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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 -
Neuroendocrinology 2023Because dopaminergic signaling pathways are one of the regulators of autoimmunity, we hypothesize that the -521C>T DRD4 gene polymorphism may associate with the risk...
INTRODUCTION
Because dopaminergic signaling pathways are one of the regulators of autoimmunity, we hypothesize that the -521C>T DRD4 gene polymorphism may associate with the risk of diabetes mellitus type 1 (DM1) and its comorbidities.
METHODS
In this case-control study, we have examined 300 patients with DM1 in comparison to 300 healthy age-matched controls. Utilizing the amplification refractory mutation system-polymerase chain reaction method, we have analyzed the -521C>T polymorphism of dopamine D4 receptor-encoding gene. Obtained results have been evaluated according to diabetes comorbidities, inflammatory markers, CD14++CD16-, and CD14+CD16+ monocyte subsets as well as lipid profile.
RESULTS
The key results of our study are as follows: (1) CC genotype and C allele are associated with a reduced risk of DM1 development (OR = 0.593, p = 0.005 and OR = 0.725, p = 0.003, respectively), whereas TT genotype and T allele are associated with a higher risk of DM1 (OR = 1.408, p = 0.04 and OR = 1.380, p = 0.003, respectively); (2) CC genotype is associated with an increased risk of dyslipidemia and retinopathy in diabetic patients (OR = 2.376, p = 0.001 and OR = 2.111, p = 0.01, respectively); (3) CC genotype and C allele carriers had the highest frequency of pro-inflammatory CD16+ monocytes (p = 2*10-4 and 0.04, respectively); (4) the DRD4 -521C>T polymorphism modifies the inflammatory status as well as lipid profile in DM1 patients.
CONCLUSION
Our data imply that the dopaminergic signaling pathways may play an important role in the etiology of DM1 as well as its comorbidities and will provide a new insight into the DM1 risk management. The -521C>T DRD4 gene polymorphism could be considered a genetic marker to predict susceptibility to DM1 as well as retinopathy and dyslipidemia progress in patients with already established disease.
Topics: Humans; Case-Control Studies; Diabetes Mellitus, Type 1; Dopamine; Genotype; Lipids; Receptors, Dopamine; Receptors, Dopamine D4
PubMed: 37080173
DOI: 10.1159/000530765 -
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 -
Brain Research May 2023Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their...
Identifying neurobiological characteristics that predict the development of cocaine use disorder would be of great value in prevention efforts. Because of their importance in mediating the abuse-related effects of cocaine, brain dopamine receptors are logical candidates for investigation. We analyzed data from two recently published studies that characterized availability of dopamine D2-like receptors (D2R) with [C]raclopride PET imaging and dopamine D receptor (DR) sensitivity with quinpirole-induced yawning in cocaine-naïve rhesus monkeys who subsequently acquired cocaine self-administration and completed a cocaine self-administration dose-effect curve. The present analysis compared D2R availability in several brain areas and characteristics of quinpirole-induced yawning, both acquired when monkeys were drug-naïve, with measures of initial sensitivity to cocaine. D2R availability in the caudate nucleus was negatively correlated with the ED of the cocaine self-administration curve, although the significance of this relationship was driven by an outlier and was not present after the outlier was removed. No other significant associations were observed between D2R availability in any examined brain region and measures of sensitivity to cocaine reinforcement. However, there was a significant negative correlation between DR sensitivity, represented by the ED of the quinpirole-induced yawning curve, and the dose at which monkeys acquired cocaine self-administration. We also report no change from baseline D2R availability when a second PET scan was conducted after completion of the dose-effect curves. These data suggest the utility of DR sensitivity, but not D2R availability, as a biomarker for vulnerability and resilience to cocaine. The well-established relationships between dopamine receptors and cocaine reinforcement in cocaine-experienced humans and animals may require extensive cocaine exposure.
Topics: Humans; Animals; Male; Cocaine; Dopamine; Quinpirole; Macaca mulatta; Receptors, Dopamine D3; Dopamine Agonists; Receptors, Dopamine D2; Self Administration; Dose-Response Relationship, Drug
PubMed: 36914041
DOI: 10.1016/j.brainres.2023.148323 -
Nature Communications Jan 2024Direct interactions between receptors at the neuronal surface have long been proposed to tune signaling cascades and neuronal communication in health and disease. Yet,...
Direct interactions between receptors at the neuronal surface have long been proposed to tune signaling cascades and neuronal communication in health and disease. Yet, the lack of direct investigation methods to measure, in live neurons, the interaction between different membrane receptors at the single molecule level has raised unanswered questions on the biophysical properties and biological roles of such receptor interactome. Using a multidimensional spectral single molecule-localization microscopy (MS-SMLM) approach, we monitored the interaction between two membrane receptors, i.e. glutamatergic NMDA (NMDAR) and G protein-coupled dopamine D1 (D1R) receptors. The transient interaction was randomly observed along the dendritic tree of hippocampal neurons. It was higher early in development, promoting the formation of NMDAR-D1R complexes in an mGluR5- and CK1-dependent manner, favoring NMDAR clusters and synaptogenesis in a dopamine receptor signaling-independent manner. Preventing the interaction in the neonate, and not adult, brain alters in vivo spontaneous neuronal network activity pattern in male mice. Thus, a weak and transient interaction between NMDAR and D1R plays a structural and functional role in the developing brain.
Topics: Mice; Animals; N-Methylaspartate; Receptors, Dopamine D1; Signal Transduction; Receptors, N-Methyl-D-Aspartate; Neurons
PubMed: 38167277
DOI: 10.1038/s41467-023-44301-z -
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 -
Journal of the American Heart... Mar 2022Background Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl, indicating the existence of a gastro-renal...
Background Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl, indicating the existence of a gastro-renal axis. As one of the major natriuretic hormones secreted by both the intestines and the kidney, we hypothesized that renal uroguanylin interacts with dopamine receptors to increase sodium excretion synergistically, an impaired interaction of which may be involved in the pathogenesis of hypertension. Methods and Results In Wistar-Kyoto rats, the infusion of uroguanylin or fenoldopam (a D-like receptor agonist) induced natriuresis and diuresis. Although subthreshold dosages of uroguanylin or fenoldopam had no effect, the coinfusion of subthreshold dosages of those reagents significantly increased sodium excretion. The coinfusion of an antagonist against D-like receptors, SCH23390, or an antagonist against uroguanylin, 2-methylthioadenosine triphosphate, prevented the fenoldopam- or uroguanylin-mediated natriuresis and diuresis in Wistar-Kyoto rats. However, the natriuretic effects of uroguanylin and fenoldopam were not observed in spontaneously hypertensive rats. The uroguanylin/D-like receptor interaction was also confirmed in renal proximal tubule cells. In renal proximal tubule cells from Wistar-Kyoto rats but not spontaneously hypertensive rats, stimulation of either D-like receptors or uroguanylin inhibited Na-K-ATPase activity, an effect that was blocked in the presence of SCH23390 or 2-methylthioadenosine triphosphate. In renal proximal tubule cells from Wistar-Kyoto rats, guanylyl cyclase C receptor (uroguanylin receptor) and D receptor coimmunoprecipitated, which was increased after stimulation by either uroguanylin or fenoldopam; stimulation of one receptor increased renal proximal tubule cell membrane expression of the other. Conclusions These data suggest that there is synergism between uroguanylin and D-like receptors to increase sodium excretion. An aberrant interaction between the renal uroguanylin and D-like receptors may play a role in the pathogenesis of hypertension.
Topics: Animals; Fenoldopam; Hypertension; Kidney; Kidney Tubules, Proximal; Natriuresis; Natriuretic Peptides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Dopamine D1; Sodium; Sodium Chloride
PubMed: 35229618
DOI: 10.1161/JAHA.121.022827 -
Cells Mar 2023The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with...
The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with clinical features of dopamine deficiency: severe infantile parkinsonism-dystonia, characterised by frequent oculogyric crises, dysautonomia and global neurodevelopmental impairment. CSF neurotransmitter analysis was unexpectedly normal. Triome whole-genome sequencing revealed a homozygous variant (c.110C>A, (p.T37K)) in , encoding the most abundant dopamine receptor (D) in the central nervous system, most highly expressed in the striatum. This variant was absent from gnomAD, with a CADD score of 27.5. Using an in vitro heterologous expression system, we determined that -T37K results in loss of protein function. Structure-function modelling studies predicted reduced substrate binding, which was confirmed in vitro. Exposure of mutant protein to the selective D agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D agonists failed to rescue the cellular defect, reflected clinically in the patient, who had no benefit from dopaminergic therapy. Our study identifies as a new disease-associated gene, suggesting a crucial role for the D receptor in motor control.
Topics: Humans; Receptors, Dopamine D1; Dystonia; Dystonic Disorders; Parkinson Disease
PubMed: 37048120
DOI: 10.3390/cells12071046 -
Brain Research Bulletin Apr 2023Stress contributes to pain sensation by affecting several neural pathways, including mesolimbic-cortical dopamine neurons. Nucleus accumbens, an essential element of the...
Stress contributes to pain sensation by affecting several neural pathways, including mesolimbic-cortical dopamine neurons. Nucleus accumbens, an essential element of the mesolimbic dopaminergic pathway, plays a fundamental role in modulating pain and is differentially influenced by stressful events. Since we previously demonstrated the marked association of intra-NAc dopamine receptors with forced swim stress-evoked analgesia in acute pain state, this research was conducted to consider the contribution of intra-accumbal D1- and D2-like dopamine receptors to modulating effects of exposure to restraint stress in pain-related behaviors during the tail-flick test. Stereotaxic surgery was executed to implant a guide cannula within the NAc in male Wistar rats. On the test day, different concentrations of SCH23390 and Sulpiride as D1- and D2-like dopamine receptor antagonists, respectively, were unilaterally microinjected within the NAc. The vehicle animals received saline or 12 % DMSO (0.5 µl) instead of SCH23390 or Sulpiride into the NAc, respectively. Five minutes following receiving drug or vehicle, animals were restrained for 3 h and then their acute nociceptive threshold was measured for a 60-min period by the tail-flick test. Our data revealed that RS considerably enhanced antinociceptive reaction in acute pain states. The analgesia evoked by RS dramatically declined following blocking either D1- or D2-like dopamine receptors in the NAc, an effect was more noticeable by D1-like dopamine receptor antagonist. These findings indicated that intra-NAc dopamine receptors are considerably mediated in the RS-produced analgesia in acute pain states, suggesting their possible role in psychological stress and disease.
Topics: Rats; Animals; Male; Sulpiride; Rats, Wistar; Acute Pain; Receptors, Dopamine D2; Receptors, Dopamine D1; Dopamine Antagonists; Nucleus Accumbens; Analgesics
PubMed: 36889361
DOI: 10.1016/j.brainresbull.2023.03.003 -
ENeuro 2021Dopaminergic modulation is essential for the control of voluntary movement; however, the role of dopamine in regulating the neural excitability of the primary motor...
Dopaminergic modulation is essential for the control of voluntary movement; however, the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined whether chronic depletion of dopaminergic input to the entire motor circuit, via a mouse model of Parkinson's disease, was sufficient to shift M1 neuron excitability. We show that D1 receptor (D1R) and D2R antagonism altered subthreshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission. In contrast, chronic depletion of dopamine to the motor circuit with 6-hydroxydopamine induced layer-specific synaptic transmission-dependent shifts in M1 neuron excitability that only partially overlapped with the effects of acute D1R antagonism. These results suggest that while acute and chronic changes in dopamine modulate the input/output function of M1 neurons, the mechanisms engaged are distinct depending on the duration and origin of the manipulation. Our study highlights the broad influence of dopamine on M1 excitability by demonstrating the consequences of local and global dopamine depletion on neuronal input/output function.
Topics: Animals; Dopamine; Dopamine D2 Receptor Antagonists; Mice; Motor Cortex; Neurons; Pyramidal Cells; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 34556558
DOI: 10.1523/ENEURO.0548-19.2021