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Dopamine receptor and Gα(olf) expression in DYT1 dystonia mouse models during postnatal development.PloS One 2015DYT1 dystonia is a heritable, early-onset generalized movement disorder caused by a GAG deletion (ΔGAG) in the DYT1 gene. Neuroimaging studies and studies using mouse...
BACKGROUND
DYT1 dystonia is a heritable, early-onset generalized movement disorder caused by a GAG deletion (ΔGAG) in the DYT1 gene. Neuroimaging studies and studies using mouse models suggest that DYT1 dystonia is associated with dopamine imbalance. However, whether dopamine imbalance is key to DYT1 or other forms of dystonia continues to be debated.
METHODOLOGY/PRINCIPAL FINDINGS
We used Dyt1 knock out (Dyt1 KO), Dyt1 ΔGAG knock-in (Dyt1 KI), and transgenic mice carrying one copy of the human DYT1 wild type allele (DYT1 hWT) or human ΔGAG mutant allele (DYT1 hMT). D1R, D2R, and Gα(olf) protein expression was analyzed by western blot in the frontal cortex, caudate-putamen and ventral midbrain in young adult (postnatal day 60; P60) male mice from all four lines; and in the frontal cortex and caudate putamen in juvenile (postnatal day 14; P14) male mice from the Dyt1 KI and KO lines. Dopamine receptor and Gα(olf) protein expression were significantly decreased in multiple brain regions of Dyt1 KI and Dyt1 KO mice and not significantly altered in the DYT1 hMT or DYT1 hWT mice at P60. The only significant change at P14 was a decrease in D1R expression in the caudate-putamen of the Dyt1 KO mice.
CONCLUSION/SIGNIFICANCE
We found significant decreases in key proteins in the dopaminergic system in multiple brain regions of Dyt1 KO and Dyt1 KI mouse lines at P60. Deletion of one copy of the Dyt1 gene (KO mice) produced the most pronounced effects. These data offer evidence that impaired dopamine receptor signaling may be an early and significant contributor to DYT1 dystonia pathophysiology.
Topics: Age Factors; Animals; Animals, Newborn; Brain; Disease Models, Animal; Dystonia Musculorum Deformans; GTP-Binding Protein alpha Subunits; Gene Expression; Genotype; Humans; Male; Mice; Mice, Transgenic; Receptors, Dopamine
PubMed: 25860259
DOI: 10.1371/journal.pone.0123104 -
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 -
Behavioural Brain Research Aug 2021Dopamine (DA) in the striatum is essential to influence motor behavior and may lead to movement impairment in Parkinson's disease (PD). The present study examined the...
Dopamine (DA) in the striatum is essential to influence motor behavior and may lead to movement impairment in Parkinson's disease (PD). The present study examined the different functions of the DA D1 receptor (D1R) and DA D2 receptor (D2R) by intrastriatal injection of the D1R agonist SKF38393 and the D2R agonist quinpirole in 6-hydroxydopamine (6-OHDA)-lesioned and control rats. All rats separately underwent dose-response behavior testing for SKF38393 (0, 0.5, 1.0, and 1.5 μg/site) or quinpirole (0, 1.0, 2.0, and 3.0 μg/site) to determine the effects of the optimal modulating threshold dose. Two behavior assessment indices, the time of latency to fall and the number of steps on a rotating treadmill, were used as reliable readouts of motor stimulation variables for quantifying the motor effects of the drugs. The findings indicate that at threshold doses, SKF38393 (1.0 μg/site) and quinpirole (1.0 μg/site) produce a dose-dependent increase in locomotor activity compared to vehicle injection. The ameliorated behavioral responses to either SKF38393 or quinpirole in lesioned rats were greater than those in unlesioned control rats. Moreover, the dose-dependent increase in locomotor capacity for quinpirole was greater than that for SKF38393 in lesioned rats. These results can clarify several key issues related to DA receptors directly and may provide a basis for exploring the potential of future selective dopamine therapies for PD in humans.
Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Agonists; Locomotion; Male; Motor Activity; Parkinson Disease; Parkinsonian Disorders; Quinpirole; Rats; Rats, Wistar; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 33945831
DOI: 10.1016/j.bbr.2021.113339 -
The Journal of Neuroscience : the... Apr 2020The neuromodulator dopamine plays a key role in motivation, reward-related learning, and normal motor function. The different affinity of striatal D1 and D2 dopamine...
The neuromodulator dopamine plays a key role in motivation, reward-related learning, and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signaling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, because of slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signaling. Current models of basal ganglia function are often based on a distinction of two types of dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view does not take into account the rates for the binding and unbinding of dopamine to D1 and D2 receptors. By incorporating these kinetics into a computational model we show that D1 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications for the processing of reward-related and motivational signals in the basal ganglia.
Topics: Animals; Brain; Computer Simulation; Dopamine; Humans; Kinetics; Models, Neurological; Neurons; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 32071139
DOI: 10.1523/JNEUROSCI.1951-19.2019 -
Molecular Neurobiology Oct 2020Anterior cingulate cortex (ACC) is a critical brain center for chronic pain processing. Dopamine signaling in the brain has been demonstrated to contribute to descending...
Anterior cingulate cortex (ACC) is a critical brain center for chronic pain processing. Dopamine signaling in the brain has been demonstrated to contribute to descending pain modulation. However, the role of ACC dopamine receptors in chronic neuropathic pain remains unclear. In this study, we investigated the effect of optogenetic activation of ACC dopamine receptors D1- and D2-expressing neurons on trigeminal neuropathic pain. Chronic constriction injury of infraorbital nerve (CCI-ION) was carried out to induce trigeminal neuropathic pain in mice. We conducted optogenetic stimulation to specifically activate D1- and D2-expressing neurons in the ACC. Western blotting and immunofluorescence staining were used to examine ACC D1 and D2 expression and localization. The von Frey and real-time place preference tests were performed to measure evoked mechanical pain and nonreflexive emotional pain behaviors, respectively. We observed that dopamine receptors D1 and D2 in the ACC are primarily expressed in excitatory neurons and that the D2 receptor is differentially regulated in the early and late phases of trigeminal neuropathic pain. Optogenetic activation of D1-expressing neurons in the ACC markedly exacerbates CCI-ION-induced trigeminal neuropathic pain in both early and late phases, but optogenetic activation of D2-expressing neurons in the ACC robustly ameliorates such pain in its late phase. Our results suggest that dopamine receptors D1 and D2 in the ACC play different roles in the modulation of trigeminal neuropathic pain.
Topics: Animals; Constriction, Pathologic; Dopaminergic Neurons; Gyrus Cinguli; Male; Mice, Inbred C57BL; Neuralgia; Optogenetics; Receptors, Dopamine D1; Receptors, Dopamine D2; Trigeminal Ganglion
PubMed: 32654077
DOI: 10.1007/s12035-020-02020-2 -
Expert Opinion on Pharmacotherapy Oct 2016Dopamine agonists (DA) are a class of agents which directly stimulate dopamine receptors mimicking the endogenous neurotransmitter dopamine. At first used as adjunctive... (Review)
Review
INTRODUCTION
Dopamine agonists (DA) are a class of agents which directly stimulate dopamine receptors mimicking the endogenous neurotransmitter dopamine. At first used as adjunctive therapy in the advanced phases of the disease, over the years a significant role was found for DA monotherapy as a first approach in the initial stage of Parkinson's disease (PD). Several reviews have already reported efficacy and safety of DA in PD and differences between DA and levodopa. Therefore the objective of this review is to gather recent updates in DA therapy. A thorough knowledge of recent literature evidences, would help clinician in the management of treatment with DA.
AREAS COVERED
Our review investigates recent updates on DA therapy, the role of these compounds in controlling non-motor symptoms (NMS) as well as new formulations under clinical evaluation and newly emerged post-marketing safety considerations. A literature search has been performed using Medline and reviewing the bibliographies of selected articles.
EXPERT OPINION
DA represents a very important option in the treatment of PD, even though there are still some criticisms and unmet needs. A better knowledge of dopamine receptors could lead to identification of new compounds able to better balance clinical efficacy and side effects.
Topics: Antiparkinson Agents; Dopamine Agonists; Humans; Levodopa; Parkinson Disease; Receptors, Dopamine
PubMed: 27561098
DOI: 10.1080/14656566.2016.1219337 -
Cerebral Cortex (New York, N.Y. : 1991) May 2019Considerable evidence has shown that prefrontal neurons expressing D1-type dopamine receptors (D1DRs) are critical for working memory, flexibility, and timing. This line...
Considerable evidence has shown that prefrontal neurons expressing D1-type dopamine receptors (D1DRs) are critical for working memory, flexibility, and timing. This line of work predicts that frontal neurons expressing D1DRs mediate cognitive processing. During timing tasks, one form this cognitive processing might take is time-dependent ramping activity-monotonic changes in firing rate over time. Thus, we hypothesized the prefrontal D1DR+ neurons would strongly exhibit time-dependent ramping during interval timing. We tested this idea using an interval-timing task in which we used optogenetics to tag D1DR+ neurons in the mouse medial frontal cortex (MFC). While 23% of MFC D1DR+ neurons exhibited ramping, this was significantly less than untagged MFC neurons. By contrast, MFC D1DR+ neurons had strong delta-frequency (1-4 Hz) coherence with other MFC ramping neurons. This coherence was phase-locked to cue onset and was strongest early in the interval. To test the significance of these interactions, we optogenetically stimulated MFC D1DR+ neurons early versus late in the interval. We found that 2-Hz stimulation early in the interval was particularly effective in rescuing timing-related behavioral performance deficits in dopamine-depleted animals. These findings provide insight into MFC networks and have relevance for disorders such as Parkinson's disease and schizophrenia.
Topics: Action Potentials; Animals; Delta Rhythm; Frontal Lobe; Mice, Transgenic; Neurons; Prefrontal Cortex; Receptors, Dopamine D1; Time Factors
PubMed: 29897417
DOI: 10.1093/cercor/bhy083 -
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 -
Metabolic Brain Disease Jun 2021Dysfunctions of the neurotransmitter system are related to the development of many psychological diseases including autism spectrum disorder (ASD). Single nucleotide...
Dysfunctions of the neurotransmitter system are related to the development of many psychological diseases including autism spectrum disorder (ASD). Single nucleotide polymorphisms (SNPs) are correlated with varied susceptibility of ASD and response to treatments. The association between SNPs in genes encoding serotonin and dopamine receptors and childhood ASD was examined in a Chinese Han population. Both autistic children (n = 319) and age-and gender-matched healthy controls (n = 347) were recruited from a local district. Disease severity was evaluated by the childhood autism rating scale (CARS). SNPs of rs6311 and rs6313 in the serotonin receptor HTR2A gene, rs4630328 in the dopamine receptor D2 (DRD2) gene and rs167771 in the DRD3 gene were examined. The CC genotype of rs6311 was significantly associated with an increased risk of ASD (odds ratio (OD) = 1.8 vs TT, 95% confidence interval (CI): 1.2-2.8, P = 0.0085). Carriers of the C allele of rs6311 had a significantly higher risk of childhood ASD (OD =1.3, 95% CI = 1.1-1.7, P = 0.0094). A strong linkage disequilibrium was observed between rs6311 and rs6313 (D' = 0.93, r = 0.86). There were significant correlations between haplotypes (T-A and C-G of rs6311-rs6313) and risk of childhood ASD. In contrast, the frequencies of genotypes and alleles of rs6313, rs4630328 and rs167771 were not significantly different between the case and control groups. All the SNPs examined were not associated with severity of the disease. Our study demonstrates that certain SNPs in the HTR2A gene, but not the DRD2 and DRD3, are associated with susceptibility to childhood ASD.
Topics: Adolescent; Alleles; Autism Spectrum Disorder; Child; Child, Preschool; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Male; Patient Acuity; Polymorphism, Single Nucleotide; Receptors, Dopamine; Receptors, Serotonin
PubMed: 33644845
DOI: 10.1007/s11011-021-00699-3 -
Genes, Brain, and Behavior Apr 2018Dopamine (DA) plays a significant role in cognition, motor function and social behavior. The objectives of this study were to (1) quantify the temporal expression of...
Dopamine (DA) plays a significant role in cognition, motor function and social behavior. The objectives of this study were to (1) quantify the temporal expression of transcripts (DA receptors, transporters and tyrosine hydroxylase) associated with DA signaling during early stages of zebrafish development and (2) determine their expression profiles following treatment with a D receptor antagonist domperidone (DMP). We also assessed locomotor behavior following treatment with DMP using alternating periods of light and dark (ie, dark photokinesis), as DA plays a key role in behavior. Relative expression levels of transcripts that were investigated and related to the DA system were detected after the first 24 hours postfertilization (hpf). Some DA receptor transcripts (eg, drd4c) increased in abundance earlier in the embryo compared with other receptors (eg, drd3), suggesting that DA receptor paralogs may have unique roles in development. Treatment of larvae with DMP resulted in the upregulation of DA receptor transcripts (ie, drd1, drd7, drd4b, drd4c) and DA transporter 1 (ie, slc6a3), and it is hypothesized that upregulation of genes related to the DA system is a compensatory neurophysiological response to DA receptor antagonism. Larval activity during dark photokinesis (measured by distance traveled) was also elevated by DMP. We hypothesize that behavioral responses observed with DMP may be related to the regulation of deep brain photoreception in zebrafish (Danio rerio) (ZF) larvae by DA.
Topics: Animals; Central Nervous System Stimulants; Domperidone; Dopamine; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Gene Expression Regulation, Developmental; Larva; Locomotion; Receptors, Dopamine; Receptors, Dopamine D2; Transcriptional Activation; Transcriptome; Tyrosine 3-Monooxygenase; Up-Regulation; Zebrafish
PubMed: 29377542
DOI: 10.1111/gbb.12460