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1
Livingstone, C. D., P. G. Strange, and L. H. Naylor. "Molecular modelling of D2-like dopamine receptors." Biochemical Journal 287, no. 1 (October 1, 1992): 277–82. http://dx.doi.org/10.1042/bj2870277.
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Three-dimensional computer models of the rat D2, D3 and D4 dopamine receptor subtypes have been constructed based on the diffraction co-ordinates for bacteriorhodopsin, another membrane-bound protein containing seven transmembrane domains presumed to be arranged in a similar spatial orientation. Models were assembled by aligning the putative transmembrane domains of the dopamine receptors with those of bacteriorhodopsin using sequence similarities, and then superimposing these modelled alpha-helices on to the bacteriorhodopsin-derived co-ordinates. These models explore the potential hydrogen bonding, electrostatic and stacking interactions within the receptor which may be important for maintaining the conformation of these receptors, and thereby provide target sites for agonist binding. Proposed interactions between the catecholamine ligands and these receptors appear to account for the affinity, although not the specificity, of these agonist ligands for the different dopamine receptor subtypes. Such models will be useful for establishing structure-function relationships between ligands and the dopamine receptors, and may ultimately provide a template for the design of receptor-specific drugs.
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Ramanathan, Sankari, Tatiana Tkatch, Jeremy F. Atherton, Charles J. Wilson, and Mark D. Bevan. "D2-Like Dopamine Receptors Modulate SKCa Channel Function in Subthalamic Nucleus Neurons Through Inhibition of Cav2.2 Channels." Journal of Neurophysiology 99, no. 2 (February 2008): 442–59. http://dx.doi.org/10.1152/jn.00998.2007.
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The activity patterns of subthalamic nucleus (STN) neurons are intimately related to motor function/dysfunction and modulated directly by dopaminergic neurons that degenerate in Parkinson's disease (PD). To understand how dopamine and dopamine depletion influence the activity of the STN, the functions/signaling pathways/substrates of D2-like dopamine receptors were studied using patch-clamp recording. In rat brain slices, D2-like dopamine receptor activation depolarized STN neurons, increased the frequency/irregularity of their autonomous activity, and linearized/enhanced their firing in response to current injection. Activation of D2-like receptors in acutely isolated neurons reduced transient outward currents evoked by suprathreshold voltage steps. Modulation was inhibited by a D2-like receptor antagonist and occluded by voltage-dependent Ca2+ (Cav) channel or small-conductance Ca2+-dependent K+ (SKCa) channel blockers or Ca2+-free media. Because Cav channels are targets of Gi/o-linked receptors, actions on step- and action potential waveform-evoked Cav channel currents were studied. D2-like receptor activation reduced the conductance of Cav2.2 but not Cav1 channels. Modulation was mediated, in part, by direct binding of Gβγ subunits because it was attenuated by brief depolarization. D2 and/or D3 dopamine receptors may mediate modulation because a D4-selective agonist was ineffective and mRNA encoding D2 and D3 but not D4 dopamine receptors was detectable. Brain slice recordings confirmed that SKCa channel-mediated action potential afterhyperpolarization was attenuated by D2-like dopamine receptor activation. Together, these data suggest that D2-like dopamine receptors potently modulate the negative feedback control of firing that is mediated by the functional coupling of Cav2.2 and SKCa channels in STN neurons.
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Mizuta, Kentaro, Yi Zhang, Dingbang Xu, Eiji Masaki, Reynold A. Panettieri, and Charles W. Emala. "The dopamine D2 receptor is expressed and sensitizes adenylyl cyclase activity in airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 3 (February 1, 2012): L316—L324. http://dx.doi.org/10.1152/ajplung.00130.2011.
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Dopamine receptors are G protein-coupled receptors that are divided into two subgroups, “D1-like” receptors (D1 and D5) that couple to the Gs protein and “D2-like” receptors (D2, D3, and D4) that couple to Gi. Although inhaled dopamine has been reported to induce bronchodilation in patients with asthma, functional expression of dopamine receptor subtypes has never been described on airway smooth muscle (ASM) cells. Acute activation of Gi-coupled receptors inhibits adenylyl cyclase activity and cAMP synthesis, which classically impairs ASM relaxation. In contrast, chronic activation of Gi-coupled receptors produces a paradoxical enhancement of adenylyl cyclase activity referred to as heterologous sensitization. We questioned whether the dopamine D2-like receptor is expressed on ASM, whether it exhibits classical Gi-coupling, and whether it modulates ASM function. We detected the mRNA encoding the dopamine D2 receptor in total RNA isolated from native human ASM and from cultured human airway smooth muscle (HASM) cells. Immunoblots identified the dopamine D2 receptor protein in both native human and guinea pig ASM and cultured HASM cells. The dopamine D2 receptor protein was immunohistochemically localized to both human and guinea pig ASM. Acute activation of the dopamine D2 receptor by quinpirole inhibited forskolin-stimulated adenylyl cyclase activity in HASM cells, which was blocked by the dopamine D2 receptor antagonist L-741626. In contrast, the chronic pretreatment (1 h) with quinpirole potentiated forskolin-stimulated adenylyl cyclase activity, which was inhibited by L-741626, the phospholipase C inhibitor U73122, or the protein kinase C inhibitor GF109203X. Quinpirole also stimulated inositol phosphate synthesis, which was inhibited by L-741626 or U73122. Chronic pretreatment (1 h) of the guinea pig tracheal rings with quinpirole significantly potentiated forskolin-induced airway relaxation, which was inhibited by L-741626. These results demonstrate that functional dopamine D2 receptors are expressed on ASM and could be a novel therapeutic target for the relaxation of ASM.
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Barbanti, P., G. Fabbrini, A. Ricci, M. Paola Pascali, E. Bronzetti, F. Amenta, GL Lenzi, and R. Cerbo. "Migraine Patients Show an Increased Density of Dopamine D3 and D4 Receptors on Lymphocytes." Cephalalgia 20, no. 1 (February 2000): 15–19. http://dx.doi.org/10.1046/j.1468-2982.2000.00001.x.
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Recent studies have revealed peculiar functional and genetic features of dopamine receptors in migraine. As peripheral blood lymphocytes (PBL) may represent a tool for peripheral detection of neuroreceptors, we compared the expression of dopamine D3 (DRD3) and D4 (DRD4) receptors on PBL in migraine patients and in healthy controls using radioligand binding assay techniques in the presence of antidopamine D2-like receptor antibodies. The dopamine D2-like receptor agonist [3H]7-OH-DPAT was used as a radioligand. An increased density of both DRD3 ( P = 0.0006) and DRD4 ( P = 0.002) on PBL was observed in migraineurs compared with controls. This up-regulation might reflect central and/or peripheral dopamine receptor hypersensitivity due to hypofunction of the dopaminergic system. These findings support the view that dopamine D2-like receptors are involved in the determination of the so-called migraine trait, which may help to elucidate several clinical features of the disease.
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Ladines, Cecilia A., Chunyu Zeng, Laureano D. Asico, Xiaoguang Sun, Felice Pocchiari, Claudio Semeraro, Joseph Pisegna, et al. "Impaired renal D1-like and D2-like dopamine receptor interaction in the spontaneously hypertensive rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, no. 4 (October 1, 2001): R1071—R1078. http://dx.doi.org/10.1152/ajpregu.2001.281.4.r1071.
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D1-like (D1, D5) and D2-like (D2, D3, D4) dopamine receptors interact in the kidney to produce a natriuresis and a diuresis. Disruption of D1 or D3 receptors in mice results in hypertension that is caused, in part, by a decreased ability to excrete an acute saline load. We studied D1-like and D2-like receptor interaction in anesthetized spontaneously hypertensive rats (SHR) by the intrarenal infusion of Z-1046 (a novel dopamine receptor agonist with rank order potency of D3≥D4>D2>D5>D1). Z-1046 increased glomerular filtration rate (GFR), urine flow, and sodium excretion in normotensive Wistar-Kyoto rats but not in SHRs. The lack of responsiveness to Z-1046 in SHRs was not an epiphenomenon, because intrarenal cholecystokinin infusion increased GFR, urine flow, and sodium excretion to a similar extent in the two rat strains. We conclude that renal D1-like and D2-like receptor interaction is impaired in SHRs. The impaired D1-like and D2-like receptor interaction in SHRs is not caused by alterations in the coding sequence of the D3 receptor, the D2-like receptor expressed in rat renal tubules that has been shown to be involved in sodium transport. Because the diuretic and natriuretic effects of D1-like receptors are, in part, caused by an interaction with D2-like receptors, it is possible that the decreased Z-1046 action in SHRs is secondary to the renal D1-like receptor dysfunction in this rat strain.
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Tomassoni, Daniele, Enea Traini, Manuele Mancini, Vincenzo Bramanti, Syed Sarosh Mahdi, and Francesco Amenta. "Dopamine, vesicular transporters, and dopamine receptor expression in rat major salivary glands." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 309, no. 5 (September 2015): R585—R593. http://dx.doi.org/10.1152/ajpregu.00455.2014.
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The localization of dopamine stores and the expression and localization of dopamine (DAT) and vesicular monoamine transporters (VMAT) type-1 and -2 and of dopamine D1-like and D2-like receptor subtypes were investigated in rat submandibular, sublingual, and parotid salivary glands by HPLC with electrochemical detection, as well as immunochemical and immunohistochemical techniques. Male Wistar rats of 2 mo of age were used. The highest dopamine levels were measured in the parotid gland, followed by the submandibular and sublingual glands. Western blot analysis revealed DAT, VMAT-1, VMAT-2, and dopamine receptors immunoreactivity in membrane preparations obtained from the three glands investigated. Immunostaining for dopamine and transporters was developed within striated ducts. Salivary glands processed for dopamine receptors immunohistochemistry developed an immunoreaction primarily in striated and excretory ducts. In the submandibular gland, acinar cells displayed strong immunoreactivity for the D2 receptor, while cells of the convoluted granular tubules were negative for both D1-like and D2-like receptors. Parotid glands acinar cells displayed the highest immunoreactivity for both D1 and D2 receptors compared with other salivary glands. The above localization of dopamine and dopaminergic markers investigated did not correspond closely with neuron-specific enolase (NSE) localization. This indicates that at least in part, catecholamine stores and dopaminergic markers are independent from glandular innervation. These findings suggest that rat major salivary glands express a dopaminergic system probably involved in salivary secretion. The stronger immunoreactivity for dopamine transporters and receptors in striated duct cells suggests that the dopaminergic system could regulate not only quality, but also volume and ionic concentration of saliva.
7
Jose, P. A., J. R. Raymond, M. D. Bates, A. Aperia, R. A. Felder, and R. M. Carey. "The renal dopamine receptors." Journal of the American Society of Nephrology 2, no. 8 (February 1992): 1265–78. http://dx.doi.org/10.1681/asn.v281265.
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Dopamine is an endogenous catecholamine that modulates many functions including behavior, movement, nerve conduction, hormone synthesis and release, blood pressure, and ion fluxes. Dopamine receptors in the brain have been classically divided into D1 and D2 subtypes, based on pharmacological data. However, molecular biology techniques have identified many more dopamine receptor subtypes. Several of the receptors cloned from the brain correspond to the classically described D1 and D2 receptors. Several D1 receptor subtypes have been cloned (D1A, D1B, and D5) and are each coupled to the stimulation of adenylyl cyclase. The D2 receptor has two isoforms, a shorter form, composed of 415 amino acids, is termed the D2short receptor. The long form, called the D2long receptor, is composed of 444 amino acids; both are coupled to the inhibition of adenylyl cyclase. The D3 and D4 receptors are closely related to, but clearly distinct from, the D2 receptor. They have not yet been linked to adenylyl cyclase activity. Outside of the central nervous system, the peripheral dopamine receptors have been classified into the DA1 and DA2 subtypes, on the basis of synaptic localization. The pharmacological properties of DA1 receptors roughly approximate those of D1 and D5 receptors, whereas those of DA2 receptors approximate those of D2 receptors. A renal dopamine receptor with some pharmacological features of the D2 receptor but not linked to adenylyl cyclase has been described in the renal cortex and inner medulla. In the inner medulla, this D2-like receptor, termed DA2k, is linked to stimulation of prostaglandin E2 production, apparently due to stimulation of phospholipase A2. Of the cloned dopamine receptors, only the mRNA of the D3 receptor has been reported in the kidney. The DA1 receptor in the kidney is associated with renal vasodilation and an increase in electrolyte excretion. The DA1-related vasodilation and inhibition of electrolyte transport is mediated by cAMP. The role of renal DA2 receptors remains to be clarified. Although DA1 and DA2 receptors may act in concert to decrease transport in the renal proximal convoluted tubule, the overall function of DA2 receptors may be actually the opposite of those noted for DA1 receptors. Dopamine has been postulated to act as an intrarenal natriuretic hormone. Moreover, an aberrant renal dopaminergic system may play a role in the pathogenesis of some forms of hypertension. A decreased renal production of dopamine and/or a defective transduction of the dopamine signal is/are present in some animal models of experimental hypertension as well as in some forms of human essential hypertension.
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Sunahara, Roger K., Philip Seeman, Hubert H. M. Van Tol, and Hyman B. Niznik. "Dopamine Receptors and Antipsychotic Drug Response." British Journal of Psychiatry 163, S22 (December 1993): 31–38. http://dx.doi.org/10.1192/s000712500029257x.
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Dopamine receptors have been divided into two major types – D1 and D2 – based primarily on pharmacological and biochemical criteria. Recent advances in the molecular biology of the dopamine receptor system have allowed the identification and characterisation of at least five distinct neuronal dopamine receptor genes (D1 to D5). These genes encode dopamine receptors belonging to the D1 receptor family, termed D1 and D5, and three D2-like receptors, termed D2, D3 and D4. These receptors are distinguished on the basis of their primary structure, chromosomal location, mRNA size and tissue distribution, and biochemical and pharmacological differences. Although individually these receptor subtypes may not be directly and exclusively involved in the maintenance or expression of schizophrenia, alterations of any of the receptors may contribute to the perturbation or instability of dopaminergic homeostasis in the brain. What was once thought to be a simple two-receptor system seems to have emerged as an intricate and interactive entity. This review summarises what is currently understood about dopamine receptors, their role in antipsychotic drug action, and their association with psychosis.
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Zeng, Chunyu, Meng Zhang, Laureano D. Asico, Gilbert M. Eisner, and Pedro A. Jose. "The dopaminergic system in hypertension." Clinical Science 112, no. 12 (May 14, 2007): 583–97. http://dx.doi.org/10.1042/cs20070018.
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Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport, vascular smooth muscle contractility and production of reactive oxygen species and by interacting with the renin–angiotensin and sympathetic nervous systems. Dopamine receptors are classified into D1-like (D1 and D5) and D2-like (D2, D3 and D4) subtypes based on their structure and pharmacology. Each of the dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors regulate blood pressure by influencing the central and/or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents. This review summarizes the physiology of the different dopamine receptors in the regulation of blood pressure, and the relationship between dopamine receptor subtypes and hypertension.
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George, Susan R., and Brian F. O'Dowd. "A Novel Dopamine Receptor Signaling Unit in Brain: Heterooligomers of D1 And D2 Dopamine Receptors." Scientific World JOURNAL 7 (2007): 58–63. http://dx.doi.org/10.1100/tsw.2007.223.
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The ability of G protein coupled receptors to heterooligomerize and create novel signaling complexes has demonstrated the tremendous potential of these receptors to access diverse signaling cascades, as well as to modulate the nature of the transduced signal. In the dopamine receptor field, the existence of a D1-like receptor in brain that activated phospatidylinositol turnover has been shown, but definition of the molecular entity remained elusive. We discovered that the D1 and D2 receptors form a heterooligomer, which on activation of both receptors, coupled to Gq to activate phospholipase C and generate intracellular calcium release. The activation of Gq by the D1-D2 heterooligomer has been shown to occur in cells expressing both receptors, as well as in striatum, distinct from Gs/olf or Gi/o activation by the D1 and D2 receptor homooligomers, respectively. The activation of the D1-D2 receptor heterooligomer in brain led to a calcium signal–mediated increase in phosphorylation of calmodulin kinase lla. The calcium signal rapidly desensitized and the receptors cointernalized after occupancy of either the D1 or D2 binding pocket. Thus, the D1-D2 heterooligomer directly links the action of dopamine to rapid calcium signaling and likely has important effects on dopamine-mediated synaptic plasticity and its functional correlates in brain.
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Bracci, Enrico, Diego Centonze, Giorgio Bernardi, and Paolo Calabresi. "Dopamine Excites Fast-Spiking Interneurons in the Striatum." Journal of Neurophysiology 87, no. 4 (April 1, 2002): 2190–94. http://dx.doi.org/10.1152/jn.00754.2001.
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The striatum is the main recipient of dopaminergic innervation. Striatal projection neurons are controlled by cholinergic and GABAergic interneurons. The effects of dopamine on projection neurons and cholinergic interneurons have been described. Its action on GABAergic interneurons, however, is still unknown. We studied the effects of dopamine on fast-spiking (FS) GABAergic interneurons in vitro, with intracellular recordings. Bath application of dopamine elicited a depolarization accompanied by an increase in membrane input resistance (an effect that persisted in the presence of tetrodotoxin) and action-potential discharge. These effects were mimicked by the D1-like dopamine receptor agonist SKF38393 but not by the D2-like agonist quinpirole. Evoked corticostriatal glutamatergic synaptic currents were not affected by dopamine. Conversely, GABAergic currents evoked by intrastriatal stimulation were reversibly depressed by dopamine and D2-like, but not D1-like, agonists. Cocaine elicited effects similar to those of dopamine on membrane potential and synaptic currents. These results show that endogenous dopamine exerts a dual excitatory action on FS interneurons, by directly depolarizing them (through D1-like receptors) and by reducing their synaptic inhibition (through presynaptic D2-like receptors).
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Zeng, Chunyu, Ines Armando, Yingjin Luo, Gilbert M. Eisner, Robin A. Felder, and Pedro A. Jose. "Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 2 (February 2008): H551—H569. http://dx.doi.org/10.1152/ajpheart.01036.2007.
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Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones/humoral factors, such as aldosterone, angiotensin, catecholamines, endothelin, oxytocin, prolactin pro-opiomelancortin, reactive oxygen species, renin, and vasopressin. Dopamine receptors are classified into D1-like (D1 and D5) and D2-like (D2, D3, and D4) subtypes based on their structure and pharmacology. In recent years, mice deficient in one or more of the five dopamine receptor subtypes have been generated, leading to a better understanding of the physiological role of each of the dopamine receptor subtypes. This review summarizes the results from studies of various dopamine receptor mutant mice on the role of individual dopamine receptor subtypes and their interactions with other G protein-coupled receptors in the regulation of blood pressure.
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MISSALE, CRISTINA, S. RUSSEL NASH, SUSAN W. ROBINSON, MOHAMED JABER, and MARC G. CARON. "Dopamine Receptors: From Structure to Function." Physiological Reviews 78, no. 1 (January 1, 1998): 189–225. http://dx.doi.org/10.1152/physrev.1998.78.1.189.
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Missale, Cristina, S. Russel Nash, Susan W. Robinson, Mohamed Jaber, and Marc G. Caron. Dopamine Receptors: From Structure to Function. Physiol. Rev. 78: 189–225, 1998. — The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2 , D3 , and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine secretion. In the periphery, dopamine receptors are present more prominently in kidney, vasculature, and pituitary, where they affect mainly sodium homeostasis, vascular tone, and hormone secretion. Numerous genetic linkage analysis studies have failed so far to reveal unequivocal evidence for the involvement of one of these receptors in the etiology of various central nervous system disorders. However, targeted deletion of several of these dopamine receptor genes in mice should provide valuable information about their physiological functions.
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Wong, Dean F., Godfrey D. Pearlson, Larry E. Tune, L. Trevor Young, Carolyn Cidis Meltzer, Robert F. Dannals, Hayden T. Ravert, Jakob Reith, Michael J. Kuhar, and Albert Gjedde. "Quantification of Neuroreceptors in the Living Human Brain: IV. Effect of Aging and Elevations of D2-Like Receptors in Schizophrenia and Bipolar Illness." Journal of Cerebral Blood Flow & Metabolism 17, no. 3 (March 1997): 331–42. http://dx.doi.org/10.1097/00004647-199703000-00010.
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In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C] methylspiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.
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Bigliani, Valeria, Rachel S. Mulligan, Paul D. Acton, Dimitris Visvikis, Peter J. Ell, Caroline Stephenson, Robert W. Kerwin, and Lyn S. Pilowsky. "In vivo occupancy of striatal and temporal cortical D2/D3 dopamine receptors by typical antipsychotic drugs." British Journal of Psychiatry 175, no. 3 (September 1999): 231–38. http://dx.doi.org/10.1192/bjp.175.3.231.
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BackgroundThe dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade.AimTo evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride.Method[123I]-epidepride SPETscans were performed on 12 patients with schizophrenia treated with antipsychotics and 11 age-matched healthy controls. [123I]-epidepride specific binding to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs determined.ResultsMean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively.ConclusionsTypical antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.
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Shaw, P., and L. S. Pilowsky. "Probing Cortical Sites of Antipsychotic Drug Action within vivoReceptor Imaging." Behavioural Neurology 12, no. 1-2 (2000): 3–9. http://dx.doi.org/10.1155/2000/184707.
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Imaging receptors using radioactive ligands has allowed direct determination of the sites of action of antipsychotic drugs. Initial studies relating antipsychotic drug efficacy to action at striatal dopamine D2-like receptors have recently been undermined. Developments in imaging extrastriatal dopamine D2-like receptors suggest rather that antagonism of these receptors in the temporal cortex is the common site of action for antipsychotic drugs, with occupancy at striatal receptors relating more closely to extrapyramidal side effects. Further work into dopamine receptor subtypes and other receptor groups such as serotonin and GABA neurotransmitters awaits the development of suitable probes, but there are some initial finding. Again a main site of antipsychotic drug action is at cortical levels with high degrees of cortical D1 and 5HT2areceptor occupancy attained particularly by atypical antipsychotic drugs.
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Jose, Pedro A., Laureano D. Asico, Gilbert M. Eisner, Felice Pocchiari, Claudio Semeraro, and Robin A. Felder. "Effects of costimulation of dopamine D1- and D2-like receptors on renal function." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 275, no. 4 (October 1, 1998): R986—R994. http://dx.doi.org/10.1152/ajpregu.1998.275.4.r986.
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In vitro studies have suggested that dopamine D1- and D2-like receptors interact to inhibit renal sodium transport. We used Z-1046, a dopamine receptor agonist with the rank-order potency D3 ≥ D4 > D2 > D5 > D1, to test the hypothesis that D1- and D2-like receptors interact to inhibit renal sodium transport in vivo in anesthetized rats. Increasing doses of Z-1046, administered via the right renal artery, increased renal blood flow (RBF), urine flow, and absolute and fractional sodium excretion without affecting glomerular filtration rate. For determination of the dopamine receptor involved in the renal functional effects of Z-1046, another group of rats received Z-1046 at 2 μg ⋅ kg−1 ⋅ min−1( n = 10) in the presence or absence of the D2-like receptor antagonist domperidone and/or the D1-like antagonist SCH-23390. Domperidone alone had no effect but blocked the Z-1046-mediated increase in urine flow and sodium excretion; it enhanced the increase in RBF after Z-1046. SCH-23390 by itself decreased urine flow and sodium excretion without affecting RBF and blocked the diuretic, natriuretic, and renal vasodilatory effect of Z-1046. We conclude that the renal vasodilatory effect of Z-1046 is D1-like receptor dependent, whereas the diuretic and natriuretic effects are both D1- and D2-like receptor dependent.
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Gómez, María de Jesús, Guy Rousseau, Réginald Nadeau, Roberto Berra, Gonzalo Flores, and Jorge Suárez. "Functional and autoradiographic characterization of dopamine D2-like receptors in the guinea pig heart." Canadian Journal of Physiology and Pharmacology 80, no. 6 (June 1, 2002): 578–87. http://dx.doi.org/10.1139/y02-081.
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Dopamine receptors include the D1- (D1 and D5 subtypes) and D2-like (D2, D3, and D4 subtypes) families. D1-like receptors are positively and D2-like receptors negatively coupled to the adenylyl cyclase. Dopamine D2-like (D4 subtype) receptors have been identified in human and rat hearts. However the presence of D2 and D3 receptor subtypes is unclear. Furthermore, their role in cardiac functions is unknown. By autoradiographic studies of guinea pig hearts, we identified D3 and D4 receptors, using the selective radioligands [3H]-7-OH-DPAT and [3H]emonapride (YM-09151-2 plus raclopride). Western blot analysis confirmed D3 and D4 receptors in the right and left ventricle of the same species. Selective agonists of D3 and D4 receptors (±)-7-OH-DPAT and PD 168 077 (109 to 105 M, respectively) induced a significant negative chronotropic and inotropic effect in the isolated guinea pig heart preparation. Negative inotropic effect induced by PD 168 077 was associated with an inhibition in cyclase activity. No changes in cyclase activity were found with (±)-7-OH-DPAT. The aim of this study is to support the presence of D3 and D4 receptors in the heart. Although our results suggest that D3 and D4 receptors are functionally active in the heart, we need additional information with an antagonist and an agonist of improved potency and selectivity to understand the respective roles of D3 and D4 receptors in the cardiac functions.Key words: Dopamine receptors (D2, D3, D4 subtypes), autoradiography, Western blot, cAMP, heart.
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Galvan, Adriana, Xing Hu, Karen S. Rommelfanger, Jean-Francois Pare, Zafar U. Khan, Yoland Smith, and Thomas Wichmann. "Localization and function of dopamine receptors in the subthalamic nucleus of normal and parkinsonian monkeys." Journal of Neurophysiology 112, no. 2 (July 15, 2014): 467–79. http://dx.doi.org/10.1152/jn.00849.2013.
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The subthalamic nucleus (STN) receives a dopaminergic innervation from the substantia nigra pars compacta, but the role of this projection remains poorly understood, particularly in primates. To address this issue, we used immuno-electron microscopy to localize D1, D2, and D5 dopamine receptors in the STN of rhesus macaques and studied the electrophysiological effects of activating D1-like or D2-like receptors in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys. Labeling of D1 and D2 receptors was primarily found presynaptically, on preterminal axons and putative glutamatergic and GABAergic terminals, while D5 receptors were more significantly expressed postsynaptically, on dendritic shafts of STN neurons. The electrical spiking activity of STN neurons, recorded with standard extracellular recording methods, was studied before, during, and after intra-STN administration of the dopamine D1-like receptor agonist SKF82958, the D2-like receptor agonist quinpirole, or artificial cerebrospinal fluid (control injections). In normal animals, administration of SKF82958 significantly reduced the spontaneous firing but increased the rate of intraburst firing and the proportion of pause-burst sequences of firing. Quinpirole only increased the proportion of such pause-burst sequences in STN neurons of normal monkeys. In MPTP-treated monkeys, the D1-like receptor agonist also reduced the firing rate and increased the proportion of pause-burst sequences, while the D2-like receptor agonist did not change any of the chosen descriptors of the firing pattern of STN neurons. Our data suggest that dopamine receptor activation can directly modulate the electrical activity of STN neurons by pre- and postsynaptic mechanisms in both normal and parkinsonian states, predominantly via activation of D1 receptors.
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Schwarz, Peter B., and John H. Peever. "Dopamine triggers skeletal muscle tone by activating D1-like receptors on somatic motoneurons." Journal of Neurophysiology 106, no. 3 (September 2011): 1299–309. http://dx.doi.org/10.1152/jn.00230.2011.
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The dopamine system plays an integral role in motor physiology. Dopamine controls movement by modulation of higher-order motor centers (e.g., basal ganglia) but may also regulate movement by directly controlling motoneuron function. Even though dopamine cells synapse onto motoneurons, which themselves express dopamine receptors, it is unknown whether dopamine modulates skeletal muscle activity. Therefore, we aimed to determine whether changes in dopaminergic neurotransmission at a somatic motor pool affect motor outflow to skeletal muscles. We used microinjection, neuropharmacology, electrophysiology, and histology to determine whether manipulation of D1- and D2-like receptors on trigeminal motoneurons affects masseter and/or tensor palatini muscle tone in anesthetized rats. We found that apomorphine (a dopamine analog) activated trigeminal motoneurons and triggered a potent increase in both masseter and tensor palatini tone. This excitatory effect is mediated by D1-like receptors because specific D1-like receptor activation strengthened muscle tone and blockade of these receptors prevented dopamine-driven activation of motoneurons. Blockade of D1-like receptors alone had no detectable effect on basal masseter/tensor palatini tone, indicating the absence of a functional dopamine drive onto trigeminal motoneurons, at least during isoflurane anesthesia. Finally, we showed that D2-like receptors do not affect either trigeminal motoneuron function or masseter/tensor palatini muscle tone. Our results provide the first demonstration that dopamine can directly control movement by manipulating somatic motoneuron behavior and skeletal muscle tone.
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Amenta, Francesco, Livio Chiandussi, Maurizio Mancini, Alberto Ricci, Marina Schena, and Franco Veglio. "Pharmacological characterization and autoradiographic localization of dopamine receptors in the human adrenal cortex." European Journal of Endocrinology 131, no. 1 (July 1994): 91–96. http://dx.doi.org/10.1530/eje.0.1310091.
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Amenta F, Chiandussi L, Mancini M, Ricci A, Schena M, Veglio F. Pharmacological characterization and autoradiographic localization of dopamine receptors in the human adrenal cortex. Eur J Endocrinol 1994;131:91–6. ISSN 0804–4643 The pharmacological characteristics and the anatomical localization of dopamine D1-like and D2-like receptors were studied in sections of the human adrenal cortex using radioligand binding and autoradiographic techniques. [3H]SCH23390 was used as a ligand of D1-like receptors, whereas [3H]spiroperidol was used to label D2-like receptors. No specific [3H]SCH 23390 binding was detectable in sections of the human adrenal cortex. On the other hand, [3H]spiroperidol was bound to sections of the adrenal gland in a manner consistent with the labelling of dopamine D2-like receptor sites. The binding was time, temperature and concentration dependent, belonging in the range of concentrations of the radioligand used for a single class of high-affinity sites. The dissociation constant (Kd) averaged 2.7 nmol/l, whereas the maximum density of binding sites (Bmax) was 160 nmol/mg tissue. Experiments on the pharmacological specificity of [3H]spiroperidol binding to sections of the human adrenal cortex revealed that clozapine was the most powerful displacer of [3H]spiroperidol from sections of the human adrenal cortex. This suggests the presence in the human adrenal cortex of dopamine receptors of the D4 subtype. Light microscope autoradiography showed the highest density of specific [3H]spiroperidol binding sites in the zona glomerulosa and to a lesser extent in the zona reticularis. Only sparse [3H]spiroperidol binding sites were localized in the zona fasciculata. The possible functional consequences of this localization of dopamine D2-like receptor sites in the human adrenal cortex are discussed. Francesco Amenta, Istituto di Farmacologia, Via Scalzino 5, 62032 Camerino, Italy
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Sahlholm, Kristoffer, Daniel Marcellino, Johanna Nilsson, Kjell Fuxe, and Peter Århem. "Differential voltage-sensitivity of D2-like dopamine receptors." Biochemical and Biophysical Research Communications 374, no. 3 (September 2008): 496–501. http://dx.doi.org/10.1016/j.bbrc.2008.07.052.
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Gershon, Ari A., Tali Vishne, and Leon Grunhaus. "Dopamine D2-Like Receptors and the Antidepressant Response." Biological Psychiatry 61, no. 2 (January 2007): 145–53. http://dx.doi.org/10.1016/j.biopsych.2006.05.031.
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Huber, Daniela, Stefan Löber, Harald Hübner, and Peter Gmeiner. "Bivalent molecular probes for dopamine D2-like receptors." Bioorganic & Medicinal Chemistry 20, no. 1 (January 2012): 455–66. http://dx.doi.org/10.1016/j.bmc.2011.10.063.
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Żuk, Justyna, Damian Bartuzi, Dariusz Matosiuk, and Agnieszka A. Kaczor. "Preferential Coupling of Dopamine D2S and D2L Receptor Isoforms with Gi1 and Gi2 Proteins—In Silico Study." International Journal of Molecular Sciences 21, no. 2 (January 9, 2020): 436. http://dx.doi.org/10.3390/ijms21020436.
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The dopamine D2 receptor belongs to rhodopsin-like G protein-coupled receptors (GPCRs) and it is an important molecular target for the treatment of many disorders, including schizophrenia and Parkinson’s disease. Here, computational methods were used to construct the full models of the dopamine D2 receptor short (D2S) and long (D2L) isoforms (differing with 29 amino acids insertion in the third intracellular loop, ICL3) and to study their coupling with Gi1 and Gi2 proteins. It was found that the D2L isoform preferentially couples with the Gi2 protein and D2S isoform with the Gi1 protein, which is in accordance with experimental data. Our findings give mechanistic insight into the interplay between isoforms of dopamine D2 receptors and Gi proteins subtypes, which is important to understand signaling by these receptors and their mediation by pharmaceuticals, in particular psychotic and antipsychotic agents.
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Saito, Osamu, Yasuhiro Ando, Eiji Kusano, and Yasushi Asano. "Functional characterization of basolateral and luminal dopamine receptors in rabbit CCD." American Journal of Physiology-Renal Physiology 281, no. 1 (July 1, 2001): F114—F122. http://dx.doi.org/10.1152/ajprenal.2001.281.1.f114.
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Previous studies reported the existence of both D1- and D2-like receptors in the cortical collecting duct (CCD). However, especially with regard to natriuresis, it remains controversial. In the present study, rabbit CCD was perfused to characterize the receptor subtypes responsible for the tubular actions. Basolateral dopamine (DA) induced a dose-dependent depolarization of transepithelial voltage. Basolateral domperidone, a D2-like receptor antagonist, abolished depolarization, whereas SKF-81297, a D1-like receptor agonist, showed no significant change. In addition, bromocriptine, a D2-like receptor agonist, also caused depolarization, whereas SKF-81297, a D1-like receptor agonist, did not depolarize significantly. Moreover, RBI-257, a D4-specific antagonist, reversed the basolateral DA-induced depolarization. In contrast to the basolateral side, luminal DA caused depolarization via a D1-like receptor; however the change was less than that for basolateral DA. For further evaluation, 22Na+ flux ( J Na) was measured to confirm the effect of DA on Na+ transport. Basolateral DA also caused a suppression of J Na, and this reaction was abolished by domperidone. These results suggested that the basolateral D2-like receptor is mainly responsible for the natriuretic action of DA in rabbit CCD.
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Liu, Xinhuai, and Allan E. Herbison. "Dopamine Regulation of Gonadotropin-Releasing Hormone Neuron Excitability in Male and Female Mice." Endocrinology 154, no. 1 (January 1, 2013): 340–50. http://dx.doi.org/10.1210/en.2012-1602.
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Numerous in vivo studies have shown that dopamine is involved in the regulation of LH secretion in mammals. However, the mechanisms through which this occurs are not known. In this study, we used green fluorescent protein-tagged GnRH neurons to examine whether and how dopamine may modulate the activity of adult GnRH neurons in the mouse. Bath-applied dopamine (10-80 μm) potently inhibited the firing of approximately 50% of GnRH neurons. This resulted from direct postsynaptic inhibitory actions through D1-like, D2-like, or both receptors. Further, one third of GnRH neurons exhibited an increase in their basal firing rate after administration of SCH23390 (D1-like antagonist) and/or raclopride (D2-like antagonist) indicating tonic inhibition by endogenous dopamine in the brain slice. The role of dopamine in presynaptic modulation of the anteroventral periventricular nucleus (AVPV) γ-aminobutyric acid/glutamate input to GnRH neurons was examined. Exogenous dopamine was found to presynaptically inhibit AVPV-evoked γ-aminobutyric acid /glutamate postsynaptic currents in about 50% of GnRH neurons. These effects were, again, mediated by both D1- and D2-like receptors. Neither postsynaptic nor presynaptic actions of dopamine were found to be different between diestrous, proestrous, and estrous females, or males. Approximately 20% of GnRH neurons were shown to receive a dopaminergic input from AVPV neurons in male and female mice. Together, these observations show that dopamine is one of the most potent inhibitors of GnRH neuron excitability and that this is achieved through complex pre- and postsynaptic actions that each involve D1- and D2-like receptor activation.
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Sharples, Simon A., Jennifer M. Humphreys, A. Marley Jensen, Sunny Dhoopar, Nicole Delaloye, Stefan Clemens, and Patrick J. Whelan. "Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord." Journal of Neurophysiology 113, no. 7 (April 2015): 2500–2510. http://dx.doi.org/10.1152/jn.00849.2014.
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Dopamine is now well established as a modulator of locomotor rhythms in a variety of developing and adult vertebrates. However, in mice, while all five dopamine receptor subtypes are present in the spinal cord, it is unclear which receptor subtypes modulate the rhythm. Dopamine receptors can be grouped into two families—the D1/5 receptor group and the D2/3/4 group, which have excitatory and inhibitory effects, respectively. Our data suggest that dopamine exerts contrasting dose-dependent modulatory effects via the two receptor families. Our data show that administration of dopamine at concentrations >35 μM slowed and increased the regularity of a locomotor rhythm evoked by bath application of 5-hydroxytryptamine (5-HT) and N-methyl-d(l)-aspartic acid (NMA). This effect was independent of the baseline frequency of the rhythm that was manipulated by altering the NMA concentration. We next examined the contribution of the D1- and D2-like receptor families on the rhythm. Our data suggest that the D1-like receptor contributes to enhancement of the stability of the rhythm. Overall, the D2-like family had a pronounced slowing effect on the rhythm; however, quinpirole, the D2-like agonist, also enhanced rhythm stability. These data indicate a receptor-dependent delegation of the modulatory effects of dopamine on the spinal locomotor pattern generator.
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Bigliani, V., and L. S. Pilowsky. "In vivo neuropharmacology of schizophrenia." British Journal of Psychiatry 174, S38 (May 1999): 23–33. http://dx.doi.org/10.1192/s0007125000298085.
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Since the introduction of chlorpromazine in the 1950s, followed by the discovery (with in vitro receptor binding assays), in the mid-1970s, that antipsychotic drugs block a subtype of dopamine receptor (D2/D2-like) (Creese et al, 1976) and that affinity for these receptors appears to correlate directly with clinical potency for antipsychotics (Peroutka & Synder, 1980), the study of neurotransmitters and receptors has been a major target of schizophrenia research (Owens, 1996). In 1983, the first visualisation, by positron emission tomography (PET), of the binding of D2 dopamine receptors in the brain of a living human subject was reported (Wagner et al, 1983). Following this, the number of research studies using PET and single photon emission tomography (SPET) has increased enormously.
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NARKAR, VIHANG A., TAHIR HUSSAIN, CARLOS PEDEMONTE, and MUSTAFA F. LOKHANDWALA. "Dopamine D2 Receptor Activation Causes Mitogenesis via p44/42 Mitogen-Activated Protein Kinase in Opossum Kidney Cells." Journal of the American Society of Nephrology 12, no. 9 (September 2001): 1844–52. http://dx.doi.org/10.1681/asn.v1291844.
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Abstract. This study was conducted to determine the expression of dopamine D2-like receptors in opossum kidney (OK) cells and to examine the potential role of these receptors in mitogenesis. First, the presence of D2-like receptor binding sites in OK cell membranes was demonstrated by radioligand binding, using [3H]spiperone. The D2-like receptor subtypes expressed in OK cells were subsequently demonstrated, by Western blotting, to be D2, D3, and D4 receptors. OK cells were stimulated with bromocriptine, (±)-2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin hydrochloride, (R)-(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide, or PD 168,077 maleate (D2-like, D2, D3, and D4 receptor agonists, respectively), and mitogenesis was measured as a function of [3H]thymidine incorporation. It was observed that, whereas bromocriptine and (±)-2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin hydrochloride produced increases in [3H]thymidine incorporation, (R)-(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide and PD 168,077 maleate did not produce such an effect, indicating the involvement of D2 receptors in the mitogenic response. Pertussis toxin and PD 98059 blocked the mitogenesis caused by bromocriptine, suggesting a role for Gi or Go proteins and p44/42 mitogen-activated protein kinase (MAPK), respectively. Furthermore, it was observed that bromocriptine produced a time-dependent increase in the phosphorylation (activation) of p44/42 MAPK, which was blocked by domperidone, pertussis toxin, or PD 98059. Therefore, this study demonstrates that, although OK cells express D2, D3, and D4 receptors, activation of only D2 receptors causes mitogenesis via phosphorylation of p44/42 MAPK. Furthermore, the cellular mechanisms contributing to D2 receptor-mediated phosphorylation of p44/42 MAPK seem to involve the tyrosine kinase, phosphatidylinositol-3-kinase, and protein kinase C pathways. It is likely that bromocriptine and other preferential D2 receptor agonists might provide protection against ischemic reperfusion injury in renal proximal tubular cells, by increasing the survival rates for ischemic cells.
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Wong, Dean F., David Young, P. David Wilson, Carolyn Cidis Meltzer, and Albert Gjedde. "Quantification of Neuroreceptors in the Living Human Brain: III. D2-Like Dopamine Receptors: Theory, Validation, and Changes during Normal Aging." Journal of Cerebral Blood Flow & Metabolism 17, no. 3 (March 1997): 316–30. http://dx.doi.org/10.1097/00004647-199703000-00009.
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Dopamine receptor density is believed to decline in normal aging. To test this hypothesis, we measured the density of dopamine D2-like receptors in vivo in the neostriatum of normal living humans by using the graphical method. This method determines the D2-like dopamine receptor density in the human brain with an occupying ligand (unlabeled haloperidol) and a radioligand (labeled 3- N-methylspiperone). The method was examined critically, and the assumptions underlying the method were shown to be valid. The validation included comparison of the representation of tracer metabolism by high-pressure liquid chromatography and model assays, calculation of the lumped constant Dw from the value of its components, and comparable tracer partition coefficients in vitro and in vivo. In error analysis, the method consistently performed as well as the direct least-squares regression at statistical noise levels appropriate for the tomograph used in these studies. The method revealed that the density of the D2-like receptors that bind haloperidol in the caudate nucleus of normal humans declined 1% per year after the age of 18 years.
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Bananej, Maryam, Ahmad Karimi-Sori, Mohammad Reza Zarrindast, and Shamseddin Ahmadi. "D1 and D2 dopaminergic systems in the rat basolateral amygdala are involved in anxiogenic-like effects induced by histamine." Journal of Psychopharmacology 26, no. 4 (May 31, 2011): 564–74. http://dx.doi.org/10.1177/0269881111405556.
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Involvement of the dopamine receptors in the basolateral amygdala (BLA) in the effects of histamine on anxiety-like behaviors of the elevated plus maze in male Wistar rats was investigated. The results showed that bilateral intra-BLA injections of histamine (2.5, 5 and 7.5 µg/rat) induced an anxiogenic-like effect, revealed by decreases in percentage of open arm time (%OAT) and open arm entries (%OAE). Intra-BLA administration of dopamine D1 receptor agonist, SKF38393 (0.25 µg/rat), and dopamine D2 receptor agonist, quinpirole (0.03 and 0.05 µg/rat), decreased %OAT but not %OAE. Conversely, intra-BLA administration of dopamine D1 receptor antagonist, SCH23390 (0.5 and 1 µg/rat), and dopamine D2 receptor antagonist, sulpiride (0.3 and 0.5 µg/rat), increased %OAT and %OAE, suggesting an anxiolytic-like effect for both drugs. Interestingly, co-administration of a silent dose of SCH23390 or sulpiride prevented anxiogenic-like effects of SKF38393 and quinpirole, respectively. Conjoint administration of a sub-effective dose of SKF38393 (0.125 µg/rat) or quinpirole (0.01 µg/rat) along with lower doses of histamine (1 and 2.5 µg/rat) induced anxiolytic-like effects. On the other hand, intra-BLA pretreatment with a silent dose of SCH23390 (0.25 µg/rat) or sulpiride (0.1 µg/rat) prevented the anxiogenic-like effect of higher doses of histamine (5 and 7.5 µg/rat). No significant change was observed in total closed arm entries, as an index for motor activity of the animals. It can be concluded that the dopamine D1 and D2 receptors in the BLA may be involved in the anxiogenic-like effects induced by histamine.
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Pizzinat, Nathalie, Sophie Marchal-Victorion, Agnes Maurel, Catherine Ordener, Guy Bompart, and Angelo Parini. "Substrate-dependent regulation of MAO-A in rat mesangial cells: involvement of dopamine D2-like receptors." American Journal of Physiology-Renal Physiology 284, no. 1 (January 1, 2003): F167—F174. http://dx.doi.org/10.1152/ajprenal.00113.2002.
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In the present study, we investigated the existence of a back-regulation of the catecholamine-degrading enzyme monoamine oxidase (MAO)-A by dopamine in rat renal cells. In proximal tubule cells, MAO-A expression was not modified after dopamine receptor stimulation. In contrast, in mesangial cells, enzyme assay and Western blots showed that MAO activity and protein increased by ∼80% after 48-h incubation with the D2-like receptor agonist bromocriptine and quinpirole but not with the D1-like receptor agonist SKF-38393. This effect was prevented by the D2-receptor antagonist sulpiride and domperidone. The increase in MAO-A protein was preceded by an augmentation of MAO-A mRNA that was prevented by the transcriptional inhibitor actinomycin D. Bromocriptine effect was mimicked by the PKA inhibitor H89 and inhibited by the PKA activator 8-bromo-cAMP. These results show for the first time the existence of a dopamine-dependent MAO-A regulation involving D2-like receptors, inhibition of the cAMP-PKA pathway, and an ex novo enzyme synthesis.
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Ohara, Koichi, Yuhei Nakamura, Dar-Win Xie, Tatsuya Ishigaki, Zong-Lin Deng, Kunihiko Tani, Hai-Yin Zhang, et al. "Polymorphisms of dopamine D2-like (D2, D3, and D4) receptors in schizophrenia." Biological Psychiatry 40, no. 12 (December 1996): 1209–17. http://dx.doi.org/10.1016/0006-3223(95)00673-7.
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Seeman, Philip. "Psychosis and dopamine High D2 receptors: Schizophrenia is a state of behavioural dopamine supersensitivity." Biochemist 35, no. 3 (June 1, 2013): 20–23. http://dx.doi.org/10.1042/bio03503020.
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Individuals with psychosis, particularly schizophrenia, are behaviorally supersensitive to dopamine-like drugs such as amphetamine or methylphenidate. Such supersensitivity may be associated with an increased pre-synaptic release of dopamine or a post-synaptic elevation of D2 receptors or of D2High receptors. The pre-synaptic release of dopamine is normal in remitted patients with schizophrenia. Brain imaging studies find that D2 receptors are only increased by 6% in anti-psychotic-naive schizophrenia patients. Therefore it is probable that the behavioural supersensitivity may arise from more D2High receptors in schizophrenia. After reducing endogenous dopamine, recent studies revealed an increase in apparent D2High receptors in schizophrenia. Animal models of psychosis, including dopamine-supersensitive animals pre-treated with amphetamine, marijuana or phencyclidine, or animals with gene knockouts in various neurotransmitter pathways, including those for glutamate receptors, have elevated levels of D2High receptors, consistent with behavioural dopamine supersensitivity in schizophrenia.
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Wang, Xia-qing, Tahmineh Mokhtari, Yu-xuan Zeng, Lu-peng Yue, and Li Hu. "The Distinct Functions of Dopaminergic Receptors on Pain Modulation: A Narrative Review." Neural Plasticity 2021 (February 22, 2021): 1–11. http://dx.doi.org/10.1155/2021/6682275.
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Chronic pain is considered an economic burden on society as it often results in disability, job loss, and early retirement. Opioids are the most common analgesics prescribed for the management of moderate to severe pain. However, chronic exposure to these drugs can result in opioid tolerance and opioid-induced hyperalgesia. On pain modulation strategies, exploiting the multitarget drugs with the ability of the superadditive or synergistic interactions attracts more attention. In the present report, we have reviewed the analgesic effects of different dopamine receptors, particularly D1 and D2 receptors, in different regions of the central nervous system, including the spinal cord, striatum, nucleus accumbens (NAc), and periaqueductal gray (PAG). According to the evidence, these regions are not only involved in pain modulation but also express a high density of DA receptors. The findings can be categorized as follows: (1) D2-like receptors may exert a higher analgesic potency, but D1-like receptors act in different manners across several mechanisms in the mentioned regions; (2) in the spinal cord and striatum, antinociception of DA is mainly mediated by D2-like receptors, while in the NAc and PAG, both D1- and D2-like receptors are involved as analgesic targets; and (3) D2-like receptor agonists can act as adjuvants of μ-opioid receptor agonists to potentiate analgesic effects and provide a better approach to pain relief.
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Myslivecek, Jaromir. "Dopamine and Dopamine-Related Ligands Can Bind Not Only to Dopamine Receptors." Life 12, no. 5 (April 19, 2022): 606. http://dx.doi.org/10.3390/life12050606.
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The dopaminergic system is one of the most important neurotransmitter systems in the central nervous system (CNS). It acts mainly by activation of the D1-like receptor family at the target cell. Additionally, fine-tuning of the signal is achieved via pre-synaptic modulation by the D2-like receptor family. Some dopamine drugs (both agonists and antagonists) bind in addition to DRs also to α2-ARs and 5-HT receptors. Unfortunately, these compounds are often considered subtype(s) specific. Thus, it is important to consider the presence of these receptor subtypes in specific CNS areas as the function virtually elicited by one receptor type could be an effect of other—or the co-effect of multiple receptors. However, there are enough molecules with adequate specificity. In this review, we want to give an overview of the most common off-targets for established dopamine receptor ligands. To give an overall picture, we included a discussion on subtype selectivity. Molecules used as antipsychotic drugs are reviewed too. Therefore, we will summarize reported affinities and give an outline of molecules sufficiently specific for one or more subtypes (i.e., for subfamily), the presence of DR, α2-ARs, and 5-HT receptors in CNS areas, which could help avoid ambiguous results.
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Sobczuk, Paweł, Michał Łomiak, and Agnieszka Cudnoch-Jędrzejewska. "Dopamine D1 Receptor in Cancer." Cancers 12, no. 11 (November 2, 2020): 3232. http://dx.doi.org/10.3390/cancers12113232.
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Dopamine is a biologically active compound belonging to catecholamines. It plays its roles in the human body, acting both as a circulating hormone and neurotransmitter. It acts through G-protein-coupled receptors divided into two subgroups: D1-like receptors (D1R and D5R) and D2-like receptors (D2R, D3R, D4R). Physiologically, dopamine receptors are involved in central nervous system functions: motivation or cognition, and peripheral actions such as blood pressure and immune response modulation. Increasing evidence indicates that the dopamine D1 receptor may play a significant role in developing different human neoplasms. This receptor’s value was presented in the context of regulating various signaling pathways important in tumor development, including neoplastic cell proliferation, apoptosis, autophagy, migration, invasiveness, or the enrichment of cancer stem cells population. Recent studies proved that its activation by selective or non-selective agonists is associated with significant tumor growth suppression, metastases prevention, and tumor microvasculature maturation. It may also exert a synergistic anti-cancer effect when combined with tyrosine kinase inhibitors or temozolomide. This review provides a comprehensive insight into the heterogeneity of dopamine D1 receptor molecular roles and signaling pathways in human neoplasm development and discusses possible perspectives of its therapeutic targeting as an adjunct anti-cancer strategy of treatment. We highlight the priorities for further directions in this research area.
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Frankowska, Małgorzata, Joanna Miszkiel, Lucyna Pomierny-Chamioło, Bartosz Pomierny, Giuseppe Giannotti, Agata Suder, and Małgorzata Filip. "Alternation in dopamine D2-like and metabotropic glutamate type 5 receptor density caused by differing housing conditions during abstinence from cocaine self-administration in rats." Journal of Psychopharmacology 33, no. 3 (January 15, 2019): 372–82. http://dx.doi.org/10.1177/0269881118821113.
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Background: Environmental conditions have an important function in substance use disorder, increasing or decreasing the risks of relapse. Several studies strongly support the role of the dopamine D2-like and metabotropic glutamate type 5 receptors in maladaptive neurobiological responses to cocaine reward and relapse. Aims: The present study employed cocaine self-administration with yoked-triad procedure in rats to explore whether drug abstinence in different housing conditions affects the drug-seeking behaviour and the dopamine D2-like and metabotropic glutamate type 5 receptor density and affinity in several regions of the animal brain. Methods: Rats were trained to self-administer cocaine and later they were forced to abstain either in: (a) enriched environment or (b) isolation cage conditions to evaluate the effect of housing conditions on the drug-seeking behaviour and to assess changes concerning receptors in animals brain. Results: Our results show that exposure to enriched environment conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated a significant increase in the dopamine D2-like receptor density in the prefrontal cortex in animals following drug abstinence in isolation cage or enriched environment conditions, and the reduction in their density in the dorsal striatum provoked by isolation cage conditions. The metabotropic glutamate type 5 receptor density decreased only in the prefrontal cortex after isolation cage and enriched environment abstinence. Conclusions: This study shows the different impacts caused by the type of housing conditions during abstinence from cocaine self-administration on drug-seeking behaviour in rats. The observed changes in the dopamine D2-like and metabotropic glutamate type 5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of cocaine.
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Gao, D. Q., L. M. Canessa, M. M. Mouradian, and P. A. Jose. "Expression of the D2 subfamily of dopamine receptor genes in kidney." American Journal of Physiology-Renal Physiology 266, no. 4 (April 1, 1994): F646—F650. http://dx.doi.org/10.1152/ajprenal.1994.266.4.f646.
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The D2, D3, and D4 dopamine receptors cloned from brain correspond to the classically described "D2" receptors. Although radioligand binding and biochemical and functional studies have demonstrated the presence of D2-like receptors in the kidney, the expression of D2, D3, or D4 receptor genes has not been conclusively demonstrated in the kidney. Since Northern blot analysis may have precluded demonstration of dopamine receptor mRNAs because of their relative low abundance, the expression of the D2long and D3 receptor genes was studied by reverse transcription-polymerase chain reaction (RT-PCR). We were able to amplify PCR products of the predicted size using mRNA from glomeruli, proximal tubules, outer medulla, inner medulla, and renal microvessels from normotensive Wistar-Kyoto rats (WKY). Specificities of the amplified products were confirmed by restriction analysis and by sequencing the D2long product and Southern blotting the D3 product. Because some studies have suggested that D2-like receptor actions may be different between WKY and spontaneously hypertensive rats (SHR), similar studies were performed in this rat strain. In the SHR, as in WKY, PCR products of the predicted size were amplified, and restriction enzyme digestion patterns were as predicted from the cDNA sequence. The PCR-generated cDNA from the glomeruli of SHR was subcloned and sequenced and was revealed to be identical to the D2long receptor cDNA from WKY. We conclude that the D2long and D3 receptor genes are expressed in specific regions of the kidney including the glomeruli. No differences in the sequence of the D2long receptor cDNA in part of the 3rd cytoplasmic loop were noted between WKY and SHR. These studies do not rule out the possibility that mutations in other segments of the receptor exist in the SHR.
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Yasumoto, S., E. Tanaka, G. Hattori, H. Maeda, and H. Higashi. "Direct and Indirect Actions of Dopamine on the Membrane Potential in Medium Spiny Neurons of the Mouse Neostriatum." Journal of Neurophysiology 87, no. 3 (March 1, 2002): 1234–43. http://dx.doi.org/10.1152/jn.00514.2001.
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Many studies have shown dopamine (DA) to have a modulatory effect on neuronal excitability, which cannot be simply classified as excitatory or inhibitory in the neostriatum. To clarify whether the responses to DA (10–30 μM) are excitatory or inhibitory in the mouse medium spiny neurons, we examined the effects of DA agonists on the synchronous potential trajectory from the resting potential to the subthreshold potential. The DA-induced potential changes, which were estimated at the subthreshold potential (approximately −60 mV), were summarized as the combination of three kinds of responses: an initial hyperpolarization lasting approximately 1 min and a slow depolarization and/or hyperpolarization lasting more than 20 min. A D1-like receptor agonist, R(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF81297, 1 μM) mainly induced the initial hyperpolarization and slow depolarization. A D2-like receptor agonist, trans-(−)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3,4-g]quinoline hydrochloride (quinpirole, 1 μM), mainly induced the initial hyperpolarization and slow hyperpolarization. D1-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390, 1 μM) depressed both the initial hyperpolarization and slow depolarization. D2-like receptor antagonist sulpiride (1 μM) depressed all the DA-induced responses except for the slow depolarization. TTX (0.5 μM) abolished all the DA-induced responses. Bicuculline (20 μM) and atropine (1 μM) abolished the DA-induced initial hyperpolarization and slow depolarization, respectively. Eitherdl-2-amino-5-phosphonopentanoic acid (AP5; 100 μM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 20 μM) blocked both the initial hyperpolarization and slow depolarization. The application of exogenous glutamate (Glu) mimicked the initial hyperpolarization and slow depolarization. These results suggest that the initial hyperpolarization is mainly due to GABA release via the cooperative action of D1- and D2-like receptors and Glu receptors in GABAergic interneurons, whereas the slow depolarization is mediated by acetylcholine (ACh) release via the cooperative action of mainly D1-like receptors and Glu receptors in cholinergic interneurons. The potential oscillation was generated at the subthreshold level in a Ba2+-, AP5-, CNQX-, bicuculline-, and atropine-containing medium. The oscillation depressed after the addition of TTX, Co2+, or DA. In DA agonists, quinpirole rather than SKF81297 had a more depressive effect on the potential oscillation. These results indicate that the slow hyperpolarization is due to the suppression of noninactivating Na+-Ca2+ conductances via mainly D2-like receptors in the medium spiny neurons. In conclusion, the DA actions on the medium spiny neurons show a transient inhibition by the activation of D1- and D2-like receptors in mainly GABAergic interneurons and a tonic excitation and/or inhibition by the activation of mainly D1-like receptors in cholinergic interneurons and by the activation of mainly D2-like receptors in the medium spiny neurons, respectively.
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Lamers, A. E., P. J. Ter Brugge, G. Flik, and S. E. Wendelaar Bonga. "Acid stress induces a D1-like dopamine receptor in pituitary MSH cells of Oreochromis mossambicus." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 273, no. 1 (July 1, 1997): R387—R392. http://dx.doi.org/10.1152/ajpregu.1997.273.1.r387.
Full textAbstract:
A 7-day exposure of tilapia (Oreochromis mossambicus) to water with a pH of 4.5 activates their pituitary melanophore-stimulating hormone (MSH) cells to preferentially release diacetyl alpha-MSH as an important corticotrope (13). We here focus on the control of alpha-MSH release by dopamine in tilapia exposed to water with low pH ("low-pH tilapia"). The MSH cells of low-pH tilapia showed a decreased sensitivity to inhibitory concentrations (10(-7)-10(-5) M) of dopamine compared with controls. Low concentrations (10(-14)-10(-8) M) of dopamine stimulated the release of alpha-MSH in low-pH tilapia but not in controls. Strong pharmacological evidence for a stimulatory dopamine receptor (D1-like) was obtained: the D1-agonists SKF-38393 and 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazep ine hydrobromide (6-chloro APB) had a stimulatory effect on the release of alpha-MSH in low-pH tilapia MSH cells but not in controls. The selective D2-agonists quinpirole and 2-hydroxy apomorphin inhibited the release of alpha-MSH in controls as well as in low-pH tilapia, and there was no difference in the sensitivity of the cells to these agonists. We conclude that only MSH cells of low-pH exposed tilapia exhibit a D1-like receptor activity. A comparable D2-like receptor activity, as demonstrated by specific D2-receptor agonists, is present in both controls and low-pH-adapted fish. The apparent loss of sensitivity of the MSH cells to inhibitory concentrations of dopamine, therefore, must be caused by the activation of the D1-like receptors and not by changes in the activity of the D2-like receptor proper. Stimulatory concentrations of dopamine not only quantitatively but also qualitatively enhanced the corticotropic activity of the released alpha-MSH, as indicated by the elevated ratio of diacetyl and monoacetyl alpha-MSH. This effect was mimicked by the D1-like agonists SKF-38393 and 6-chloro APB, indicating that the D1-like receptor activity is responsible for the enhancement of the di/mono ratio.
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Michino, Mayako, R. Benjamin Free, Trevor B. Doyle, David R. Sibley, and Lei Shi. "Structural basis for Na+-sensitivity in dopamine D2 and D3 receptors." Chemical Communications 51, no. 41 (2015): 8618–21. http://dx.doi.org/10.1039/c5cc02204e.
Full textAbstract:
To understand the structural basis for the Na+-sensitivity of ligand binding to dopamine D2-like receptors, using computational analysis in combination with binding assays, we identified interactions critical in propagating the impact of Na+on receptor conformations and on the ligand-binding site.
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Gomes, Pedro, M. A. Vieira-Coelho, and P. Soares-da-Silva. "Ouabain-insensitive acidification by dopamine in renal OK cells: primary control of the Na+/H+exchanger." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, no. 1 (July 1, 2001): R10—R18. http://dx.doi.org/10.1152/ajpregu.2001.281.1.r10.
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The present study was aimed at evaluating the role of D1- and D2-like receptors and investigating whether inhibition of Na+ transepithelial flux by dopamine is primarily dependent on inhibition of the apical Na+/H+ exchanger, inhibition of the basolateral Na+-K+-ATPase, or both. The data presented here show that opossum kidney cells are endowed with D1- and D2-like receptors, the activation of the former, but not the latter, accompanied by stimulation of adenylyl cyclase (EC50 = 220 ± 2 nM), marked intracellular acidification (IC50 = 58 ± 2 nM), and attenuation of amphotericin B-induced decreases in short-circuit current (28.6 ± 4.5% reduction) without affecting intracellular pH recovery after CO2 removal. These results agree with the view that dopamine, through the activation of D1- but not D2-like receptors, inhibits both the Na+/H+ exchanger (0.001933 ± 0.000121 vs. 0.000887 ± 0.000073 pH unit/s) and Na+-K+-ATPase without interfering with the Na+-independent HCO[Formula: see text] transporter. It is concluded that dopamine, through the action of D1-like receptors, inhibits both the Na+/H+ exchanger and Na+-K+-ATPase, but its marked acidifying effects result from inhibition of the Na+/H+exchanger only, without interfering with the Na+-independent HCO[Formula: see text] transporter and Na+-K+-ATPase.
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Baik, Ja-Hyun, Roberto Picetti, Adolfo Saiardi, Graziella Thiriet, Andrée Dierich, Antoine Depaulis, Marianne Le Meur, and Emiliana Borrelli. "Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors." Nature 377, no. 6548 (October 1995): 424–28. http://dx.doi.org/10.1038/377424a0.
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Soto, Paul L., Takato Hiranita, Ming Xu, Steven R. Hursh, David K. Grandy, and Jonathan L. Katz. "Dopamine D2-Like Receptors and Behavioral Economics of Food Reinforcement." Neuropsychopharmacology 41, no. 4 (July 24, 2015): 971–78. http://dx.doi.org/10.1038/npp.2015.223.
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Gjedde, Albert, Jakob Reith, and Dean F. Wong. "In schizophrenia, some dopamine D2-like receptors are still elevated." Psychiatry Research: Neuroimaging 67, no. 2 (July 1996): 159–61. http://dx.doi.org/10.1016/0925-4927(96)02953-8.
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Felder, R. A., C. C. Felder, G. M. Eisner, and P. A. Jose. "The dopamine receptor in adult and maturing kidney." American Journal of Physiology-Renal Physiology 257, no. 3 (September 1, 1989): F315—F327. http://dx.doi.org/10.1152/ajprenal.1989.257.3.f315.
Full textAbstract:
Dopamine, like other neurotransmitters, exerts its biological effects by occupation of specific receptor subtypes. The dopamine receptors in the central nervous system and certain endocrine organs are classified into the D1/D2 subtypes. Outside the central nervous system, the dopamine receptors are classified into the DA1/DA2 subtypes. The D1/D2 and DA1/DA2 receptor have marked similarities and some differences, the most notable of which is the lower affinity of the DA dopamine compared with the D dopamine receptor. DA1 receptor activation increases renal blood flow (RBF); stimulation of DA1 and DA2 receptors may also increase glomerular filtration rate (GFR). DA1 agonists inhibit fluid and electrolyte transport indirectly via hemodynamic mechanisms and directly by occupation of DA1 receptors in specific nephron segments. In the proximal tubule, DA1 agonists simulate adenylate cyclase and inhibit Na+-H+ antiport activity. They also increase phospholipase C and inhibit Na+-K+-ATPase activity (presumably as a consequence of protein kinase C activation). The latter effects may be facilitated by DA2 agonists. In cortical collecting ducts, dopamine antagonizes the effects of mineralocorticoids and the hydrosomotic effect of antidiuretic hormone. It has also been suggested that DA1 may also decrease sodium transport by influencing other hormones, such as atrial natriuretic peptide. Studies of dopamine in the young are complicated because of the propensity for dopamine to stimulate alpha-adrenoceptors. Dopamine alone may actually decrease RBF in the perinatal period. In some animals, the renal vasodilatory and natriuretic effects of dopamine increase with age. Renal tubular DA1-stimulated adenylate cyclase activity increases, whereas renal tubular DA1 receptors decrease with age. Renal DA2 receptor density is greater in the fetus; after birth renal DA2 receptors do not change. Endogenous dopamine may regulate sodium excretion in the young differently than in the adult. In the adult, sodium surfeit is associated with an increase in urinary dopamine; the opposite occurs in the young. A decrease in dopamine production or blockade of dopamine receptors results in an antinatriuresis in the adult; dopamine blockade in the young results in a natriuresis. It remains to be determined whether these age-related differences in dopamine effects are due to changes in receptor DA subtype density, second messengers, and/or interaction with other receptors.
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Kline, David D., Gabriel Hendricks, Gerlinda Hermann, Richard C. Rogers, and Diana L. Kunze. "Dopamine Inhibits N-Type Channels in Visceral Afferents to Reduce Synaptic Transmitter Release Under Normoxic and Chronic Intermittent Hypoxic Conditions." Journal of Neurophysiology 101, no. 5 (May 2009): 2270–78. http://dx.doi.org/10.1152/jn.91304.2008.
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Glutamatergic synaptic currents elicited in second-order neurons in the nucleus of the solitary tract (nTS) by activation of chemosensory and other visceral afferent fibers are severely reduced following 10 days of chronic intermittent hypoxia (CIH). The mechanism by which this occurs is unknown. A strong candidate for producing the inhibition is dopamine, which is also released from the presynaptic terminals and which we have shown exerts a tonic presynaptic inhibition on glutamate release. We postulated that tonic activation of the D2 receptors inhibits presynaptic calcium currents to reduce transmitter release and that in CIH this occurs in conjunction with an increase in the dopamine inhibitory response due to the increase in presynaptic D2 receptors or an increase in dopamine release further suppressing the evoked excitatory postsynaptic current (eEPSC). Thus we predicted that blockade of the D2 receptors would return the EPSC to values of animals maintained under normoxic conditions. We found that dopamine and quinpirole, the selective D2-like agonist, inhibit calcium currents via the D2 receptors by acting on the N-type calcium channel in presynaptic neurons and their nTS central terminals. However, in brain slice studies from CIH animals, although the D2 antagonist sulpiride increased the CIH-reduced amplitude of synaptic currents, EPSCs were not restored to normal levels. This indicates that while the dopamine inhibitory effect remains intact in CIH, most of the reduction in the eEPSC amplitude occurs via alternative mechanisms.
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Tomasella, Eugenia, Lucila Bechelli, Mora Belén Ogando, Camilo Mininni, Mariano N. Di Guilmi, Fernanda De Fino, Silvano Zanutto, Ana Belén Elgoyhen, Antonia Marin-Burgin, and Diego M. Gelman. "Deletion of dopamine D2 receptors from parvalbumin interneurons in mouse causes schizophrenia-like phenotypes." Proceedings of the National Academy of Sciences 115, no. 13 (March 12, 2018): 3476–81. http://dx.doi.org/10.1073/pnas.1719897115.
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Excessive dopamine neurotransmission underlies psychotic episodes as observed in patients with some types of bipolar disorder and schizophrenia. The dopaminergic hypothesis was postulated after the finding that antipsychotics were effective to halt increased dopamine tone. However, there is little evidence for dysfunction within the dopaminergic system itself. Alternatively, it has been proposed that excessive afferent activity onto ventral tegmental area dopaminergic neurons, particularly from the ventral hippocampus, increase dopamine neurotransmission, leading to psychosis. Here, we show that selective dopamine D2 receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. Conditional mutant animals show adult onset of schizophrenia-like behaviors and molecular, cellular, and physiological endophenotypes as previously described from postmortem brain studies of patients with schizophrenia. Our findings show that dopamine D2 receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system.