-
Cerebral Cortex (New York, N.Y. : 1991) Jul 2019Dopamine modulation in the prefrontal cortex (PFC) mediates diverse effects on neuronal physiology and function, but the expression of dopamine receptors at...
Dopamine modulation in the prefrontal cortex (PFC) mediates diverse effects on neuronal physiology and function, but the expression of dopamine receptors at subpopulations of projection neurons and interneurons remains unresolved. Here, we examine D1 receptor expression and modulation at specific cell types and layers in the mouse prelimbic PFC. We first show that D1 receptors are enriched in pyramidal cells in both layers 5 and 6, and that these cells project to intratelencephalic targets including contralateral cortex, striatum, and claustrum rather than to extratelencephalic structures. We then find that D1 receptors are also present in interneurons and enriched in superficial layer VIP-positive (VIP+) interneurons that coexpresses calretinin but absent from parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons. Finally, we determine that D1 receptors strongly and selectively enhance action potential firing in only a subset of these corticocortical neurons and VIP+ interneurons. Our findings define several novel subpopulations of D1+ neurons, highlighting how modulation via D1 receptors can influence both excitatory and disinhibitory microcircuits in the PFC.
Topics: Animals; Female; Interneurons; Male; Mice; Mice, Transgenic; Neurons, Efferent; Prefrontal Cortex; Receptors, Dopamine D1
PubMed: 30566584
DOI: 10.1093/cercor/bhy299 -
International Journal of Molecular... Apr 2023Dopamine receptors are classified into five subtypes, with DR and DR playing a crucial role in regulating mood, motivation, reward, and movement. Whereas DR are... (Review)
Review
Dopamine receptors are classified into five subtypes, with DR and DR playing a crucial role in regulating mood, motivation, reward, and movement. Whereas DR are distributed widely across the brain, including regions responsible for motor functions, DR are primarily found in specific areas related to cognitive and emotional functions, such as the nucleus accumbens, limbic system, and prefrontal cortex. Despite their high sequence homology and similar signaling pathways, DR and DR have distinct regulatory properties involving desensitization, endocytosis, posttranslational modification, and interactions with other cellular components. In vivo, DR is closely associated with behavioral sensitization, which leads to increased dopaminergic responses. Behavioral sensitization is believed to result from DR desensitization, which removes the inhibitory effect of DR on related behaviors. Whereas DR maintains continuous signal transduction through agonist-induced receptor phosphorylation, arrestin recruitment, and endocytosis, which recycle and resensitize desensitized receptors, DR rarely undergoes agonist-induced endocytosis and instead is desensitized after repeated agonist exposure. In addition, DR undergoes more extensive posttranslational modifications, such as glycosylation and palmitoylation, which are needed for its desensitization. Overall, a series of biochemical settings more closely related to DR could be linked to DR-mediated behavioral sensitization.
Topics: Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Signal Transduction; Dopamine Agonists; Receptors, Dopamine D1
PubMed: 37047716
DOI: 10.3390/ijms24076742 -
Journal of Applied Physiology... Dec 2020Dopamine is often used to treat hypotension in preterm infants who are at risk of hypoxic-ischemic (HI) brain injury due to cerebral hypoperfusion and impaired...
Dopamine is often used to treat hypotension in preterm infants who are at risk of hypoxic-ischemic (HI) brain injury due to cerebral hypoperfusion and impaired autoregulation. There is evidence that systemically administered dopamine crosses the preterm blood-brain barrier. However, the effects of exogenous dopamine and cerebral HI on dopaminergic signaling in the immature brain are unknown. We determined the effect of HI and dopamine on D1 and D2 receptor binding and expressions of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the striatum of the preterm fetal sheep. Fetal sheep (99 days of gestation, term = 147days) were unoperated controls ( = 6) or exposed to severe HI using umbilical cord occlusion and saline infusion (UCO + saline, = 8) or to HI with dopamine infusion (UCO + dopamine, 10 µg/kg/min, = 7) for 74 h. D1 and D2 receptor densities were measured by autoradiography in vitro. DAT, TH, and cell death were measured using immunohistochemistry. HI resulted in cell death in the caudate nucleus and putamen, and dopamine infusion started before HI did not exacerbate or ameliorate these effects. HI led to reduced D1 and D2 receptor densities in the caudate nucleus and reduction in DAT protein expression in the caudate and putamen. Fetal brains exposed to dopamine in addition to HI were not different from those exposed to HI alone in these changes in dopaminergic parameters. We conclude that dopamine infusion does not alter the striatal cell death or the reductions in D1 and D2 receptor densities and DAT protein expression induced by HI in the preterm brain. This is the first study on the effects of hypoxia-ischemia and dopamine treatment on the dopaminergic pathway in the preterm brain. In the striatum of fetal sheep (equivalent to ∼26-28 wk of human gestation), we demonstrate that hypoxia-ischemia leads to cell death, reduces D1 and D2 receptors, and reduces dopamine transporter. Intravenous dopamine infusion at clinical dosage used in preterm human infants does not alter the striatal cell death, D1 and D2 receptor density levels, and DAT protein expressions after hypoxia-ischemia in the preterm brain.
Topics: Animals; Brain; Dopamine; Humans; Hypoxia; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Premature; Ischemia; Receptors, Dopamine; Sheep
PubMed: 33054660
DOI: 10.1152/japplphysiol.00677.2020 -
The Journal of Neuroscience : the... May 2020Aminergic signaling modulates associative learning and memory. Substantial advance has been made in on the dopamine receptors and circuits mediating olfactory learning;...
Aminergic signaling modulates associative learning and memory. Substantial advance has been made in on the dopamine receptors and circuits mediating olfactory learning; however, our knowledge of other aminergic modulation lags behind. To address this knowledge gap, we investigated the role of octopamine in olfactory conditioning. Here, we report that octopamine activity through the β-adrenergic-like receptor Octβ1R drives aversive and appetitive learning: Octβ1R in the mushroom body αβ neurons processes aversive learning, whereas Octβ1R in the projection neurons mediates appetitive learning. Our genetic interaction and imaging studies pinpoint cAMP signaling as a key downstream effector for Octβ1R function. The -adenylyl cyclase synthesizes cAMP in a Ca/calmodulin-dependent manner, serving as a coincidence detector for associative learning and likely representing a downstream target for Octβ1R. Supporting this notion, the double heterozygous /+;β/+ flies perform poorly in both aversive and appetitive conditioning, while individual heterozygous /+ and β/+ flies behave like the wild-type control. Consistently, the mushroom body and projection neurons in the β brain exhibit blunted responses to octopamine when cAMP levels are monitored through the cAMP sensor. We previously demonstrated the pivotal functions of the D receptor dDA1 in aversive and appetitive learning, and the α1 adrenergic-like receptor OAMB in appetitive learning. As expected, β genetically interacts with (dDA1 mutant) in aversive and appetitive learning, but it interacts with only in appetitive learning. This study uncovers the indispensable contributions of dopamine and octopamine signaling to aversive and appetitive learning. All experiments were performed on mixed sex unless otherwise noted. Animals make flexible behavioral choices that are constantly shaped by experience. This plasticity is vital for animals to appropriately respond to the cues predicting benefit or harm. In , dopamine is known to mediate both reward-based and punishment-based learning while octopamine function is important only for reward. Here, we demonstrate that the octopamine-Octβ1R-cAMP pathway processes both aversive and appetitive learning in distinct neural sites of the olfactory circuit. Furthermore, we show that the octopamine-Octβ1R and dopamine-dDA1 signals together drive both aversive and appetitive learning, whereas the octopamine-Octβ1R and octopamine-OAMB pathways jointly facilitate appetitive, but not aversive, learning. This study identifies the cognate actions of octopamine and dopamine signaling as a key neural mechanism for associative learning.
Topics: Animals; Animals, Genetically Modified; Association Learning; Behavior, Animal; Dopamine; Drosophila melanogaster; Mushroom Bodies; Neurons; Octopamine; Receptors, Biogenic Amine; Receptors, Dopamine; Signal Transduction; Smell
PubMed: 32277043
DOI: 10.1523/JNEUROSCI.1756-19.2020 -
International Journal of Molecular... May 2021Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of... (Review)
Review
Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.
Topics: Animals; Dopamine; Dopamine Agents; Encephalomyelitis, Autoimmune, Experimental; Humans; Mice; Models, Immunological; Models, Neurological; Multiple Sclerosis; Neuroimmunomodulation; Receptors, Dopamine; Th17 Cells
PubMed: 34070011
DOI: 10.3390/ijms22105313 -
Translational Psychiatry May 2018The prediction error model is a widely used paradigm that is conceptually based on neuronal dopamine function. However, whether dopamine receptor gene alleles contribute...
The prediction error model is a widely used paradigm that is conceptually based on neuronal dopamine function. However, whether dopamine receptor gene alleles contribute to human neuroimaging prediction error results is uncertain. Recent research implicated the dopamine D2 receptor in behavior response during a prediction error paradigm and we expected that polymorphisms of that receptor would contribute to prediction error brain response. In this study, healthy female participants in the early follicular phase of the menstrual cycle underwent a taste prediction error paradigm during functional magnetic resonance imaging. Participants were also genotyped for dopamine receptor polymorphisms. Our data suggest that the dopamine D2 receptor -141C Ins/Del and Taq1A polymorphisms together with body mass index selectively explain putamen prediction error response. This was true using a region of interest analysis as well as for a whole-brain analysis (FWE corrected). Polymorphisms for dopamine D1 or D4 receptors, dopamine transporter, or COMT did not significantly contribute to prediction error activation. The prediction error model is a computational reward-learning paradigm that is important in psychiatric research and has been associated with dopamine. The results from this study indicate that dopamine D2 receptor polymorphisms together with body mass index are important determinants to include in research that tests prediction error response of the brain. Psychiatric disorders are frequently associated with elevated or reduced body weight. Adding BMI to genetic information in brain-imaging studies that use reward and the prediction error paradigm may be important to increase validity and reliability of results.
Topics: Adolescent; Adult; Body Mass Index; Brain; Brain Mapping; Female; Follicular Phase; Genotype; Humans; Magnetic Resonance Imaging; Polymorphism, Genetic; Putamen; Receptors, Dopamine D2; White People; Young Adult
PubMed: 29795192
DOI: 10.1038/s41398-018-0147-1 -
Current Neuropharmacology Apr 2017Mania seems to be associated with an increased dopamine (DA) transmission. Antidepressant treatments can induce mania in humans and potentiated DA transmission in... (Review)
Review
BACKGROUND
Mania seems to be associated with an increased dopamine (DA) transmission. Antidepressant treatments can induce mania in humans and potentiated DA transmission in animals, by sensitizing DA D2 receptors in the mesolimbic system. We have suggested that the sensitization of D2 receptors may be responsible of antidepressant-induced mania. This review aims to report the experimental evidence that led to the hypothesis that antidepressant-induced DA receptors dysregulation can be considered an animal model of bipolar disorder.
METHODS
We reviewed papers reporting preclinical and clinical studies on the role of DA in the mechanism of action of antidepressant treatments and in the patho-physiology of mood disorders.
RESULTS
A number of preclinical and clinical evidence suggests that mania could be associated with an increased DA activity, while a reduced function of this neurotransmission might underlie depression. Chronic treatment with imipramine induces a sensitization of DA D2 receptors in the mesolimbic system, followed, after drug discontinuation, by a reduced sensitivity associated with an increased immobility time in forced swimming test of depression (FST). Blockade of glutamate NMDA receptors by memantine administration prevents the imipramine effect on DA receptors sensitivity and on the FST.
CONCLUSION
We suggest that chronic treatment with antidepressants induces a behavioural syndrome that mimics mania (the sensitization of DA receptors), followed by depression (desensitization of DA receptors and increased immobility time in the FST), i.e. an animal model of bipolar disorder. Moreover the observation that memantine prevents the "bipolar-like" behavior, suggests that the drug may have an antimanic and mood stabilizing effect. Preliminary clinical observations support this hypothesis.
Topics: Animals; Antidepressive Agents; Bipolar Disorder; Disease Models, Animal; Genetic Diseases, X-Linked; Humans; Receptors, Dopamine
PubMed: 28503114
DOI: 10.2174/1570159X14666160715165648 -
Respiratory Research Apr 2018Dopamine receptors comprise two subgroups, Gs protein-coupled “D1-like” receptors (D1, D5) and Gicoupled “D2-like” receptors (D2, D3, D4). In airways, both...
BACKGROUND
Dopamine receptors comprise two subgroups, Gs protein-coupled “D1-like” receptors (D1, D5) and Gicoupled “D2-like” receptors (D2, D3, D4). In airways, both dopamine D1 and D2 receptors are expressed on airway smooth muscle and regulate airway smooth muscle force. However, functional expression of the dopamine D1 receptor has never been identified on airway epithelium. Activation of Gs-coupled receptors stimulate adenylyl cyclase leading to cyclic AMP (cAMP) production, which is known to induce mucus overproduction through the cAMP response element binding protein (CREB) in airway epithelial cells. We questioned whether the dopamine D1 receptor is expressed on airway epithelium, and whether it promotes CREB phosphorylation and MUC5AC expression.
METHODS
We evaluated the protein expression of the dopamine D1 receptor on native human airway epithelium and three sources of cultured human airway epithelial cells including primary cultured airway epithelial cells, the bronchial epithelial cell line (16HBE14o-), and the pulmonary mucoepidermoid carcinoma cell line (NCI-H292) using immunohistochemistry and immunoblotting. To characterize the stimulation of cAMP through the dopamine D1 receptor, 16HBE14o- cells and NCI-H292 cells were treated with dopamine or the dopamine D1 receptor agonists (SKF38393 or A68930) before cAMP measurements. The phosphorylation of CREB by A68930 in both 16HBE14o- and NCI-H292 cells was measured by immunoblot. The effect of dopamine or A68930 on the expression of MUC5AC mRNA and protein in NCI-H292 cells was evaluated by real-time PCR and immunofluorescence staining, respectively.
RESULTS
The dopamine D1 receptor protein was detected in native human airway epithelium and three sources of cultured human airway epithelial cells. Dopamine or the dopamine D1-like receptor agonists stimulated cAMP production in 16HBE14o- cells and NCI-H292 cells, which was reversed by the selective dopamine D1-like receptor antagonists (SCH23390 or SCH39166). A68930 significantly increased phosphorylation of CREB in both 16HBE14o- and NCI-H292 cells, which was attenuated by the inhibitors of PKA (H89) and MEK (U0126). Expression of MUC5AC mRNA and protein were also increased by either dopamine or A68930 in NCI-H292 cells.
CONCLUSIONS
These results suggest that the activation of the dopamine D1 receptor on human airway epithelium could induce mucus overproduction, which could worsen airway obstructive symptoms.
Topics: Cell Line; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Dopamine Agonists; Gene Expression; Humans; Mucin 5AC; Phosphorylation; Receptors, Dopamine D1; Respiratory Mucosa
PubMed: 29606146
DOI: 10.1186/s12931-018-0757-4 -
International Journal of Molecular... Aug 2021Protein-protein interactions between G protein-coupled receptors (GPCRs) can augment their functionality and increase the repertoire of signaling pathways they regulate....
Protein-protein interactions between G protein-coupled receptors (GPCRs) can augment their functionality and increase the repertoire of signaling pathways they regulate. New therapeutics designed to modulate such interactions may allow for targeting of a specific GPCR activity, thus reducing potential for side effects. Dopamine receptor (DR) heteromers are promising candidates for targeted therapy of neurological conditions such as Parkinson's disease since current treatments can have severe side effects. To facilitate development of such therapies, it is necessary to identify the various DR binding partners. We report here a new interaction partner for DRD and DRD, the orphan receptor G protein-coupled receptor 143 (GPR143), an atypical GPCR that plays multiple roles in pigment cells and is expressed in several regions of the brain. We previously demonstrated that the DRD/ DRD antagonist pimozide also modulates GPR143 activity. Using confocal microscopy and two FRET methods, we observed that the DRs and GPR143 colocalize and interact at intracellular membranes. Furthermore, co-expression of wildtype GPR143 resulted in a 57% and 67% decrease in DRD and DRD activity, respectively, as determined by β-Arrestin recruitment assay. GPR143-DR dimerization may negatively modulate DR activity by changing affinity for dopamine or delaying delivery of the DRs to the plasma membrane.
Topics: Dopamine; Eye Proteins; Humans; Membrane Glycoproteins; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Receptors, Dopamine D2; Receptors, Dopamine D3; Signal Transduction; beta-Arrestins
PubMed: 34361094
DOI: 10.3390/ijms22158328 -
Basic & Clinical Pharmacology &... Jun 2020Dopamine (DA) receptors play critical roles in a wide range of behaviours, including sensory processing, motor function, reward and arousal. As such, aberrant DA... (Review)
Review
Dopamine (DA) receptors play critical roles in a wide range of behaviours, including sensory processing, motor function, reward and arousal. As such, aberrant DA signalling is associated with numerous neurological and psychiatric disorders. Therefore, understanding the mechanisms by which DA neurotransmission drives intracellular signalling pathways that modulate behaviour can provide critical insights to guide the development of targeted therapeutics. Drosophila melanogaster has emerged as a powerful model with unique advantages to study the mechanisms underlying DA neurotransmission and associated behaviours in a controlled and systematic manner. Many regions in the fly brain innervated by dopaminergic neurons have been mapped and linked to specific behaviours, including associative learning and arousal. Here, we provide an overview of the homology between human and Drosophila dopaminergic systems and review the current literature on the pharmacology, molecular signalling mechanisms and behavioural outcome of DA receptor activation in the Drosophila brain.
Topics: Animals; Arousal; Brain; Dopaminergic Neurons; Drosophila Proteins; Drosophila melanogaster; Humans; Learning; Receptors, Dopamine; Sleep
PubMed: 31219669
DOI: 10.1111/bcpt.13277