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Nature Reviews. Neuroscience May 2015For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this... (Review)
Review
For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.
Topics: Animals; Behavior, Addictive; Dopamine; Humans; Receptors, Dopamine; Reward
PubMed: 25873042
DOI: 10.1038/nrn3939 -
Physiological Reviews Jan 1998The 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)... (Review)
Review
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.
Topics: Animals; Animals, Genetically Modified; Brain; Gene Expression Regulation; Humans; Hypertension; Mice; Pituitary Gland; Receptors, Dopamine; Signal Transduction
PubMed: 9457173
DOI: 10.1152/physrev.1998.78.1.189 -
Cell Feb 2021The D1- and D2-dopamine receptors (D1R and D2R), which signal through G and G, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the...
The D1- and D2-dopamine receptors (D1R and D2R), which signal through G and G, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-G and D2R-G signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amino Acid Sequence; Conserved Sequence; Cryoelectron Microscopy; Cyclic AMP; GTP-Binding Proteins; HEK293 Cells; Humans; Ligands; Models, Molecular; Mutant Proteins; Receptors, Adrenergic, beta-2; Receptors, Dopamine D1; Receptors, Dopamine D2; Signal Transduction; Structural Homology, Protein
PubMed: 33571431
DOI: 10.1016/j.cell.2021.01.027 -
Cell Jun 2014Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain...
Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1 dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics.
Topics: Animals; Calcium Signaling; Female; Mice; Neural Pathways; Nucleus Accumbens; Photometry; Receptors, Dopamine; Reward; Rhodopsin; Social Behavior; Ventral Tegmental Area
PubMed: 24949967
DOI: 10.1016/j.cell.2014.05.017 -
International Journal of Molecular... Nov 2020The renal dopaminergic system has been identified as a modulator of sodium balance and blood pressure. According to the Centers for Disease Control and Prevention, in... (Review)
Review
The renal dopaminergic system has been identified as a modulator of sodium balance and blood pressure. According to the Centers for Disease Control and Prevention, in 2018 in the United States, almost half a million deaths included hypertension as a primary or contributing cause. Renal dopamine receptors, members of the G protein-coupled receptor family, are divided in two groups: D1-like receptors that act to keep the blood pressure in the normal range, and D2-like receptors with a variable effect on blood pressure, depending on volume status. The renal dopamine receptor function is regulated, in part, by its expression in microdomains in the plasma membrane. Lipid rafts form platforms within the plasma membrane for the organization and dynamic contact of molecules involved in numerous cellular processes such as ligand binding, membrane sorting, effector specificity, and signal transduction. Understanding all the components of lipid rafts, their interaction with renal dopamine receptors, and their signaling process offers an opportunity to unravel potential treatment targets that could halt the progression of hypertension, chronic kidney disease (CKD), and their complications.
Topics: Blood Pressure; Cell Membrane; Dopamine; Humans; Hypertension; Kidney; Membrane Microdomains; Receptors, Dopamine D1; Receptors, Dopamine D2; Signal Transduction; Sodium
PubMed: 33255376
DOI: 10.3390/ijms21238909 -
Handbook of Experimental Pharmacology 2012All currently efficacious antipsychotic drugs have as part of their mechanism the ability to attenuate some or all of the signaling through the dopamine D(2) receptor.... (Review)
Review
All currently efficacious antipsychotic drugs have as part of their mechanism the ability to attenuate some or all of the signaling through the dopamine D(2) receptor. More recently, the dopamine D(1) receptor has been hypothesized to be a promising target for the treatment of negative and/or cognitive aspects of schizophrenia that are not improved by current antipsychotics. Although cAMP has been presumed to be the primary messenger for signaling through the dopamine receptors, the last decade has unveiled a complexity that has provided exciting avenues for the future discovery of antipsychotic drugs (APDs). We review the signaling mechanisms of currently approved APDs at dopamine D(2) receptors, and note that aripiprazole is a compound that is clearly differentiated from other approved drugs. Although aripiprazole has been postulated to cause dopamine stabilization due to its partial D(2) agonist properties, a body of literature suggests that an alternative mechanism, functional selectivity, is of primary importance. Finally, we review the signaling at dopamine D(1) receptors, and the idea that drugs that activate D(1) receptors may have use as APDs for improving negative and cognitive symptoms. We address the current state of drug discovery in the D(1) area and its relationship to novel signaling mechanisms. Our conclusion is that although the first APD targeting dopamine receptors was discovered more than a half-century ago, recent research advances offer the possibility that novel and/or improved drugs will emerge in the next decade.
Topics: Animals; Antipsychotic Agents; Humans; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Signal Transduction; Type C Phospholipases
PubMed: 23129328
DOI: 10.1007/978-3-642-25761-2_3 -
Pathology Oncology Research : POR Jul 2020In preclinical studies serotonin stimulates and dopamine inhibits tumour growth and angiogenesis. Information regarding serotonin and dopamine receptor (5-HTR and DRD)...
In preclinical studies serotonin stimulates and dopamine inhibits tumour growth and angiogenesis. Information regarding serotonin and dopamine receptor (5-HTR and DRD) expression in human cancers is limited. Therefore, we screened a large tumour set for receptor mRNA overexpression using functional genomic mRNA (FGmRNA) profiling, and we analysed protein expression and location of 5-HTR1B, 5-HTR2B, DRD1, and DRD2 with immunohistochemistry in different tumour types. With FGmRNA profiling 11,756 samples representing 43 tumour types were compared to 3,520 normal tissue samples to analyse receptor overexpression. 5-HTR2B overexpression was present in many tumour types, most frequently in uveal melanomas (56%). Receptor overexpression in rare cancers included 5-HTR1B in nasopharyngeal carcinoma (17%), DRD1 in ependymoma (30%) and synovial sarcoma (21%), and DRD2 in astrocytoma (13%). Immunohistochemistry demonstrated high 5-HTR2B protein expression on melanoma and gastro-intestinal stromal tumour cells and endothelial cells of colon, ovarian, breast, renal and pancreatic tumours. 5-HTR1B expression was predominantly low. High DRD2 protein expression on tumour cells was observed in 48% of pheochromocytomas, and DRD1 expression ranged from 14% in melanoma to 57% in renal cell carcinoma. In conclusion, 5-HTR1B, 5-HTR2B, DRD1, and DRD2 show mRNA overexpression in a broad spectrum of common and rare cancers. 5-HTR2B protein is frequently highly expressed in human cancers, especially on endothelial cells. These findings support further investigation of especially 5HTR2B as a potential treatment target.
Topics: Biomarkers, Tumor; Humans; Neoplasms; Receptors, Dopamine; Receptors, Serotonin
PubMed: 31478179
DOI: 10.1007/s12253-019-00734-w -
Frontiers in Immunology 2021Dopamine (DA) receptor, a significant G protein-coupled receptor, is classified into two families: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptor families,... (Review)
Review
Dopamine (DA) receptor, a significant G protein-coupled receptor, is classified into two families: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptor families, with further formation of homodimers, heteromers, and receptor mosaic. Increasing evidence suggests that the immune system can be affected by the nervous system and neurotransmitters, such as dopamine. Recently, the role of the DA receptor in inflammation has been widely studied, mainly focusing on NLRP3 inflammasome, NF-ÎșB pathway, and immune cells. This article provides a brief review of the structures, functions, and signaling pathways of DA receptors and their relationships with inflammation. With detailed descriptions of their roles in Parkinson disease, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, this article provides a theoretical basis for drug development targeting DA receptors in inflammatory diseases.
Topics: Animals; Biomarkers; Carrier Proteins; Disease Susceptibility; Dopamine; Humans; Immunomodulation; Inflammation; Organ Specificity; Protein Binding; Protein Multimerization; Receptors, Dopamine; Signal Transduction
PubMed: 33897712
DOI: 10.3389/fimmu.2021.663102 -
Biomolecules Mar 2021Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not...
Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not discriminate among different DR subtypes and may even stimulate alpha1 and beta-adrenoceptors. Here, we tested the hypothesis that D2R and/or D3R may specifically induce vasoconstriction in isolated mouse aorta. Aorta, isolated from wild-type (WT) and D3R/ mice, was mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE), acetylcholine (ACh), and the D3R agonist 7-hydrxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT), with or without the D2R antagonist L741,626 and the D3R antagonist SB-277011-A. The vasoconstriction to PE and the vasodilatation to ACh were not different in WT and D3R/; in contrast, the contractile responses to 7-OH-DPAT were significantly weaker in D3R/, though not abolished. L741,626 did not change the contractile response induced by 7-OH-DPAT in WT or in D3R/, whereas SB-277011-A significantly reduced it in WT but did not in D3R/. D3R mRNA (assessed by qPCR) was about 5-fold more abundant than D2R mRNA in aorta from WT and undetectable in aorta from D3R/. Following transduction with lentivirus (72-h incubation) delivering synthetic microRNAs to specifically inactivate D2R (LV-miR-D2) or D3R (LV-miR-D3), the contractile response to 7-OH-DPAT was unaffected by LV-miR-D2, while it was significantly reduced by LV-miR-D3. These data indicate that, at least in mouse aorta, D3R stimulation induces vasoconstriction, while D2R stimulation does not. This is consistent with the higher expression level of D3R. The residual vasoconstriction elicited by high concentration D3R agonist in D3R/ and/or in the presence of D3R antagonist is likely to be unrelated to DRs.
Topics: Animals; Aorta; Indoles; Male; Mice, Inbred C57BL; Mice, Knockout; Nitriles; Piperidines; RNA, Messenger; Receptors, Dopamine D2; Receptors, Dopamine D3; Tetrahydroisoquinolines; Tetrahydronaphthalenes; Vasoconstriction; Mice
PubMed: 33799860
DOI: 10.3390/biom11030418 -
International Journal of Molecular... Apr 2021Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present differences in both clinical progression and response to drug therapy that are partly affected by genetic factors. Despite extensive knowledge on genetic variability of dopaminergic receptors (DR), few studies have addressed their relevance as possible influencers of clinical heterogeneity in PD patients. In this review, we summarized available evidence regarding the role of genetic polymorphisms in DR as possible determinants of PD development, progression and treatment response. Moreover, we examined the role of DR in the modulation of peripheral immunity, in light of the emerging role of the peripheral immune system in PD pathophysiology. A better understanding of all these aspects represents an important step towards the development of precise and personalized disease-modifying therapies for PD.
Topics: Humans; Parkinson Disease; Polymorphism, Genetic; Receptors, Dopamine
PubMed: 33917417
DOI: 10.3390/ijms22073781