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Author: Mufida El-Ghundi
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Languages : en
Pages :
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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.
Author: Mufida El-Ghundi
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
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.
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Languages : en
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![Insights Into the Role of the Dopamine D1 Receptor in Brain Function [microform] : Studies Using a Gene Deletion Model PDF](https://books.google.com/books/content/images/frontcover/bfafAAAACAAJ?fife=w80-h100)
Author: Mufida El-Ghundi
Publisher: National Library of Canada = Bibliothèque nationale du Canada
ISBN: 9780612637405
Category :
Languages : en
Pages : 576
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Author: Emily Frieben
Publisher:
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Category :
Languages : en
Pages :
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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.
Author: N. V. Bhagavan
Publisher: Academic Press
ISBN: 0120954400
Category : Medical
Languages : en
Pages : 1068
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Book Description
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.
Author: Satoru Otani
Publisher: Springer Science & Business Media
ISBN: 1402077661
Category : Medical
Languages : en
Pages : 331
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Book Description
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.
Author: Amitabha Chattopadhyay
Publisher: CRC Press
ISBN: 1420005758
Category : Medical
Languages : en
Pages : 230
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Book Description
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
Author: Heinz Steiner
Publisher: Academic Press
ISBN: 008091215X
Category : Medical
Languages : en
Pages : 729
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Book Description
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
Author: Michael W. Hoffmann
Publisher: Cambridge University Press
ISBN: 1108456006
Category : Medical
Languages : en
Pages : 245
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Book Description
Understand the neuro-archeology of the executive brain, in its supervisory function, to better treat illnesses and behavior.
Author: Gaetano Di Chiara
Publisher: Springer Science & Business Media
ISBN: 3642560512
Category : Medical
Languages : en
Pages : 355
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With contributions by numerous experts
