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Brain, Behavior and Evolution 2015Dopamine neurotransmission regulates various brain functions, and its regulatory roles are mediated by two families of G protein-coupled receptors: the D1 and D2... (Review)
Review
Dopamine neurotransmission regulates various brain functions, and its regulatory roles are mediated by two families of G protein-coupled receptors: the D1 and D2 receptor families. In mammals, the D1 family comprises two receptor subtypes (D1 and D5), while the D2 family comprises three receptor subtypes (D2, D3 and D4). Phylogenetic analyses of dopamine receptor genes strongly suggest that the common ancestor of Osteichthyes (bony jawed vertebrates) possessed four subtypes in the D1 family and five subtypes in the D2 family. Mammals have secondarily lost almost half of the ancestral dopamine receptor genes, whereas nonmammalian species kept many of them. Although the mammalian situation is an exception among Osteichthyes, the current classification and characterization of dopamine receptors are based on mammalian features, which have led to confusion in the identification of dopamine receptor subtypes in nonmammalian species. Here we begin by reviewing the history of the discovery of dopamine receptors in vertebrates. The recent genome sequencing of coelacanth, gar and elephant shark led to the proposal of a refined scenario of evolution of dopamine receptor genes. We also discuss a current problem of nomenclature of dopamine receptors. Following the official nomenclature of mammalian dopamine receptors from D1 to D5, we propose to name newly identified receptor subtypes from D6 to D9 in order to facilitate the use of an identical name for orthologous genes among different species. To promote a nomenclature change which allows distinguishing the two dopamine receptor families, a nomenclature consortium is needed. This comparative perspective is crucial to correctly interpret data obtained in animal studies on dopamine-related brain disorders, and more fundamentally, to understand the characteristics of dopamine neurotransmission in vertebrates.
Topics: Animals; Biological Evolution; Fish Proteins; Fishes; Receptors, Dopamine; Terminology as Topic
PubMed: 26613258
DOI: 10.1159/000441550 -
The Journal of Neuroscience : the... Oct 2010Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons,...
Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation of the boundaries of dopaminergic volume transmission. Bursts primarily increase occupancy of D(1) receptors, whereas pauses translate into low occupancy of D(1) and D(2) receptors. Phasic firing patterns, composed of bursts and pauses, reduce the average D(2) receptor occupancy and increase average D(1) receptor occupancy compared with equivalent tonic firing. Receptor occupancy is crucially dependent on synchrony and the balance between tonic and phasic firing modes. Our results provide quantitative insight in the dynamics of volume transmission and complement experimental data obtained with electrophysiology, positron emission tomography, microdialysis, amperometry, and voltammetry.
Topics: Algorithms; Axons; Corpus Striatum; Dopamine; Electrophysiology; Extracellular Space; Kinetics; Models, Neurological; Models, Statistical; Nerve Endings; Neurons; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 20962248
DOI: 10.1523/JNEUROSCI.1894-10.2010 -
Technology in Cancer Research &... 2021The dopamine receptors (DRs) family includes 5 members with differences in signal transduction and ligand affinity. Abnormal DRs expression has been correlated multiple... (Review)
Review
The dopamine receptors (DRs) family includes 5 members with differences in signal transduction and ligand affinity. Abnormal DRs expression has been correlated multiple tumors with their clinical outcome. Thus, it has been proposed that DRs-targeting drugs-developed for other diseases as schizophrenia or Parkinson's disease-could be helpful in managing neoplastic diseases. In this review, we discuss the role of DRs and the effects of DRs-targeting in tumor progression and cancer cell biology using multiple high-prevalence neoplasms as examples. The evidence shows that DRs are valid therapeutic targets for certain receptor/disease combinations, but the data are inconclusive or contradictory for others. In either case, further studies are required to define the precise role of DRs in tumor progression and propose better therapeutic strategies for their targeting.
Topics: Animals; Dopamine Agonists; Dopamine Antagonists; Humans; Molecular Targeted Therapy; Neoplasms; Receptors, Dopamine; Signal Transduction
PubMed: 34212819
DOI: 10.1177/15330338211027913 -
Developmental Dynamics : An Official... Jul 2004We mined the zebrafish genomic sequence database and identified contigs containing segments of several dopamine receptor genes. By using a polymerase chain reaction...
We mined the zebrafish genomic sequence database and identified contigs containing segments of several dopamine receptor genes. By using a polymerase chain reaction amplification strategy, we generated full-length cDNAs encoding a single dopamine D3 receptor and three distinct D2 receptor subtypes. Zebrafish dopamine receptor genes were mapped by using the T51 radiation hybrid panel. The D3 receptor gene (drd3) mapped to linkage group (LG) 24. The three D2 receptor genes were localized to LG 15 (drd2a), LG 16, (drd2b), and LG 5 (drd2c). With the exception of the drd2b gene, each of these map positions was syntenic with regions of human chromosomes containing orthologs of the zebrafish dopamine receptor genes. Whole-mount in situ hybridization was used to investigate expression of the D2 and D3 receptor genes. Expression of the drd3 gene was first detected at mid-somitogenesis and was particularly prominent in somites. Thereafter, the drd3 gene was expressed diffusely throughout the brain and spinal cord. The three D2 receptor genes were expressed throughout the central nervous system (CNS) in distinct but overlapping patterns. In early embryos, the drd2a gene was expressed exclusively in the epiphysis, whereas the drd2c gene was localized to the notochord. After 24 hpf, the drd2a, drd2b, and drd2c genes were differentially expressed throughout the CNS. The identification of dopamine receptor genes in zebrafish should allow us to use the power of zebrafish genetics to analyze the functional properties of this important class of neurotransmitter receptors.
Topics: Amino Acid Sequence; Animals; Central Nervous System; Chromosome Mapping; Conserved Sequence; Embryo, Nonmammalian; Evolution, Molecular; Exons; Genetic Linkage; Humans; Introns; Molecular Sequence Data; Phylogeny; Protein Structure, Tertiary; Receptors, Dopamine D2; Receptors, Dopamine D3; Sequence Homology, Amino Acid; Somites; Synteny; Tissue Distribution; Zebrafish
PubMed: 15188433
DOI: 10.1002/dvdy.20075 -
Neuron Feb 2006The dopamine hypothesis of schizophrenia is based on evidence that the major antipsychotic drugs act by blocking dopamine D2 receptors and that dopamine-releasing drugs...
The dopamine hypothesis of schizophrenia is based on evidence that the major antipsychotic drugs act by blocking dopamine D2 receptors and that dopamine-releasing drugs worsen symptoms. In this issue of Neuron, Kellendonk et al. report an elegant conditional transgenic mouse overexpressing dopamine D2 receptors selectively in the striatum. Strikingly, these animals display selective cognitive impairment typically associated with frontal cortical defects and abnormal dopamine markers in the prefrontal cortex, suggesting that striatal dopamine receptors can influence cortical dopamine function.
Topics: Animals; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Mice; Prefrontal Cortex; Receptors, Dopamine D2
PubMed: 16476659
DOI: 10.1016/j.neuron.2006.02.002 -
Neurobiology of Disease Jan 2010Low doses of psychostimulants produce beneficial behavioral effects in ADHD patients but the mechanisms underlying the response are not understood. Here we use the...
Low doses of psychostimulants produce beneficial behavioral effects in ADHD patients but the mechanisms underlying the response are not understood. Here we use the hyperactive mouse mutant coloboma to identify D2-like dopamine receptor subtypes that mediate the hyperactivity and response to amphetamine; we have previously demonstrated that D1-like dopamine receptors are not involved. Targeted deletion of the D2, but not the D3 or the D4, dopamine receptor in coloboma mice eliminated the hyperactivity; depleting D2 dopamine receptors also restored the excess dopamine overflow that may drive the hyperactivity to normal concentrations. Similar to its effects on ADHD patients, amphetamine reduced the hyperactivity of coloboma mice. The D2 dopamine receptor-selective antagonist L-741,626, but not D3 or D4 dopamine receptor-selective antagonists, blocked the amphetamine-induced reduction in locomotor activity. Thus, the D2 dopamine receptor subtype mediates both the hyperactivity and response to amphetamine, suggesting a specific target for novel therapeutics in ADHD.
Topics: Amphetamine; Animals; Attention Deficit Disorder with Hyperactivity; Benzopyrans; Corpus Striatum; Dihydroxyphenylalanine; Disease Models, Animal; Dopamine; Dopamine Agents; Dopamine D2 Receptor Antagonists; Extracellular Space; Indoles; Locomotion; Mice; Mice, Knockout; Mice, Mutant Strains; Piperidines; Pyridines; Pyrroles; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Dopamine D4
PubMed: 19840852
DOI: 10.1016/j.nbd.2009.10.009 -
Clinical Cancer Research : An Official... Apr 2019Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other...
PURPOSE
Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anticancer small molecule in clinical trials for high-grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201.
EXPERIMENTAL DESIGN
The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in >1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. IHC staining of DRD2/DRD5 was performed on tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies.
RESULTS
DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from patients with recurrent glioblastoma treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes.
CONCLUSIONS
These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.
Topics: Antineoplastic Agents; Biomarkers; Cell Line, Tumor; Cell Survival; Dopamine D2 Receptor Antagonists; Drug Resistance; Gene Expression; Humans; Imidazoles; Immunohistochemistry; Magnetic Resonance Imaging; Neoplasm Grading; Neoplasm Staging; Neoplasms; Prognosis; Protein Binding; Pyridines; Pyrimidines; Receptors, Dopamine D2; Receptors, Dopamine D5; Signal Transduction
PubMed: 30559168
DOI: 10.1158/1078-0432.CCR-18-2572 -
Scientific Reports Jun 2023The striatum integrates dense neuromodulatory inputs from many brain regions to coordinate complex behaviors. This integration relies on the coordinated responses from...
The striatum integrates dense neuromodulatory inputs from many brain regions to coordinate complex behaviors. This integration relies on the coordinated responses from distinct striatal cell types. While previous studies have characterized the cellular and molecular composition of the striatum using single-cell RNA-sequencing at distinct developmental timepoints, the molecular changes spanning embryonic through postnatal development at the single-cell level have not been examined. Here, we combine published mouse striatal single-cell datasets from both embryonic and postnatal timepoints to analyze the developmental trajectory patterns and transcription factor regulatory networks within striatal cell types. Using this integrated dataset, we found that dopamine receptor-1 expressing spiny projection neurons have an extended period of transcriptional dynamics and greater transcriptional complexity over postnatal development compared to dopamine receptor-2 expressing neurons. Moreover, we found the transcription factor, FOXP1, exerts indirect changes to oligodendrocytes. These data can be accessed and further analyzed through an interactive website ( https://mouse-striatal-dev.cells.ucsc.edu ).
Topics: Animals; Mice; Neurons; Corpus Striatum; Neostriatum; Transcription Factors; Receptors, Dopamine
PubMed: 37270616
DOI: 10.1038/s41598-023-36255-5 -
Journal of Internal Medicine May 2013Methamphetamine is a synthetic drug consumed by millions of users despite its neurotoxic effects in the brain, leading to loss of dopaminergic fibres and cell bodies.... (Review)
Review
Methamphetamine is a synthetic drug consumed by millions of users despite its neurotoxic effects in the brain, leading to loss of dopaminergic fibres and cell bodies. Moreover, clinical reports suggest that methamphetamine abusers are predisposed to Parkinson's disease. Therefore, it is important to elucidate the mechanisms involved in methamphetamine-induced neurotoxicity. Dopamine receptors may be a plausible target to prevent this neurotoxicity. Genetic inactivation of dopamine D1 or D2 receptors protects against the loss of dopaminergic fibres in the striatum and loss of dopaminergic neurons in the substantia nigra. Protection by D1 receptor inactivation is due to blockade of hypothermia, reduced dopamine content and turnover and increased stored vesicular dopamine in D1R(-/-) mice. However, the neuroprotective impact of D2 receptor inactivation is partially dependent on an effect on body temperature, as well as on the blockade of dopamine reuptake by decreased dopamine transporter activity, which results in reduced intracytosolic dopamine levels in D2R(-/-) mice.
Topics: Animals; Dopamine Agents; Humans; Methamphetamine; Mice; Neurotoxicity Syndromes; Oxidative Stress; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 23600399
DOI: 10.1111/joim.12049 -
Brain Research Jan 2011We have recently established the socially monogamous prairie vole (Microtus ochrogaster) as an animal model with which to investigate the involvement of...
We have recently established the socially monogamous prairie vole (Microtus ochrogaster) as an animal model with which to investigate the involvement of mesocorticolimbic dopamine (DA) in the amphetamine (AMPH)-induced impairment of social behavior. As the majority of our work, to date, has focused on males, and sex differences are commonly reported in the behavioral and neurobiological responses to AMPH, the current study was designed to examine the behavioral and neurobiological effects of AMPH treatment in female prairie voles. We used a conditioned place preference (CPP) paradigm to determine a dose-response curve for the behavioral effects of AMPH in female prairie voles, and found that conditioning with low to intermediate (0.2 and 1.0 mg/kg), but not very low (0.1 mg/kg), doses of AMPH induced a CPP. We also found that exposure to a behaviorally relevant dose of AMPH (1.0 mg/kg) induced an increase in DA concentration in the nucleus accumbens (NAcc) and caudate putamen but not the medial prefrontal cortex or ventral tegmental area (VTA). Finally, repeated AMPH exposure (1.0 mg/kg once per day for 3 consecutive days; an injection paradigm that has been recently shown to alter DA receptor expression and impair social bonding in male prairie voles) increased D1, but not D2, receptor mRNA in the NAcc, and decreased D2 receptor mRNA and D2-like receptor binding in the VTA. Together, these data indicate that AMPH alters mesocorticolimbic DA neurotransmission in a region- and receptor-specific manner, which, in turn, could have profound consequences on social behavior in female prairie voles.
Topics: Amphetamine; Animals; Arvicolinae; Behavior, Animal; Brain; Central Nervous System Stimulants; Chromatography, High Pressure Liquid; Conditioning, Operant; Dopamine; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Protein Binding; RNA, Messenger; Receptors, Dopamine
PubMed: 20933511
DOI: 10.1016/j.brainres.2010.09.109