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      Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

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          Abstract

          Dopamine receptors are widely distributed within the brain where they play critical modulator roles on motor functions, motivation and drive, as well as cognition. The identification of five genes coding for different dopamine receptor subtypes, pharmacologically grouped as D1- (D1 and D5) or D2-like (D2S, D2L, D3, and D4) has allowed the demonstration of differential receptor function in specific neurocircuits. Recent observation on dopamine receptor signaling point at dopamine—glutamate-NMDA neurobiology as the most relevant in schizophrenia and for the development of new therapies. Progress in the chemistry of D1- and D2-like receptor ligands (agonists, antagonists, and partial agonists) has provided more selective compounds possibly able to target the dopamine receptors homo and heterodimers and address different schizophrenia symptoms. Moreover, an extensive evaluation of the functional effect of these agents on dopamine receptor coupling and intracellular signaling highlights important differences that could also result in highly differentiated clinical pharmacology. The review summarizes the recent advances in the field, addressing the relevance of emerging new targets in schizophrenia in particular in relation to the dopamine – glutamate NMDA systems interactions.

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          Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.

          The dopamine system is unique among the brain's modulatory systems in that it has discrete projections to specific brain regions involved in motor behaviour, cognition and emotion. Dopamine neurons exhibit several activity patterns - including tonic and phasic firing - that are determined by a combination of endogenous pacemaker conductances and regulation by multiple afferent systems. Emerging evidence suggests that disruptions in these regulatory systems may underlie the pathophysiology of several psychiatric disorders, including schizophrenia and depression.
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            Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist.

            Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.
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              What does dopamine mean?

              Dopamine is a critical modulator of both learning and motivation. This presents a problem: how can target cells know whether increased dopamine is a signal to learn, or to move? It is often presumed that motivation involves slow (“tonic”) dopamine changes, while fast (“phasic”) dopamine fluctuations convey reward prediction errors for learning. Yet recent studies have shown that dopamine conveys motivational value, and promotes movement, even on sub-second timescales. Here I describe an alternative account of how dopamine regulates ongoing behavior. Dopamine release related to motivation is rapidly and locally sculpted by receptors on dopamine terminals, independently from dopamine cell firing. Target neurons abruptly switch between learning and performance modes, with striatal cholinergic interneurons providing one candidate switch mechanism. The behavioral impact of dopamine varies by subregion, but in each case dopamine provides a dynamic estimate of whether it is worth expending a limited internal resource, such as energy, attention, or time.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/599442
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                14 July 2020
                2020
                : 11
                : 1003
                Affiliations
                [1] 1 Independent Researcher , Amos, QC, Canada
                [2] 2 McArthur and Associates , Basel, Switzerland
                Author notes

                Edited by: Nikolaos Pitsikas, University of Thessaly, Greece

                Reviewed by: Estefanía Moreno, University of Barcelona, Spain; Katerina Antoniou, University of Ioannina, Greece

                *Correspondence: Silvia Gatti McArthur, silvia.gatti_mcarthur@ 123456rmcaa.org

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2020.01003
                7379027
                32765257
                6b3be278-6cc9-4cda-b51a-66a3b320c0e5
                Copyright © 2020 Martel and Gatti McArthur

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 April 2020
                : 22 June 2020
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 245, Pages: 17, Words: 9169
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                schizophrenia,dopamine receptor,nmda,antipsychotic,psychosis,d1,d2,d3
                Pharmacology & Pharmaceutical medicine
                schizophrenia, dopamine receptor, nmda, antipsychotic, psychosis, d1, d2, d3

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