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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 -
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 Feb 2021Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney...
Dopamine receptors, including D1- and D2-like receptors, are important therapeutic targets in a variety of neurological syndromes, as well as cardiovascular and kidney diseases. Here, we present five cryoelectron microscopy (cryo-EM) structures of the dopamine D1 receptor (DRD1) coupled to Gs heterotrimer in complex with three catechol-based agonists, a non-catechol agonist, and a positive allosteric modulator for endogenous dopamine. These structures revealed that a polar interaction network is essential for catecholamine-like agonist recognition, whereas specific motifs in the extended binding pocket were responsible for discriminating D1- from D2-like receptors. Moreover, allosteric binding at a distinct inner surface pocket improved the activity of DRD1 by stabilizing endogenous dopamine interaction at the orthosteric site. DRD1-Gs interface revealed key features that serve as determinants for G protein coupling. Together, our study provides a structural understanding of the ligand recognition, allosteric regulation, and G protein coupling mechanisms of DRD1.
Topics: Allosteric Regulation; Allosteric Site; Amino Acid Motifs; Amino Acid Sequence; Binding Sites; Catechols; Cryoelectron Microscopy; Fenoldopam; GTP-Binding Protein alpha Subunits, Gs; HEK293 Cells; Humans; Ligands; Models, Molecular; Protein Multimerization; Receptors, Dopamine D1; Receptors, Dopamine D2; Signal Transduction; Structural Homology, Protein
PubMed: 33571432
DOI: 10.1016/j.cell.2021.01.028 -
Translational Psychiatry Sep 2022Social isolation and discrimination are growing public health concerns associated with poor physical and mental health. They are risk factors for increased morbidity and... (Review)
Review
Social isolation and discrimination are growing public health concerns associated with poor physical and mental health. They are risk factors for increased morbidity and mortality and reduced quality of life. Despite their detrimental effects on health, there is a lack of knowledge regarding translation across the domains of experimental research, clinical studies, and real-life applications. Here, we review and synthesize evidence from basic research in animals and humans to clinical translation and interventions. Animal models indicate that social separation stress, particularly in early life, activates the hypothalamic-pituitary-adrenal axis and interacts with monoaminergic, glutamatergic, and GABAergic neurotransmitter systems, inducing long-lasting reductions in serotonin turnover and alterations in dopamine receptor sensitivity. These findings are of particular importance for human social isolation stress, as effects of social isolation stress on the same neurotransmitter systems have been implicated in addictive, psychotic, and affective disorders. Children may be particularly vulnerable due to lasting effects of social isolation and discrimination stress on the developing brain. The effects of social isolation and loneliness are pronounced in the context of social exclusion due to discrimination and racism, during widespread infectious disease related containment strategies such as quarantine, and in older persons due to sociodemographic changes. This highlights the importance of new strategies for social inclusion and outreach, including gender, culture, and socially sensitive telemedicine and digital interventions for mental health care.
Topics: Aged; Animals; Child; Humans; Hypothalamo-Hypophyseal System; Mental Health; Neurotransmitter Agents; Pituitary-Adrenal System; Quality of Life; Receptors, Dopamine; Serotonin; Social Isolation
PubMed: 36130935
DOI: 10.1038/s41398-022-02178-4 -
Cell Jan 2015Inflammasomes are involved in diverse inflammatory diseases, so the activation of inflammasomes needs to be tightly controlled to prevent excessive inflammation....
Inflammasomes are involved in diverse inflammatory diseases, so the activation of inflammasomes needs to be tightly controlled to prevent excessive inflammation. However, the endogenous regulatory mechanisms of inflammasome activation are still unclear. Here, we report that the neurotransmitter dopamine (DA) inhibits NLRP3 inflammasome activation via dopamine D1 receptor (DRD1). DRD1 signaling negatively regulates NLRP3 inflammasome via a second messenger cyclic adenosine monophosphate (cAMP), which binds to NLRP3 and promotes its ubiquitination and degradation via the E3 ubiquitin ligase MARCH7. Importantly, in vivo data show that DA and DRD1 signaling prevent NLRP3 inflammasome-dependent inflammation, including neurotoxin-induced neuroinflammation, LPS-induced systemic inflammation, and monosodium urate crystal (MSU)-induced peritoneal inflammation. Taken together, our results reveal an endogenous mechanism of inflammasome regulation and suggest DRD1 as a potential target for the treatment of NLRP3 inflammasome-driven diseases.
Topics: Animals; Autophagy; Carrier Proteins; Cyclic AMP; Dopamine; Inflammasomes; Inflammation; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Neurotransmitter Agents; Protein Aggregates; Receptors, Dopamine; Receptors, Dopamine D1; Signal Transduction; Ubiquitination
PubMed: 25594175
DOI: 10.1016/j.cell.2014.11.047 -
Nature Neuroscience Aug 2023Elevated dopamine transmission in psychosis is assumed to unbalance striatal output through D1- and D2-receptor-expressing spiny-projection neurons (SPNs). Antipsychotic...
Elevated dopamine transmission in psychosis is assumed to unbalance striatal output through D1- and D2-receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by blocking D2 receptors (D2Rs). In this study, we found that amphetamine-driven dopamine release unbalanced D1-SPN and D2-SPN Ca activity in mice, but that antipsychotic efficacy was associated with the reversal of abnormal D1-SPN, rather than D2-SPN, dynamics, even for drugs that are D2R selective or lacking any dopamine receptor affinity. By contrast, a clinically ineffective drug normalized D2-SPN dynamics but exacerbated D1-SPN dynamics under hyperdopaminergic conditions. Consistent with antipsychotic effect, selective D1-SPN inhibition attenuated amphetamine-driven changes in locomotion, sensorimotor gating and hallucination-like perception. Notably, antipsychotic efficacy correlated with the selective inhibition of D1-SPNs only under hyperdopaminergic conditions-a dopamine-state-dependence exhibited by D1R partial agonism but not non-antipsychotic D1R antagonists. Our findings provide new insights into antipsychotic drug mechanism and reveal an important role for D1-SPN modulation.
Topics: Mice; Animals; Antipsychotic Agents; Dopamine; Corpus Striatum; Neurons; Interneurons; Receptors, Dopamine D2; Receptors, Dopamine D1
PubMed: 37443282
DOI: 10.1038/s41593-023-01390-9 -
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 -
Frontiers in Endocrinology 2022The functional and pharmacological significance of the dopamine D receptor (DR) has remained the least well understood of all the dopamine receptor subtypes. Even more... (Review)
Review
The functional and pharmacological significance of the dopamine D receptor (DR) has remained the least well understood of all the dopamine receptor subtypes. Even more enigmatic has been the role of the very prevalent human gene polymorphisms in the region that encodes the third intracellular loop of the receptor. The most common polymorphisms encode a DR with 4 or 7 repeats of a proline-rich sequence of 16 amino acids (DR and DR). polymorphisms have been associated with individual differences linked to impulse control-related neuropsychiatric disorders, with the most consistent associations established between the gene encoding DR and attention-deficit hyperactivity disorder (ADHD) and substance use disorders. The function of DR and its polymorphic variants is being revealed by addressing the role of receptor heteromerization and the relatively avidity of norepinephrine for DR. We review the evidence conveying a significant and differential role of DR and DR in the dopaminergic and noradrenergic modulation of the frontal cortico-striatal pyramidal neuron, with implications for the moderation of constructs of impulsivity as personality traits. This differential role depends on their ability to confer different properties to adrenergic α receptor (αR)-DR heteromers and dopamine D receptor (DR)-DR heteromers, preferentially localized in the perisomatic region of the frontal cortical pyramidal neuron and its striatal terminals, respectively. We also review the evidence to support the DR as a therapeutic target for ADHD and other impulse-control disorders, as well as for restless legs syndrome.
Topics: Humans; Receptors, Dopamine D4; Dopamine; Norepinephrine; Adrenergic Agents; Amino Acids; Proline
PubMed: 36267569
DOI: 10.3389/fendo.2022.1014678 -
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-κB 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 -
Neoplasia (New York, N.Y.) May 2023Recent studies indicate that signaling molecules traditionally associated with central nervous system function play critical roles in cancer. Dopamine receptor signaling...
Recent studies indicate that signaling molecules traditionally associated with central nervous system function play critical roles in cancer. Dopamine receptor signaling is implicated in various cancers including glioblastoma (GBM) and it is a recognized therapeutic target, as evidenced by recent clinical trials with a selective dopamine receptor D2 (DRD2) inhibitor ONC201. Understanding the molecular mechanism(s) of the dopamine receptor signaling will be critical for development of potent therapeutic options. Using the human GBM patient-derived tumors treated with dopamine receptor agonists and antagonists, we identified the proteins that interact with DRD2. DRD2 signaling promotes glioblastoma (GBM) stem-like cells and GBM growth by activating MET. In contrast, pharmacological inhibition of DRD2 induces DRD2-TRAIL receptor interaction and subsequent cell death. Thus, our findings demonstrate a molecular circuitry of oncogenic DRD2 signaling in which MET and TRAIL receptors, critical factors for tumor cell survival and cell death, respectively, govern GBM survival and death. Finally, tumor-derived dopamine and expression of dopamine biosynthesis enzymes in a subset of GBM may guide patient stratification for DRD2 targeting therapy.
Topics: Humans; Cell Line, Tumor; Dopamine; Glioblastoma; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; Receptors, Dopamine D2
PubMed: 36972629
DOI: 10.1016/j.neo.2023.100894