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General Physiology and Biophysics Jul 2020It is known that early-life stress events induce profound consequences on emotional brain regions including amygdala, involved in emotional processing and the ventral...
Dopamine concentrations and dopamine receptor gene expression in emotion-related brain structures of female adult rats exposed to stress of chronic isolation from weaning.
It is known that early-life stress events induce profound consequences on emotional brain regions including amygdala, involved in emotional processing and the ventral tegmental area (VTA), which contains neuron cell bodies of the mesolimbic dopaminergic system. The aim of this study is to test the hypothesis that stress induced by long-term social isolation from weaning in female rats is associated with alterations in amygdalar dopamine receptor gene expression and VTA dopamine concentrations. Rats were weaned on postnatal day 21 and then exposed to stress of chronic isolation for 9 weeks. Control animals were housed socially. Amygdalar dopamine D1 but not D2 receptor gene expression was decreased in isolated rats compared to controls. Dopamine concentrations in the VTA were enhanced following chronic isolation. A negative correlation was observed between amygdalar D1 gene expression and dopamine concentrations in the VTA. In conclusion, a reduction of dopamine D1 receptor gene expression in the amygdala in response to stress induced by chronic isolation in female rats was accompanied by an increase in dopamine concentration in the VTA. Further studies are needed to understand the physiological significance, if any, of negative association of amygdalar dopamine receptor D1 gene expression and dopamine concentrations in the VTA.
Topics: Animals; Dopamine; Emotions; Female; Rats; Receptors, Dopamine D2; Social Isolation; Stress, Psychological; Ventral Tegmental Area; Weaning
PubMed: 32902408
DOI: 10.4149/gpb_2020015 -
Neurochemical Research May 2023Values of binding potentials (BP) of dopamine D receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due...
Values of binding potentials (BP) of dopamine D receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. We tested the claim that both striatal and extrastriatal dopamine D receptor availabilities vary with age in vivo in humans by determining the values of BP of the specific radioligand [C]raclopride. We determined values of BP in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. We estimated values of BP in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BP in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BP used the multi-linear regression version of SRTM. Age-dependent changes of the binding potential presented with an inverted U-shape with peak binding potentials reached between the ages of 20 and 30. The estimates of BP declined significantly with age after the peak in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade). The sites of the greatest declines are of particular interest because of the clinical implications.
Topics: Humans; Adult; Young Adult; Dopamine; Receptors, Dopamine D2; Brain; Raclopride; Corpus Striatum; Positron-Emission Tomography; Receptors, Dopamine D3
PubMed: 36525123
DOI: 10.1007/s11064-022-03825-4 -
Nature Communications Jun 2022An organism's ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity...
An organism's ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction, acts in-part through a cell non-autonomous signaling pathway that is inhibited by the presence of attractive smells. Using an intestinal reporter for a key gene induced by dietary restriction but suppressed by attractive smells, we identify three compounds that block food odor effects in C. elegans, thereby increasing longevity as dietary restriction mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor. We further identify a chemosensory neuron that likely perceives food odor, an enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster. Thus, blocking food odor signaling through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.
Topics: Aging; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Dopamine; Drosophila melanogaster; Longevity; Odorants; Receptors, Dopamine; Serotonin
PubMed: 35672307
DOI: 10.1038/s41467-022-30869-5 -
Journal of Chemical Information and... Jun 2021Targeting the D3 dopamine receptor (D3R) is a promising pharmacotherapeutic strategy for the treatment of many disorders. The structure of the D3R is similar to the D2...
Targeting the D3 dopamine receptor (D3R) is a promising pharmacotherapeutic strategy for the treatment of many disorders. The structure of the D3R is similar to the D2 dopamine receptor (D2R), especially in the transmembrane spanning regions that form the orthosteric binding site, making it difficult to identify D3R selective pharmacotherapeutic agents. Here, we examine the molecular basis for the high affinity D3R binding and D3R vs D2R binding selectivity of substituted phenylpiperazine thiopheneamides. We show that removing the thiophenearylamide portion of the ligand consistently decreases the affinity of these ligands at D3R, while not affecting their affinity at the D2R. Our long (>10 μs) molecular dynamics simulations demonstrated that both dopamine receptor subtypes adopt two major conformations that we refer to as closed or open conformations, with D3R sampling the open conformation more frequently than D2R. The binding of ligands with conjoined orthosteric-allosteric binding moieties causes the closed conformation to populate more often in the trajectories. Also, significant differences were observed in the extracellular loops (ECL) of these two receptor subtypes leading to the identification of several residues that contribute differently to the ligand binding for the two receptors that could potentially contribute to ligand binding selectivity. Our observations also suggest that the displacement of ordered water in the binding pocket of D3R contributes to the affinity of the compounds containing an allosteric binding motif. These studies provide a better understanding of how a bitopic mode of engagement can determine ligands that bind selectively to D2 and D3 dopamine receptor subtypes.
Topics: Ligands; Molecular Conformation; Protein Binding; Receptors, Dopamine D3; Structure-Activity Relationship
PubMed: 33988991
DOI: 10.1021/acs.jcim.1c00036 -
Movement Disorders : Official Journal... Aug 2021Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine... (Meta-Analysis)
Meta-Analysis Review
Dopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine receptors emerge as a consequence of the loss of dopamine nerve terminals or dopaminergic pharmacotherapy. We performed a systematic review and meta-analysis of the available PET and single-photon emission computed tomography studies that have investigated dopamine receptors in PD, PSP and MSA. The inclusion criteria were studies including human PET or single-photon emission computed tomography imaging; dopamine receptor tracers (D1-like or D2-like) and idiopathic PD, PSP, or MSA patients compared with healthy controls. The 67 included D2-like studies had 1925 patients. Data were insufficient for an analysis of D1-like studies. PD patients had higher striatal binding early in the disease, but after a disease duration of 4.36 years, PD patients had lower binding values than healthy controls. Striatal D2R binding was highest in unmedicated early PD patients and in the striatum contralateral to the predominant motor symptoms. PSP and MSA-P patients had lower striatal D2R binding than PD patients (14.2% and 21.8%, respectively). There is initial upregulation of striatal D2Rs in PD, which downregulate on average 4 years after motor symptom onset, possibly because of agonist-induced effects. The consistent upregulation of D2Rs in the PD striatum contralateral to the predominant motor symptoms indicates that receptor changes are driven by neurodegeneration and loss of striatal neuropil. Both PSP and MSA patients have clearly lower striatal D2R binding values than PD patients, which offers an opportunity for differential diagnostics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Parkinson Disease; Receptors, Dopamine D2; Tomography, Emission-Computed, Single-Photon
PubMed: 33955044
DOI: 10.1002/mds.28632 -
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 -
Biological Psychiatry Jun 2020Addiction is characterized by a compulsive pattern of drug seeking and consumption and a high risk of relapse after withdrawal that are thought to result from persistent... (Review)
Review
Addiction is characterized by a compulsive pattern of drug seeking and consumption and a high risk of relapse after withdrawal that are thought to result from persistent adaptations within brain reward circuits. Drugs of abuse increase dopamine (DA) concentration in these brain areas, including the striatum, which shapes an abnormal memory trace of drug consumption that virtually highjacks reward processing. Long-term neuronal adaptations of gamma-aminobutyric acidergic striatal projection neurons (SPNs) evoked by drugs of abuse are critical for the development of addiction. These neurons form two mostly segregated populations, depending on the DA receptor they express and their output projections, constituting the so-called direct (D receptor) and indirect (D receptor) SPN pathways. Both SPN subtypes receive converging glutamate inputs from limbic and cortical regions, encoding contextual and emotional information, together with DA, which mediates reward prediction and incentive values. DA differentially modulates the efficacy of glutamate synapses onto direct and indirect SPN pathways by recruiting distinct striatal signaling pathways, epigenetic and genetic responses likely involved in the transition from casual drug use to addiction. Herein we focus on recent studies that have assessed psychostimulant-induced alterations in a cell-type-specific manner, from remodeling of input projections to the characterization of specific molecular events in each SPN subtype and their impact on long-lasting behavioral adaptations. We discuss recent evidence revealing the complex and concerted action of both SPN populations on drug-induced behavioral responses, as these studies can contribute to the design of future strategies to alleviate specific behavioral components of addiction.
Topics: Corpus Striatum; Dopamine; Neurons; Receptors, Dopamine D1; Signal Transduction
PubMed: 31928716
DOI: 10.1016/j.biopsych.2019.11.001 -
Biomolecules Oct 2023The D2 dopamine receptor (D2R) signals through both G proteins and β-arrestins to regulate important physiological processes, such as movement, reward circuitry,...
G Protein-Coupled Receptor Kinase 2 Selectively Enhances β-Arrestin Recruitment to the D Dopamine Receptor through Mechanisms That Are Independent of Receptor Phosphorylation.
The D2 dopamine receptor (D2R) signals through both G proteins and β-arrestins to regulate important physiological processes, such as movement, reward circuitry, emotion, and cognition. β-arrestins are believed to interact with G protein-coupled receptors (GPCRs) at the phosphorylated C-terminal tail or intracellular loops. GPCR kinases (GRKs) are the primary drivers of GPCR phosphorylation, and for many receptors, receptor phosphorylation is indispensable for β-arrestin recruitment. However, GRK-mediated receptor phosphorylation is not required for β-arrestin recruitment to the D2R, and the role of GRKs in D2R-β-arrestin interactions remains largely unexplored. In this study, we used GRK knockout cells engineered using CRISPR-Cas9 technology to determine the extent to which β-arrestin recruitment to the D2R is GRK-dependent. Genetic elimination of all GRK expression decreased, but did not eliminate, agonist-stimulated β-arrestin recruitment to the D2R or its subsequent internalization. However, these processes were rescued upon the re-introduction of various GRK isoforms in the cells with GRK2/3 also enhancing dopamine potency. Further, treatment with compound 101, a pharmacological inhibitor of GRK2/3 isoforms, decreased β-arrestin recruitment and receptor internalization, highlighting the importance of this GRK subfamily for D2R-β-arrestin interactions. These results were recapitulated using a phosphorylation-deficient D2R mutant, emphasizing that GRKs can enhance β-arrestin recruitment and activation independently of receptor phosphorylation.
Topics: Arrestins; beta-Arrestins; G-Protein-Coupled Receptor Kinases; Phosphorylation; Protein Isoforms; Receptors, Dopamine; Receptors, G-Protein-Coupled; Humans; HEK293 Cells
PubMed: 37892234
DOI: 10.3390/biom13101552 -
Brain, Behavior, and Immunity Nov 2021Parkinson's disease (PD) is a chronic neurodegenerative disease. Recently, neuroinflammation driven by CD4 T cells has been involved in PD pathophysiology. Human and...
Parkinson's disease (PD) is a chronic neurodegenerative disease. Recently, neuroinflammation driven by CD4 T cells has been involved in PD pathophysiology. Human and murine lymphocytes express all the five subtypes of dopamine receptors (DRs), DRD1 to DRD5. However, roles of DRs particularly DRD2 expressed on CD4 T cells in PD remain elucidated. Global Drd1- or Drd2-knockout (Drd1 or Drd2) mice or CD4 T cell-specific Drd2-knockout (Drd2/CD4) mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD with the different mutants. On the 7th day following MPTP injection, mice were assessed for dopaminergic neurodegeneration, locomotor impairments, microglial activation, as well as CD4 T-cell differentiation and function. Furthermore, in vitro CD4 T cells were exposed to DRD2 agonist and antagonist and then differentiation and function of the cells were determined. MPTP induced dopaminergic neuronal loss in the nigrostriatal system, motor coordinative and behavioral impairments, microglial activation, and CD4 T-cell polarization to pro-inflammatory T-helper (Th)1 and Th17 phenotypes. Importantly, either Drd2 or Drd2/CD4 mice manifested more severe dopaminergic neurodegeneration, motor deficits, microglial activation, and CD4 T-cell bias towards Th1 and Th17 phenotypes in response to MPTP, but Drd1 did not further alter MPTP intoxication. DRD2 agonist sumanirole inhibited shift of CD4 T cells obtained from MPTP-intoxicated mice to Th1 and Th17 phenotypes and DRD2 antagonist L-741,626 reversed sumanirole effects. These findings suggest that DRD2 expressed on CD4 T cells is protective against neuroinflammation and neurodegeneration in PD. Thus, developing a therapeutic strategy of stimulating DRD2 may be promising for mitigation of PD.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Dopaminergic Neurons; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neuroinflammatory Diseases; Parkinson Disease; Receptors, Dopamine D2; Receptors, Dopamine D5; Th17 Cells
PubMed: 34403737
DOI: 10.1016/j.bbi.2021.08.220 -
Scientific Reports Nov 2019Excessive sucrose consumption elicits addiction-like craving that may underpin the obesity epidemic. Opioids and dopamine mediate the rewarding effects of drugs of...
Excessive sucrose consumption elicits addiction-like craving that may underpin the obesity epidemic. Opioids and dopamine mediate the rewarding effects of drugs of abuse, and of natural rewards from stimuli such as palatable food. We investigated the effects of sucrose using PET imaging with [C]carfentanil (μ-opioid receptor agonist) and [C]raclopride (dopamine D2/3 receptor antagonist) in seven female anesthetized Göttingen minipigs. We then gave minipigs access to sucrose solution for one hour on 12 consecutive days and performed imaging again 24 hours after the final sucrose access. In a smaller sample of five minipigs, we performed an additional [C]carfentanil PET session after the first sucrose exposure. We calculated voxel-wise binding potentials (BP) using the cerebellum as a region of non-displaceable binding, analyzed differences with statistical non-parametric mapping, and performed a regional analysis. After 12 days of sucrose access, BP of both tracers had declined significantly in striatum, nucleus accumbens, thalamus, amygdala, cingulate cortex and prefrontal cortex, consistent with down-regulation of receptor densities. After a single exposure to sucrose, we found decreased binding of [C]carfentanil in nucleus accumbens and cingulate cortex, consistent with opioid release. The lower availability of opioid and dopamine receptors may explain the addictive potential associated with intake of sucrose.
Topics: Animals; Biomarkers; Brain; Functional Neuroimaging; Molecular Imaging; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Receptors, Dopamine D2; Receptors, Dopamine D3; Receptors, Opioid, mu; Sucrose; Swine; Time Factors
PubMed: 31729425
DOI: 10.1038/s41598-019-53430-9