scholarly journals Abundance compensates kinetics: Similar effect of dopamine signals on D1 and D2 receptor populations

2018 ◽  
Author(s):  
Lars Hunger ◽  
Arvind Kumar ◽  
Robert Schmidt
Keyword(s):  
Basal Ganglia ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
D2 Receptors ◽  
D1 Receptors ◽  
Striatal Neurons ◽  
D2 Dopamine Receptor ◽  
Receptor Kinetics ◽  
D1 And D2 Receptors ◽  
Dopamine Receptor Binding

AbstractThe 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 signalling 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, due to 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 signalling.Significance statementCurrent 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.

scholarly journals Quantification of [11C]FLB 457 Binding to Extrastriatal Dopamine Receptors in the Human Brain

1999 ◽  
Vol 19 (10) ◽  
pp. 1164-1173 ◽  
Author(s):  
Hans Olsson ◽  
Christer Halldin ◽  
Carl-Gunnar Swahn ◽  
Lars Farde
Keyword(s):  
Human Brain ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Compartment Model ◽  
Binding Potential ◽  
Receptor Subtypes ◽  
D2 Dopamine Receptor ◽  
Reliable Determination ◽  
Three Compartment Model ◽  
Dopamine Receptor Binding

Positron emission tomography (PET) has hitherto been used to examine D2 dopamine receptor binding in the striatum, a region with a high density of receptors. Research has been hampered by the lack of suitable radioligands for detection of the low-density D2 dopamine receptor populations in the limbic and cortical dopamine systems that are implicated in the patophysiology of schizophrenia. [11C]FLB 457 is a new radioligand with the very high affinity of 20 pmol/L (Ki) for the D2 and D3 dopamine receptor subtypes. This study in eight healthy subjects was designed to evaluate the suitability of [11C]FLB 457 for quantification of extrastriatal D2/D3 dopamine receptors. PET-data were acquired in the three-dimensional mode and the arterial input function was corrected for labeled metabolites. The standard three-compartment model and four derived approaches were applied to calculate and compare the binding potentials. Besides the striatum, conspicuous radioactivity was found in extrastriatal regions such as the thalamus, the anterior cinguli, and the temporal and frontal cortices. The time activity curves could be described by the three compartment model. The different approaches gave similar binding potential values and the rank order between regions was consistent with that found in vitro. The short time of a PET measurement using [11C]FLB 457 (63 minutes) seemed not to be sufficient for reliable determination of the high binding potential in the striatum. These results are of principal importance because they show the potential for PET quantification of minute receptor populations in the human brain.

scholarly journals Dysfunction of D2 dopamine receptor expressing neurons underlies manic-like behaviors in mice modeling SHANK3 duplication disorder

2021 ◽  
Author(s):  
Jimmy Holder ◽  
Kaifang Pang ◽  
Michel Weiwer ◽  
Kihoon Han ◽  
Wei Wang ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Critical Role ◽  
Medium Spiny Neurons ◽  
Rna Seq ◽  
Striatal Neurons ◽  
D2 Dopamine Receptor ◽  
Over Expression ◽  
Synaptic Neurotransmission ◽  
Dopamine Receptor Binding

Abstract While the contributions of some genes to neuropsychiatric disorders are clear, the downstream neuronal effects are poorly understood. Over-expression of SHANK3, which encodes a key synaptic protein, causes neuropsychiatric phenotypes in humans and manic-like behavior in mice providing an opportunity to interrogate the role of SHANK3 in a subset of neurons that might underlie the manic-like behavior. Herein, we describe Shank3’s critical role in D2 dopamine receptor (D2dr) neurons and show that Shank3 overexpression causes increased synaptic neurotransmission in D2dr, but not D1dr, expressing striatal medium spiny neurons. Either pharmacologic D2dr inhibition or genetic normalization of Shank3 abundance in D2-neurons ameliorates manic-like behaviors. Integrating bioinformatic analyses of Shank3’s striatal interactome, D1 and D2 dopamine receptor binding proteins, and single-cell RNA-seq datasets, we demonstrate a functional relationship between Shank3 and the D2dr—but not the D1dr. Thus, while Shank3 is over-expressed in both D1 and D2 dopamine receptor expressing striatal neurons, D2 neuronal dysfunction causes manic-like behaviors.

scholarly journals Chronic Exposure to Arsenic in Drinking Water Causes Alterations in Locomotor Activity and Decreases Striatal mRNA for the D2 Dopamine Receptor in CD1 Male Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Claudia Leticia Moreno Ávila ◽  
Jorge H. Limón-Pacheco ◽  
Magda Giordano ◽  
Verónica M. Rodríguez
Keyword(s):  
Drinking Water ◽  
Locomotor Activity ◽  
Dopamine Receptor ◽  
Dopaminergic System ◽  
Arsenic Exposure ◽  
D2 Receptors ◽  
Motor Memory ◽  
Arsenic Toxicity ◽  
D2 Dopamine Receptor ◽  
Cd1 Mice

Arsenic exposure has been associated with sensory, motor, memory, and learning alterations in humans and alterations in locomotor activity, behavioral tasks, and neurotransmitters systems in rodents. In this study, CD1 mice were exposed to 0.5 or 5.0 mg As/L of drinking water for 6 months. Locomotor activity, aggression, interspecific behavior and physical appearance, monoamines levels, and expression of the messenger for dopamine receptors D1 and D2 were assessed. Arsenic exposure produced hypoactivity at six months and other behaviors such as rearing and on-wall rearing and barbering showed both increases and decreases. No alterations on aggressive behavior or monoamines levels in striatum or frontal cortex were observed. A significant decrease in the expression of mRNA for D2 receptors was found in striatum of mice exposed to 5.0 mg As/L. This study provides evidence for the use of dopamine receptor D2 as potential target of arsenic toxicity in the dopaminergic system.

scholarly journals Localization and function of dopamine receptors in the subthalamic nucleus of normal and parkinsonian monkeys

2014 ◽  
Vol 112 (2) ◽  
pp. 467-479 ◽  
Author(s):  
Adriana Galvan ◽  
Xing Hu ◽  
Karen S. Rommelfanger ◽  
Jean-Francois Pare ◽  
Zafar U. Khan ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Subthalamic Nucleus ◽  
Receptor Agonist ◽  
Rhesus Macaques ◽  
Extracellular Recording ◽  
Receptor Activation ◽  
D1 Receptors ◽  
Substantia Nigra Pars Compacta ◽  
D1 And D2 Receptors ◽  
And Function

The subthalamic nucleus (STN) receives a dopaminergic innervation from the substantia nigra pars compacta, but the role of this projection remains poorly understood, particularly in primates. To address this issue, we used immuno-electron microscopy to localize D1, D2, and D5 dopamine receptors in the STN of rhesus macaques and studied the electrophysiological effects of activating D1-like or D2-like receptors in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys. Labeling of D1 and D2 receptors was primarily found presynaptically, on preterminal axons and putative glutamatergic and GABAergic terminals, while D5 receptors were more significantly expressed postsynaptically, on dendritic shafts of STN neurons. The electrical spiking activity of STN neurons, recorded with standard extracellular recording methods, was studied before, during, and after intra-STN administration of the dopamine D1-like receptor agonist SKF82958, the D2-like receptor agonist quinpirole, or artificial cerebrospinal fluid (control injections). In normal animals, administration of SKF82958 significantly reduced the spontaneous firing but increased the rate of intraburst firing and the proportion of pause-burst sequences of firing. Quinpirole only increased the proportion of such pause-burst sequences in STN neurons of normal monkeys. In MPTP-treated monkeys, the D1-like receptor agonist also reduced the firing rate and increased the proportion of pause-burst sequences, while the D2-like receptor agonist did not change any of the chosen descriptors of the firing pattern of STN neurons. Our data suggest that dopamine receptor activation can directly modulate the electrical activity of STN neurons by pre- and postsynaptic mechanisms in both normal and parkinsonian states, predominantly via activation of D1 receptors.

D1/D2 Dopamine Receptor Interactions in Basal Ganglia Functions

1997 ◽  
pp. 193-219 ◽  
Author(s):  
John F. Marshall ◽  
David N. Ruskin ◽  
Gerald J. LaHoste
Keyword(s):  
Basal Ganglia ◽  
Dopamine Receptor ◽  
D2 Dopamine Receptor ◽  
Receptor Interactions

scholarly journals Attempts to obtain anti(D2 dopamine receptor) antibodies via the anti-idiotypic route

1986 ◽  
Vol 238 (3) ◽  
pp. 817-823 ◽  
Author(s):  
W M Abbott ◽  
P G Strange
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Affinity Chromatography ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Protein A ◽  
D2 Dopamine Receptor ◽  
D2 Dopamine Receptors ◽  
Selective Ligands ◽  
Receptor Antibodies

Five stable hybridomas have been obtained that secrete monoclonal antibodies against the D2-dopamine receptor-selective drug spiperone. Each monoclonal antibody has been characterized in terms of its ability to bind a range of dopamine-receptor-selective ligands. One monoclonal antibody has been purified by Protein A affinity chromatography and used to immunize mice. Anti-idiotypic antisera and one hybridoma secreting an anti-idiotypic monoclonal antibody were obtained and shown to inhibit [3H]spiperone binding to the anti-spiperone antibody used for immunization. Neither the antisera nor the anti-idiotypic monoclonal antibody, however, inhibited binding of [3H]spiperone to D2-dopamine receptors.

scholarly journals Basal ganglia and cerebral cortical distribution of dopamine D1- and D2-receptors in neonatal and adult cat brain

1987 ◽  
Vol 73 (3) ◽  
pp. 203-208 ◽  
Author(s):  
Eric K. Richfield ◽  
Darrell L. Debowey ◽  
John B. Penney ◽  
Anne B. Young
Keyword(s):  
Basal Ganglia ◽  
D2 Receptors ◽  
D1 And D2 Receptors ◽  
Cat Brain ◽  
Adult Cat ◽  
Cortical Distribution
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