopamine (DA) D$\sb1$ receptors and whether this sensitization would be associated with biochemical changes, intact and neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats (200 $\mu$g i.c.v.) were treated daily from birth with SKF 38393 (3.0 mg/kg i.p. x 28 days) or its vehicle. In DA D$\sb1$ neonatally sensitized 6-OHDA rats, enhanced locomotor responses were observed with the first SKF 38393 challenge dose (3.0 mg/kg i.p.) at 6 weeks. This response increased further with weekly SKF 38393 treatments. Enhanced stereotyped behaviors were seen in both lesioned and sensitized rats at 8 weeks. There was no change in the percentage of high affinity D$\sb1$ sites in these groups of rats. Striatal mRNA levels for D$\sb1$ receptors were reduced in the lesioned rats, but restored to control level after treatments with SKF 38393 in adulthood. Basal, DA-, NaF- and forskolin-stimulated adenylate cyclase activities were similar among treatment groups. Striatal DA content was reduced ($>$99%), whereas serotonin (5-HT) content was elevated ($>$50%) in the 6-OHDA groups. To study possible interaction between DA and 5-HT systems, the effects of a series of 5-HT agents on the induction of oral activity were determined. The 5-HT$\sb{\rm 1C}$ receptor agonist, m-chlorophenylpiperazine (m-CPP), produced a marked increase in oral activity in 6-OHDA-lesioned rats. The respective 5-HT$\sb{\rm 1A}$ and 5-HT$\sb{\rm 1B}$ agonists, 8-OH-DPAT and CGS-12066B did not increase oral activity. The m-CPP-induced oral response in the lesioned rats was attenuated by mianserin, a 5-HT$\sb{\rm 1C}$ antagonist, but not by ketanserin or MDL-72222, 5-HT$\sb2$ and 5-HT$\sb3$ antagonists, respectively. Although the supersensitized oral response of lesioned rats to m-CPP was not attenuated by SCH 23390, the enhanced response of SKF 38393 was attenuated by mianserin. Additionally, mRNA levels for 5-HT$\sb{\rm 1C}$ receptor were not altered in both intact and lesioned rats. These findings demonstrate that ontogenetic treatments of neonatal 6-OHDA-lesioned rats with a D$\sb1$ agonist produce partial sensitization of DA D$\sb1$ receptors in adulthood without altered biochemical markers, and that this neonatal lesion is associated with both supersensitized DA D$\sb1$ and 5-HT$\sb{\rm 1C}$ receptors. Moreover, induction of oral activity by DA agonists is mediated via a serotonergic system.
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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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Sóvágó, Judit. "Methodological advances in the examination of the dopamine system in brain /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-552-6/.
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Mestlin, Monja. "Effects of dopamine D1 and D2 receptor inactivation on locomotor activity and sniffing in 11- and 17-day-old rats". CSUSB ScholarWorks, 1992. https://scholarworks.lib.csusb.edu/etd-project/785.
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