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Neuroscience Dec 2012The irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been used to study the ontogeny of dopamine (DA) receptor functioning in...
The irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been used to study the ontogeny of dopamine (DA) receptor functioning in young and adult rats. Most notably, systemic administration of EEDQ blocks the DA agonist-induced behaviors of adult rats, while leaving the behavior of preweanling rats unaffected. The purpose of the present study was to: (a) determine whether the age-dependent actions of EEDQ involve receptors located in the dorsal caudate-putamen (CPu) and (b) confirm that EEDQ's behavioral effects result from the inactivation of DA receptors rather than some other receptor type. In Experiment 1, EEDQ or DMSO was bilaterally infused into the CPu on PD 17 or PD 84. After 24h, rats were given bilateral microinjections of the full DA agonist R(-)-propylnorapomorphine (NPA) or vehicle into the dorsal CPu and behavior was assessed for 40 min. In Experiment 2, preweanling rats were treated as just described, except that DA receptors were protected from EEDQ-induced alkylation by administering systemic injections of D1 (SCH23390) and D2 (sulpiride) receptor antagonists. As predicted, microinjecting EEDQ into the dorsal CPu attenuated the NPA-induced locomotor activity and stereotypy of adult rats. In contrast, rats given bilateral EEDQ infusions on PD 17 exhibited a potentiated locomotor response when treated with NPA. Experiment 2 showed that DA receptor inactivation was responsible for NPA's actions. A likely explanation for these results is that EEDQ inactivates a sizable percentage of DA receptors on PD 17, but leaves the remaining receptors in a supersensitive state. This receptor supersensitivity, which probably involves alterations in G protein coupling, could account for NPA-induced locomotor potentiation. It is likely that adult rats to not show a similar EEDQ-induced change in receptor dynamics or DA receptor inactivation was more complete in older animals and effectively eliminated the expression of DA agonist-induced behaviors.
Topics: Aging; Animals; Autoradiography; Behavior, Animal; Caudate Nucleus; Conditioning, Operant; Dopamine Agonists; Dopamine Antagonists; Female; Male; Microinjections; Motor Activity; Putamen; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 23000622
DOI: 10.1016/j.neuroscience.2012.09.030 -
Oncogene Jun 2016Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a...
Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease. Strong to moderate immunoreactive D1R expression was found in 30% of 751 primary breast carcinomas, and was associated with larger tumors, higher tumor grades, node metastasis and shorter patient survival. DA and D1R agonists, signaling through the cGMP/protein kinase G (PKG) pathway, suppressed cell viability, inhibited invasion and induced apoptosis in multiple breast cancer cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in two mouse models with D1R-expressing xenografts by increasing both necrosis and apoptosis. D1R-expressing primary tumors and metastases in mice were detected by fluorescence imaging. In conclusion, D1R overexpression is associated with advanced breast cancer and poor prognosis. Activation of the D1R/cGMP/PKG pathway induces apoptosis in vitro and causes tumor shrinkage in vivo. Fenoldopam, which is FDA (Food and Drug Administration) approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors.
Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Dopamine Agonists; Dopamine Antagonists; Female; HEK293 Cells; Heterografts; Humans; MCF-7 Cells; Mice; Middle Aged; Molecular Targeted Therapy; Receptors, Dopamine; Signal Transduction
PubMed: 26477316
DOI: 10.1038/onc.2015.369 -
Hormones and Behavior Jan 2021Dopamine signaling mediates the formation of some types of social relationships, including reproductive pair bonds in the socially monogamous prairie vole (Microtus...
Dopamine signaling mediates the formation of some types of social relationships, including reproductive pair bonds in the socially monogamous prairie vole (Microtus ochrogaster). In addition to these pair bonds with mates, prairie voles demonstrate selective preferences for familiar same-sex peers. The dependence of peer relationships on dopamine signaling has not been tested, and the mechanisms supporting these relationships may differ from those underlying pair bonds. We examined the effects of pharmacological manipulations of dopamine signaling on peer partner preference and socially conditioned place preference in female prairie voles. Haloperidol blockade of dopamine receptors at multiple doses did not alter selective preferences for familiar same-sex partners, suggesting that dopamine neurotransmission is not necessary for the formation of prairie vole peer relationships, unlike mate relationships. Dopamine receptor agonist apomorphine facilitated peer partner preferences under conditions normally insufficient for partner preference formation; however, in the absence of effects from blockade, it is difficult to distinguish between a role for dopamine in partner preference formation and the generally rewarding properties of a dopamine agonist. Prairie voles exhibited socially conditioned place preferences for new but not long-term same-sex peers, and these preferences were not blocked by haloperidol. These results suggest that prairie vole peer relationships are less dependent on dopamine signaling than pair bonds, while still being rewarding. The data support distinct roles of dopamine and motivation in prairie vole peer relationships relative to mate relationships, suggesting that reproductive bonds are mediated differently from non-reproductive ones.
Topics: Animals; Arvicolinae; Dopamine; Dopamine Agonists; Female; Male; Motivation; Pair Bond; Peer Group; Receptors, Dopamine; Reward; Sexual Behavior, Animal; Signal Transduction; Social Behavior
PubMed: 33152338
DOI: 10.1016/j.yhbeh.2020.104876 -
International Journal of Developmental... Nov 2000The family of five dopamine receptors subtypes activate cellular effector systems through G proteins. Historically, dopamine receptors were thought to only stimulate or... (Review)
Review
The family of five dopamine receptors subtypes activate cellular effector systems through G proteins. Historically, dopamine receptors were thought to only stimulate or inhibit adenylyl cyclase, by coupling to either G(s)alpha or G(i)alpha, respectively. Recent studies in transfected cells, reviewed here, have shown that multiple and highly diverse signaling pathways are activated by specific dopamine receptor subtypes. This multiplicity of signaling responses occurs through selective coupling to distinct G proteins and each of the receptors can interact with more than one G protein. Although some of the multiple coupling of dopamine receptors to different G proteins occurs from within the same family of G proteins, these receptors can also couple to G proteins belonging to different families. Such multiple interactions between receptors and G proteins elicits functionally distinct physiological effects which acts to enhance and subsequently suppress the original receptor response, and to activate apparently distinct signaling pathways. In the brain, where coexpression of functionally distinct receptors in heterogeneous cells further adds to the complexity of dopamine signaling, minor alterations in receptor/G protein coupling states during either development or in adults, may underlie the imbalanced signaling seen in dopaminergic-linked diseases such as schizophrenia, Parkinson's disease and attention deficit hyperactivity disorder.
Topics: Animals; GTP-Binding Proteins; Humans; Nervous System; Receptors, Dopamine
PubMed: 10978845
DOI: 10.1016/s0736-5748(00)00033-2 -
Brain Imaging and Behavior Feb 2022D-like dopamine receptors in animals and humans have been shown to be linked to impulsive behaviors that are highly relevant for several psychiatric disorders. Here, we...
D-like dopamine receptors in animals and humans have been shown to be linked to impulsive behaviors that are highly relevant for several psychiatric disorders. Here, we investigate the relationship between the fronto-striatal D/D dopamine receptor availability and response inhibition in a selected population of healthy OPRM1 G-allele carriers. Twenty-two participants successively underwent blood-oxygen level dependent functional magnetic resonance imaging (fMRI) while performing a stop-signal task and a separate positron emission tomography (PET) scan. Striatal and extrastriatal D/D dopamine receptor availability was measured using the radiotracer [F]fallypride. Caudate D/D dopamine receptor availability positively correlated with stopping-related fronto-striatal fMRI activation. In addition, right prefrontal D/D dopamine receptor availability correlated positively with stopping-related striatal fMRI BOLD signal. Our study partially replicates previous findings on correlations between striatal D/D dopamine receptor availability and response inhibition in a population selected for its genetic determination of dopamine response to alcohol and as a modulator of impulse control via the endogenous opioid system. We confirm the important role of D/D dopamine receptor availability in the fronto-striatal neural circuit for response inhibition. Moreover, we extend previous findings suggesting that dopamine receptor availability in the right inferior frontal cortex, a crucial region of the stopping network, is also strongly associated with stopping-related striatal fMRI activity in healthy OPRM1 G-allele carriers.
Topics: Animals; Corpus Striatum; Dopamine; Humans; Magnetic Resonance Imaging; Positron-Emission Tomography; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 34403039
DOI: 10.1007/s11682-021-00491-y -
NeuroImage May 2009The relationship between cerebral morphology and the expression of dopamine receptors has not been extensively studied in humans. Elucidation of such relationships may...
The relationship between cerebral morphology and the expression of dopamine receptors has not been extensively studied in humans. Elucidation of such relationships may have important methodological implications for clinical studies of dopamine receptor ligand binding differences between control and patient groups. The association between cerebral morphology and dopamine receptor distribution was examined in 45 healthy subjects who completed T1-weighted structural MRI and PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Optimized voxel-based morphometry was used to create grey matter volume and density images. Grey matter volume and density images were correlated with binding potential (BP(ND)) images on a voxel-by-voxel basis using the Biological Parametric Mapping toolbox. Associations between cerebral morphology and BP(ND) were also examined for selected regions-of-interest (ROIs) after spatial normalization. Voxel-wise analyses indicated that grey matter volume and density positively correlated with BP(ND) throughout the midbrain, including the substantia nigra. Positive correlations were observed in medial cortical areas, including anterior cingulate and medial prefrontal cortex, and circumscribed regions of the temporal, frontal, and parietal lobes. ROI analyses revealed significant positive correlations between BP(ND) and cerebral morphology in the caudate, thalamus, and amygdala. Few negative correlations between morphology and BP(ND) were observed. Overall, grey matter density appeared more strongly correlated with BP(ND) than grey matter volume. Cerebral morphology, particularly grey matter density, correlates with [(18)F]fallypride BP(ND) in a regionally specific manner. Clinical studies comparing dopamine receptor availability between clinical and control groups may benefit by accounting for potential differences in cerebral morphology that exist even after spatial normalization.
Topics: Adult; Brain; Female; Fluorine Radioisotopes; Humans; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 19457373
DOI: 10.1016/j.neuroimage.2009.01.049 -
PLoS Genetics Aug 2019Holometabolous insects stop feeding at the final larval instar stage and then undergo metamorphosis; however, the mechanism is unclear. In the present study, using the...
Holometabolous insects stop feeding at the final larval instar stage and then undergo metamorphosis; however, the mechanism is unclear. In the present study, using the serious lepidopteran agricultural pest Helicoverpa armigera as a model, we revealed that 20-hydroxyecdysone (20E) binds to the dopamine receptor (DopEcR), a G protein-coupled receptor, to stop larval feeding and promote pupation. DopEcR was expressed in various tissues and its level increased during metamorphic molting under 20E regulation. The 20E titer was low during larval feeding stages and high during wandering stages. By contrast, the dopamine (DA) titer was high during larval feeding stages and low during the wandering stages. Injection of 20E or blocking dopamine receptors using the inhibitor flupentixol decreased larval food consumption and body weight. Knockdown of DopEcR repressed larval feeding, growth, and pupation. 20E, via DopEcR, promoted apoptosis; and DA, via DopEcR, induced cell proliferation. 20E opposed DA function by repressing DA-induced cell proliferation and AKT phosphorylation. 20E, via DopEcR, induced gene expression and a rapid increase in intracellular calcium ions and cAMP. 20E induced the interaction of DopEcR with G proteins αs and αq. 20E, via DopEcR, induced protein phosphorylation and binding of the EcRB1-USP1 transcription complex to the ecdysone response element. DopEcR could bind 20E inside the cell membrane or after being isolated from the cell membrane. Mutation of DopEcR decreased 20E binding levels and related cellular responses. 20E competed with DA to bind to DopEcR. The results of the present study suggested that 20E, via binding to DopEcR, arrests larval feeding and promotes pupation.
Topics: Animals; Dopamine; Dopamine Antagonists; Ecdysterone; Feeding Behavior; Flupenthixol; Gene Knockdown Techniques; Insect Proteins; Larva; Molting; Moths; RNA Interference; Receptors, Dopamine; Sf9 Cells
PubMed: 31412019
DOI: 10.1371/journal.pgen.1008331 -
Scientific Reports May 2021Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and...
Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals. Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. We found a trend for disruption of sensorimotor gating in Sapap3-KOs using the translational measure prepulse inhibition (PPI); however, there was significant heterogeneity in both PPI and compulsive grooming in KOs. Disruption of PPI was significantly correlated with a more severe compulsive phenotype. In addition, PPI disruption and compulsive grooming severity were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC). Compulsive grooming progressively worsened in Sapap3-KOs tested longitudinally, but PPI disruption was first detected in high-grooming KOs at 7 months of age. Through detailed characterization of individual differences in OCD-relevant behavioral and neurochemical measures, our findings suggest that NAcC dopamine receptor changes may be involved in disruption of sensorimotor gating and compulsive behavior relevant to OCD.
Topics: Animals; Compulsive Behavior; Dopamine; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Nucleus Accumbens; Obsessive-Compulsive Disorder; Prepulse Inhibition; Receptors, Dopamine; Sensory Gating
PubMed: 33941812
DOI: 10.1038/s41598-021-88769-5 -
ACS Chemical Neuroscience Oct 2022Dopaminergic pathways control highly consequential aspects of physiology and behavior. One of the most therapeutically important and best-studied receptors in these...
Dopaminergic pathways control highly consequential aspects of physiology and behavior. One of the most therapeutically important and best-studied receptors in these pathways is dopamine receptor D (DRD2). Unfortunately, DRD2 is challenging to study with traditional molecular biological techniques, and most drugs designed to target DRD2 are ligands for many other receptors. Here, we developed probes able to both covalently bind to DRD2 using photoaffinity labeling and provide a chemical handle for detection or affinity purification. These probes behaved like good DRD2 agonists in traditional biochemical assays and were able to perform in chemical-biological assays of cell and receptor labeling. Rat whole brain labeling and affinity enrichment using the probes permitted proteomic analysis of the probes' interacting proteins. Bioinformatic study of the hits revealed that the probes bound noncanonically targeted proteins in Parkinson's disease network as well as the retrograde endocannabinoid signaling, neuronal nitric oxide synthase, muscarinic acetylcholine receptor M1, GABA receptor, and dopamine receptor D (DRD1) signaling networks. Follow-up analysis may yield insights into how this pathway relates specifically to Parkinson's disease symptoms or provide new targets for treatments. This work reinforces the notion that the combination of chemical biology and omics-based approaches provides a broad picture of a molecule's "interactome" and may also give insight into the pleiotropy of effects observed for a drug or perhaps indicate new applications.
Topics: Animals; Rats; Receptors, Dopamine D2; Parkinson Disease; Nitric Oxide Synthase Type I; Ligands; Proteomics; Endocannabinoids; Receptors, Dopamine D1; Carrier Proteins; Receptors, GABA; Dopamine Agonists
PubMed: 36183275
DOI: 10.1021/acschemneuro.2c00544 -
Biomolecules Dec 2020Dopamine receptor and dopamine transporter genes polymorphisms have been associated with cigarette smoking behaviour in different populations. The aim of this...
Dopamine receptor and dopamine transporter genes polymorphisms have been associated with cigarette smoking behaviour in different populations. The aim of this case-control study was to evaluate polymorphisms in the dopamine transporter gene ( (rs27072)) and the dopamine receptor genes ( (rs686), (rs1800497) and (rs7653787)) and their contribution to smoking behaviour in a Malay male population. We identified 476 participants over the age of 18 years comprising 238 smokers and 238 non-smokers. Information such as age, height, weight, body mass index, systolic and diastolic blood pressures, marital status, and smoking status of close family members were taken. For the genetic study, we genotyped four genes ( (rs27072), (rs686), (rs1800497) and (rs7653787)) using the polymerase chain reaction-restriction fragment length polymorphism method and further confirmed our findings with sequencing. Dopamine receptor genes (, and ) were found to be associated with smoking behaviour in a Malay male population. The dopamine transporter gene () did not show this association. Significant differences were observed between smokers' and non-smokers' age, systolic blood pressure, marital status and family members who smoke. Smoking behaviour is significantly influenced by genetic variations of , and in a Malay male population.
Topics: Adolescent; Adult; Case-Control Studies; Cohort Studies; Dopamine Plasma Membrane Transport Proteins; Genetic Predisposition to Disease; Humans; Malaysia; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Smoking
PubMed: 33287325
DOI: 10.3390/biom10121633