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Insights Into The Role Of The Dopamine D1 Receptor In Brain Function
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Book Synopsis Insights Into the Role of the Dopamine D1 Receptor in Brain Function by : Mufida El-Ghundi
Download or read book Insights Into the Role of the Dopamine D1 Receptor in Brain Function written by Mufida El-Ghundi and published by . This book was released on 2001 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Dopamine receptors are widely expressed throughout the central and peripheral nervous systems and regulate many key functions of the brain. Five dopamine receptors have so far been cloned and classified into two main classes known as D1-like (D1 and D5) and D2-like (D2, D3 and D4) based on similarity in structure, pharmacology and coupling. Primarily because of the lack of receptor subtype-selective ligands, the precise physiological roles of these individual dopamine receptor subtypes remain unclear. The D 1 receptor subtype is highly expressed in the striatum, nucleus accumbens and prefrontal cortex, brain regions shown to modulate many functions ranging from locomotion to reward, cognition and emotion. To study the potential ' in vivo' role of the dopamine D1 receptor in the regulation of specific brain functions and drug induced behaviors, we used mice lacking the functional D1 receptor gene. In these mice the D1 receptor gene was deleted by means of homologous recombination. Based on the behavioral analysis of D1 receptor-deficient mice, we demonstrate that the D1 receptor is an abundant protein that plays a crucial role in mediating higher brain functions including some aspects of cognition (spatial learning and memory), appetitive motivation (operant responding for sucrose), alcohol seeking behavior and locomotor responses to alcohol and amphetamine. In addition, we have defined, for the first time, a role for the D1 receptor in the normal extinction of conditioned fear responses. However, D1 receptor does not appear to be essential for basal locomotor activity, working memory, sweet-taste preference or acquisition and expression of fear responses. These findings have great importance in furthering the understanding of the role of D1 receptors in brain functions.
Book Synopsis Insights Into the Role of the Dopamine D1 Receptor in Brain Function, Studies Using a Gene Deletion Model by :
Download or read book Insights Into the Role of the Dopamine D1 Receptor in Brain Function, Studies Using a Gene Deletion Model written by and published by . This book was released on 2001 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author :Mufida El-Ghundi Publisher :National Library of Canada = Bibliothèque nationale du Canada ISBN 13 :9780612637405 Total Pages :576 pages Book Rating :4.6/5 (374 download)
Book Synopsis Insights Into the Role of the Dopamine D1 Receptor in Brain Function [microform] : Studies Using a Gene Deletion Model by : Mufida El-Ghundi
Download or read book Insights Into the Role of the Dopamine D1 Receptor in Brain Function [microform] : Studies Using a Gene Deletion Model written by Mufida El-Ghundi and published by National Library of Canada = Bibliothèque nationale du Canada. This book was released on 2001 with total page 576 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Dopamine D1-like Receptors by : Emily Frieben
Download or read book Dopamine D1-like Receptors written by Emily Frieben and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The dopamine D1-like receptors (D1 and D5) are implicated in the etiology of both neurological and non-neurological conditions. For decades, the therapeutic utility of dopamine D1 receptor (D1R) agonists has been exemplified by their efficacy in animal models of Parkinson's disease (PD) and in PD patients. Despite showing promise, no centrally-available D1-like agonists have been approved, being hindered by poor pharmacokinetics and side effects. Recent advances have allowed for several non-catechol D1 agonists to advance to clinical trials for early- and late-stage PD. These compounds are functionally selective, with high bias for G protein over [beta]-arrestin signaling. There is limited knowledge, however, regarding how ligands precisely bind and activate the D1-like receptors. To guide structure-based drug design, we developed an experimentally-validated homology model of the D1 receptor that could offer understanding of how differences in ligand structure could lead to activation of specific signaling pathways. We studied molecular interactions of the D1R with three conformationally-constrained ligands [the prototypical full D1R agonist dihydrexidine (DHX), and monohydroxy analogs ("10-OH DHX", "11-OH DHX")], and compared them to dopamine and SKF38393. We focused on three critical serines in transmembrane V (TM5), residues S5.42 (S198), S5.43 (S199), and S5.46 (S202), which were mutated to alanine singly or in combination and then characterized. Docking simulations identified S5.42 and S5.46 as potentially important interactions. Binding assays were impossible with the S5.42A mutant, but functional assays revealed that the S5.42A receptor had activity when the ligand contained a 10-hydroxyl group, and none with only the 11-hydroxyl. The 11-hydroxyl position of DHX interacted with S5.42 and S5.43, whereas the 10-hydroxyl interacted with S5.46. These stereochemical preferences were apparent across the mono-hydroxy analogs. We then employed our structural model of the D1R to predict interactions for several non-catechol agonists, including the clinical candidate tavapadon/CVL-751. We identified the S5.46 interaction as a key determinant for agonist activity. Taken together, this data provides valuable insight into structural features that govern binding and activation of the D1R, which may aid in the design of clinically relevant D1 agonists. In the last decade, the D1-like receptors have been recognized for their utility in a number of non-neurological conditions. With the wide plethora of drugs and experimental compounds that target these receptors, many studies have evaluated their potential for repurposing. Of interest is the notion that the D1-like dopamine receptors, most recently the D5 receptor (D5R), may be implicated in the etiology of and/or may serve as a therapeutic target in various cancers. This idea stemmed from pharmacoepidemiological studies suggesting a lower cancer risk in patients with schizophrenia or PD, reported up-regulations of the dopamine receptors in various cancers, dopaminergic regulation of tumor behavior, and extensive research with D2 receptor antagonists in cancer. Although this seems exciting, critical analysis of the growing D5R cancer literature was instead quite illustrating. There were flawed hypotheses, experimental design without consideration of pharmacological principles, a dearth of rigorous controls, and improper applications of statistics. It is very likely that the reported "anticancer" effects actually were false positives and conclusions made erroneously. This body of confounded data suggests that there is little therapeutic value for the D5R in cancer and that more rigorous studies are warranted. The lack of rigor issue is a widespread problem and applicable across all disciplines in the biomedical sciences. Therefore, to shed light on this growing problem, we reviewed these recent studies with the D5R and put them in a broader context, with emphasis on the pharmacological fundamentals. The findings of this analysis are meant to educate and remind the greater scientific community that adherence to established biological principles must be as rigorous as the proper application of statistics. En masse, this dissertation provides understanding into the relationship between ligand structure and D1R function, as well as insight into the role of the D5R in cancer therapeutics. These data lay the foundation for more studies to investigate further the molecular interactions governing binding and activation of the D1-like receptors, which can be used to guide the design of functionally selective and/or subtype-selective ligands. Together, the findings presented herein not only affect the design of future studies, but also the interpretation of previous literature on D1-like receptor structure and function.
Book Synopsis D1:D2 Dopamine Receptor Interactions by : John L. Waddington
Download or read book D1:D2 Dopamine Receptor Interactions written by John L. Waddington and published by . This book was released on 1993 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume presents up-to-date comprehensive reviews of neuroscience research and theory on the fundamental interactions between the D1 and D2 dopamine receptor subtypes at numerous levels of investigation-from molecular biology and neuroanatomy, through electrophysiology, to the psychopharmacology of multiple forms of behavior, putative clinical significance, and therapeutic potential. This volume seeks to stand as a reference source on the evolution of the concept of D1: D2 interactions, on their substrates and psychopharmacological roles and, in such a continually evolving field, to look to the future. The Neuroscience Perspectives series aims to provide an all-round view of a current topic of great interest in neuroscience from the biochemical, pharmacological, and physiological standpoints together with the potential therapeutic applications. * SPECIAL FEATURES: * This is the ninth in Neuroscience Perspectives. * A Volume in Neuroscience Perspectives following series aim of providing all-round view of a current topic of great interest in Neuroscience from the biochemical, pharmacological and physiological standpoints together with the potential therapeutic applications. * The brain dopamine receptor has been the subject of intense interest for the past ten years owing to its involvement in motor and psychotic conditions. It is the target for the development of potential new drugs for eg. Schizophrenia and Parkinsons Diseases. Two subtypes of receptor have been found (D1 and D2). This book, edited by a respected expert in the field, examines the history of the topic, biochemistry, molecular biology and mode of interaction of the subtypes, and the therapeutic potential of the scientific discoveries, in the format of Neuroscience Perspectives. An issue of Nature in October 1990 led with the reported discovery of a D3 receptor. The implications of this for future research will be discussed in the final chapter.
Book Synopsis Medical Biochemistry by : N. V. Bhagavan
Download or read book Medical Biochemistry written by N. V. Bhagavan and published by Academic Press. This book was released on 2002 with total page 1068 pages. Available in PDF, EPUB and Kindle. Book excerpt: This text presents the fundamentals of biochemistry and related topics for all those pursuing medical or other health-related fields such as clinical chemistry, medical technology, or pharmacology.
Book Synopsis Critical Signaling and Ligand Interaction Mechanisms of the Dopamine D1 Receptor by : Sangmin Lee
Download or read book Critical Signaling and Ligand Interaction Mechanisms of the Dopamine D1 Receptor written by Sangmin Lee and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Dopamine D1 receptor full agonists have been efficacious in Parkinson's disease (PD) animal models and PD patients. SKF-83959 is reported to be a functionally selective dopamine D1 receptor ligand with high bias for D1-mediated phospholipase C (PLC) versus D1-coupled adenylate cyclase (AC) signaling. The signaling bias of SKF-83959 is commonly accepted and proposed to explain D1-mediated behavioral activity in PD animal models, but there is substantial (although not all unanimous) literature that failed to account for SKF-83959-mediated PLC activation. Thus, we decided to conduct an in-depth pharmacological characterization of SKF-83959. Contrary to common assumptions, SKF-83959 is a partial agonist (not an antagonist) at AC in vitro and ex vivo. In addition, it shows partial agonistic activity for [beta]-arrestin activation. SKF 83959 failed to show D1-mediated PLC signaling in a cellular expression system. We conclude that SKF-83959 is not a highly-biased functionally selective D1 ligand, and that its reported behavioral effects can be explained solely by its partial D1 agonism for canonical signaling pathway(s). Current dopamine D1 receptor full agonists have poor pharmacokinetic properties due to their intrinsic catechol moiety, and it is important to determine how novel non-catechol D1 ligands might be designed. To provide a scientific platform for structure-based drug design, we investigated the molecular interactions of the D1 receptor with several ergolines that have significant D1 activity and oral bioavailability, but not a catechol moiety. I focused on the conserved amino acids of the D1 receptor (T3.37, S5.42, S5.43, S5.46, F6.51, and F6.52) that are known to play a critical role in ligand interactions and/or receptor activation. Mutations to alanine (T3.37A, S5.42A, S5.43A, S5.46A, F6.51A, and F6.52A) on the D1 receptor were basically used to examine the role of the conserved amino acids in ligand interactions.A T3.37A mutation greatly decreased the D1 affinity and efficacy of the ergolines. However, a hydrogen bond-conservative T3.37S mutation markedly restored the loss of D1 affinity and efficacy suggesting the possible role of a hydrogen bond provided by T3.37. Unexpectedly, a S5.42A mutation increased the D1 affinity and efficacy for D1-mediated AC activation suggesting that this mutation may induce a favorable D1 receptor conformation for the ergolines. Although a S5.43A mutation failed to decrease the affinity of the ergolines consistently, a S5.46A mutation significantly decreased the affinity of the ergolines but to a small degree. Both the S5.43A and S5.46A mutations showed no significant effects on D1 efficacy of the ergolines. S5.42A/S5.46A and S5.43A/S5.46A double mutations elicited equal or greater effects than those of the single mutations. An F6.51A mutation dramatically decreased the D1 affinity of the ergolines, and an F6.52A mutation showed smaller, but significant decreases than the F6.51A mutation. The F6.51A mutation greatly decreased the ergoline efficacy for AC activation, but an aromatic-ring conserved F6.51W mutation markedly restored the D1 affinity and efficacy. This suggests the critical role of the hydrophobic and aromatic interactions provided by F6.51. Docking simulations illustrated that B-ring nitrogen of the ergoline agonists is located close to T3.37 and S5.46. In addition, the B-ring and the D-ring of the ergoline backbone are located close to F6.52 and F6.51, respectively.Rotigotine is another non-catechol drug that has reasonable D1 receptor efficacy. S5.42A and S5.43A mutations greatly decreased the D1 affinity and efficacy of rotigotine, whereas a S5.46A mutation failed to make changes suggesting that S5.42 and S5.43 may provide hydrogen bonds for rotigotine. An F6.51A mutation decreased the D1 affinity and efficacy of rotigotine to a far greater extent than an F6.52A mutation indicating that hydrophobic and aromatic interactions of F6.51 are particularly important. Mutagenesis results with 5-OH DPAT and 7-OH DPAT also supported the interaction between the thiophene group of rotigotine and F6.51. The simulations showed that the hydroxyl group is located close to S5.42 and S5.43 and that the thiophene group interacts closely with F6.51. In conclusion, we report that PLC activation by SKF-83959 is not a D1-mediated response, and that it is highly likely non-specific effects occurring at supra-pharmacological concentrations. Using AC activation (not PLC activation) as a functional end-point of D1 receptor signaling, we investigated the molecular interactions between the D1 receptor and non-catechol ligands (the ergolines and rotigotine). This study provides molecular mechanisms for the critical signaling and ligand interactions of the D1 receptor that may help design novel non-catechol D1 agonists.
Download or read book Prefrontal Cortex written by Satoru Otani and published by Springer Science & Business Media. This book was released on 2004-03-31 with total page 331 pages. Available in PDF, EPUB and Kindle. Book excerpt: The prefrontal cortex is regarded by many as the executive controller, which determines appropriate coupling between a sensory input and motor output to meet environmental demands. Our cognitive ability heavily relies on the function of the prefrontal cortex. Prefrontal Cortex: From Synaptic Plasticity to Cognition takes an interdisciplinary approach to characterize the function of the anterior portion of the frontal lobe in rodents and human and non-human primates. The topics in this volume are diverse. They range from membrane properties of prefrontal neurons to cognitive psychology and attempt to encompass domains of the prefrontal field in an effort to provide the bigger picture.
Book Synopsis Novel Regulatory Mechanisms of D1 Dopamine Receptor Maturation and Internalization by : Michael M. C. Kong
Download or read book Novel Regulatory Mechanisms of D1 Dopamine Receptor Maturation and Internalization written by Michael M. C. Kong and published by . This book was released on 2008 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Novel Regulatory Mechanisms of D1 Dopamine Receptor Maturation and Internalization Michael Ming Chuen Kong Degree of Doctor of Philosophy, 2008 Department of Pharmacology University of Toronto ABSTRACT Dopamine is the most abundant catecholamine neurotransmitter in the mammalian brain and controls various physiological processes. The D1 dopamine receptor (D1DR) is the predominant dopamine receptor in the brain and traditionally couples to stimulatory G proteins, such as Gs, to activate adenylyl cyclase and generate cAMP. Although the trafficking itinerary of ER/Golgi maturation, agonist-induced internalization, and recycling/degradation are features common to many G protein-coupled receptors (GPCRs), the molecular regulation of these individual processes for the D1DR is not fully elucidated. Many GPCRs have been shown to form homo-oligomers; the work presented in this thesis explores how multimerization of D1DR has a role in regulating how these receptors are trafficked to the plasma membrane. In addition, the regulation of D1DR internalization is investigated in the context of emerging evidence highlighting the importance of lipid rafts. Using strategically designed point mutations of the D1DR, specific receptor mutants were found to intracellularly sequester the wild-type receptor by oligomerization. This level of scrutiny by the quality control machinery in the cell could be circumvented by treatment with cell permeable dopaminergic agonists, but not antagonists or inverse agonists. This finding suggests that specific conformational requirements must be achieved before full maturation and anterograde trafficking of the D1DR can proceed. Furthermore, it was determined that cell surface bound D1DRs could internalize through a novel clathrin independent pathway that required binding to the scaffolding protein, caveolin-1. This interaction with caveolin-1 was identified in whole rat brain and was found to require a putative caveolin binding motif in transmembrane domain 7. Palmitoylation of D1DR was found to regulate the rate of agonist-induced caveolae mediated internalization. Finally, we determined that the integrity of caveolae was important in regulating cAMP signaling through D1DR. These findings provide novel insight into the trafficking requirements of newly synthesized D1DRs as well as alternative mechanisms of regulation of receptors after agonist activation. The oligomerization of GPCRs and the localization of GPCRs in lipid rafts represent two emerging concepts important to many aspects of GPCR function. Future work aimed at integrating these overlapping processes will further our understanding of this important group of cell surface receptors.
Book Synopsis Serotonin Receptors in Neurobiology by : Amitabha Chattopadhyay
Download or read book Serotonin Receptors in Neurobiology written by Amitabha Chattopadhyay and published by CRC Press. This book was released on 2007-05-17 with total page 230 pages. Available in PDF, EPUB and Kindle. Book excerpt: A number of developments spanning a multitude of techniques makes this an exciting time for research in serotonin receptors. A comprehensive review of the subject from a multidisciplinary perspective, Serotonin Receptors in Neurobiology is among the first books to include information on serotonin receptor knockout studies. With contributions from l
Book Synopsis Dopamine in the CNS I by : Gaetano Di Chiara
Download or read book Dopamine in the CNS I written by Gaetano Di Chiara and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 355 pages. Available in PDF, EPUB and Kindle. Book excerpt: With contributions by numerous experts
Book Synopsis Receptor-Receptor Interactions by : Kjell Fuxe
Download or read book Receptor-Receptor Interactions written by Kjell Fuxe and published by Springer Science & Business Media. This book was released on 2013-03-13 with total page 577 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Handbook of Basal Ganglia Structure and Function by : Heinz Steiner
Download or read book Handbook of Basal Ganglia Structure and Function written by Heinz Steiner and published by Academic Press. This book was released on 2010-03-17 with total page 729 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Basal Ganglia comprise a group of forebrain nuclei that are interconnected with the cerebral cortex, thalamus and brainstem. Basal ganglia circuits are involved in various functions, including motor control and learning, sensorimotor integration, reward and cognition. The importance of these nuclei for normal brain function and behavior is emphasized by the numerous and diverse disorders associated with basal ganglia dysfunction, including Parkinson's disease, Tourette's syndrome, Huntington's disease, obsessive-compulsive disorder, dystonia, and psychostimulant addiction. The Handbook of Basal Ganglia provides a comprehensive overview of the structural and functional organization of the basal ganglia, with special emphasis on the progress achieved over the last 10-15 years. Organized in six parts, the volume describes the general anatomical organization and provides a review of the evolution of the basal ganglia, followed by detailed accounts of recent advances in anatomy, cellular/molecular, and cellular/physiological mechanisms, and our understanding of the behavioral and clinical aspects of basal ganglia function and dysfunction. - Synthesizes widely dispersed information on the behavioral neurobiology of the basal ganglia, including advances in the understanding of anatomy, cell-molecular and cell-physiological mechanisms, and behavioral/clinical aspects of function and dysfunction - Features a truly international cast of the preeminent researchers in the field - Fully explores the clinically relevant impact of the basal ganglia on various psychiatric and neurological diseases
Download or read book Neuroproteomics written by Oscar Alzate and published by CRC Press. This book was released on 2009-10-26 with total page 356 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this, the post-genomic age, our knowledge of biological systems continues to expand and progress. As the research becomes more focused, so too does the data. Genomic research progresses to proteomics and brings us to a deeper understanding of the behavior and function of protein clusters. And now proteomics gives way to neuroproteomics as we beg
Book Synopsis Assembly of the Executive Mind by : Michael W. Hoffmann
Download or read book Assembly of the Executive Mind written by Michael W. Hoffmann and published by Cambridge University Press. This book was released on 2019-01-10 with total page 245 pages. Available in PDF, EPUB and Kindle. Book excerpt: Understand the neuro-archeology of the executive brain, in its supervisory function, to better treat illnesses and behavior.
Book Synopsis Parkinson's Disease and Other Movement Disorders by : Mark Edwards
Download or read book Parkinson's Disease and Other Movement Disorders written by Mark Edwards and published by Oxford University Press, USA. This book was released on 2008 with total page 336 pages. Available in PDF, EPUB and Kindle. Book excerpt: A reference on the management of Parkinson's disease and other movement disorders, this book offers practical advice on the classification and diagnosis of patients, and available treatment options.
Book Synopsis NeuroPsychopharmacotherapy by : Peter Riederer
Download or read book NeuroPsychopharmacotherapy written by Peter Riederer and published by Springer Nature. This book was released on 2022-11-04 with total page 4652 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides a reference guide describing the current status of medication in all major psychiatric and neurological indications, together with comparisons of pharmacological treatment strategies in clinical settings in Europe, USA, Japan and China. In addition, it highlights herbal medicine as used in China and Japan, as well as complementary medicine and nutritional aspects. This novel approach offers international readers a global approach in a single dedicated publication and is also a valuable resource for anyone interested in comparing treatments for psychiatric disorders in three different cultural areas. There are three volumes devoted to Basic Principles and General Aspects, offering a general overview of psychopharmacotherapy (Vol. 1); Classes, Drugs and Special Aspects covering the role of psychotropic drugs in the field of psychiatry and neurology (Vol. 2) and Applied Psychopharmacotherapy focusing on applied psychopharmacotherapy (Vol. 3). These books are invaluable to psychiatrists, neurologists, neuroscientists, medical practitioners and clinical psychologists.
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