Dopamine Receptor Binding Research Articles

Epigenetic Effects of Finasteride on Dopaminergic Signaling Pathways: A potential contributor to Post-Finasteride Syndrome

Dopamine, a widely-distributed neurotransmitter in the brain and elsewhere, is important for regulating reward-motivated behavior, sexual impetus, concentration, pleasure, emotions, and genital arousal. Findings have previously implicated aberrant dopaminergic neurotransmission in mental disorders, as well as sexual and erectile dysfunction. To evaluate the epigenetic effects of finasteride on dopaminergic signaling pathways, we treated human Leydig cells with finasteride and identified several dopaminergic pathways that were altered by differential methylation of component genes. These genes included those involved in the regulation of dopamine secretion and transport (OR56A4, OR13F1 and SYT4), the Phospholipase C-activating dopamine receptor signaling pathway (OR56A4 and OR13F1), the dopaminergic synapse (CALML4, COMT, GNAI2, GNAS, GNG10, GRIA1, GSK3A, GSK3B, KCNJ9, PPP2R2C, PPP2R3B, PPP2R3C, PPP2R5A, PPP2R5E) and the dopamine receptor activity and binding pathway (OR56A4, OR13F1). This alteration of gene methylation suggests a potential role of altered epigenetic regulation of dopaminergic pathways in the etiology and pathophysiology of post-finasteride syndrome (PFS), which should be further investigated. National Institutes of Health (NIH) R25 Resource Grant (1 R25 AG047843-01) to ABC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Portuguese observational cross-sectional clinical imaging study protocol to investigate central dopaminergic mechanisms of successful weight loss through bariatric surgery

IntroductionBariatric surgery (BS) is the treatment of choice for refractory obesity. Although weight loss (WL) reduces the prevalence of obesity-related comorbidities, not all patients maintain it. It has been suggested...

Milkshake Acutely Stimulates Dopamine Release in Ventral and Dorsal Striatum in Healthy-Weight Individuals and Patients with Severe Obesity Undergoing Bariatric Surgery: A Pilot Study.

The overconsumption of palatable energy-dense foods drives obesity, but few human studies have investigated dopamine (DA) release in response to the consumption of a palatable meal, a putative mediator of excess intake in obesity. We imaged [11C]raclopride in the brain with positron emission tomography (PET) to assess striatal dopamine (DA) receptor binding pre- and post-consumption of a highly palatable milkshake (250 mL, 420 kcal) in 11 females, 6 of whom had severe obesity, and 5 of whom had healthy-weight. Those with severe obesity underwent assessments pre- and 3 months post-vertical sleeve gastrectomy (VSG). Our results demonstrated decreased post- vs. pre-meal DA receptor binding in the ventral striatum (p = 0.032), posterior putamen (p = 0.012), and anterior caudate (p = 0.018), consistent with meal-stimulated DA release. Analysis of each group separately suggested that results in the caudate and putamen were disproportionately driven by meal-associated changes in the healthy-weight group. Baseline (pre-meal) DA receptor binding was lower in severe obesity than in the healthy-weight group. Baseline DA receptor binding and DA release did not change from pre- to post-surgery. The results of this small pilot study suggest that milkshake acutely stimulates DA release in the ventral and dorsal striatum. This phenomenon likely contributes to the overconsumption of highly palatable foods in the modern environment.

Sex differences in the transcriptome of extracellular vesicles secreted by fetal neural stem cells and effects of chronic alcohol exposure

BackgroundPrenatal alcohol (ethanol) exposure (PAE) results in brain growth restriction, in part, by reprogramming self-renewal and maturation of fetal neural stem cells (NSCs) during neurogenesis. We recently showed that ethanol resulted in enrichment of both proteins and pro-maturation microRNAs in sub-200-nm-sized extracellular vesicles (EVs) secreted by fetal NSCs. Moreover, EVs secreted by ethanol-exposed NSCs exhibited diminished efficacy in controlling NSC metabolism and maturation. Here we tested the hypothesis that ethanol may also influence the packaging of RNAs into EVs from cell-of-origin NSCs.MethodsSex-specified fetal murine iso-cortical neuroepithelia from three separate pregnancies were maintained ex vivo, as neurosphere cultures to model the early neurogenic niche. EVs were isolated by ultracentrifugation from NSCs exposed to a dose range of ethanol. RNA from paired EV and cell-of-origin NSC samples was processed for ribosomal RNA-depleted RNA sequencing. Differential expression analysis and exploratory weighted gene co-expression network analysis (WGCNA) identified candidate genes and gene networks that were drivers of alterations to the transcriptome of EVs relative to cells.ResultsThe RNA content of EVs differed significantly from cell-of-origin NSCs. Biological sex contributed to unique transcriptome variance in EV samples, where > 75% of the most variant transcripts were also sex-variant in EVs but not in cell-of-origin NSCs. WGCNA analysis also identified sex-dependent enrichment of pathways, including dopamine receptor binding and ectoderm formation in female EVs and cell-substrate adhesion in male EVs, with the top significant DEGs from differential analysis of overall individual gene expressions, i.e., Arhgap15, enriched in female EVs, and Cenpa, enriched in male EVs, also serving as WCGNA hub genes of sex-biased EV WGCNA clusters. In addition to the baseline RNA content differences, ethanol exposure resulted in a significant dose-dependent change in transcript expression in both EVs and cell-of-origin NSCs that predominantly altered sex-invariant RNAs. Moreover, at the highest dose, ~ 73% of significantly altered RNAs were enriched in EVs, but depleted in NSCs.ConclusionsThe EV transcriptome is distinctly different from, and more sex-variant than, the transcriptome of cell-of-origin NSCs. Ethanol, a common teratogen, results in dose-dependent sorting of RNA transcripts from NSCs to EVs which may reprogram the EV-mediated endocrine environment during neurogenesis.

Striatal increase of dopamine receptor 2 density in idiopathic and syndromic mouse models of autism spectrum disorder.

Autism spectrum disorder (ASD) comprises a wide range of neurodevelopmental phenotypes united by impaired social interaction and repetitive behavior. Environmental and genetic factors are associated with the pathogenesis of ASD, while other cases are classified as idiopathic. The dopaminergic system has a profound impact in the modulation of motor and reward-motivated behaviors, and defects in dopaminergic circuits are implicated in ASD. In our study, we compare three well-established mouse models of ASD, one idiopathic, the BTBR strain, and two syndromic, Fmr1 and Shank3 mutants. In these models, and in humans with ASD, alterations in dopaminergic metabolism and neurotransmission were highlighted. Still, accurate knowledge about the distribution of dopamine receptor densities in the basal ganglia is lacking. Using receptor autoradiography, we describe the neuroanatomical distribution of D1 and D2 receptors in dorsal and ventral striatum at late infancy and adulthood in the above-mentioned models. We show that D1 receptor binding density is different among the models irrespective of the region. A significant convergence in increased D2 receptor binding density in the ventral striatum at adulthood becomes apparent in BTBR and Shank3 lines, and a similar trend was observed in the Fmr1 line. Altogether, our results confirm the involvement of the dopaminergic system, showing defined alterations in dopamine receptor binding density in three well-established ASD lines, which may provide a plausible explanation to some of the prevalent traits of ASD. Moreover, our study provides a neuroanatomical framework to explain the utilization of D2-acting drugs such as Risperidone and Aripiprazole in ASD.

D2-LIKE DOPAMINE RECEPTOR DISTRIBUTION IN THE BRAIN OF RATS WITH DIFFERENT TYPES OF GENETIC EPILEPSY

The study investigated D2-like dopamine receptor (D2DR) binding densities in cortex and striatum between rats with absence and/or audiogenic genetically determined epilepsy and normal Wistar rats by autoradiography. It was shown that D2DR binding density was lower in the dorsal and ventrolateral aspects of nucleus accumbens in epileptic vs non-epileptic rats. Additionally, audiogenic rats had higher motor, somatosensory cortex, and dorsal striatum binding as in contrast with non-audiogenic groups. This data suggests that there is a common neuronal circuit involved in the pathogenesis of generalized epilepsy of both convulsive and non-convulsive forms.

Clinical effects of Cariprazine and their relationship with polymorphisms of dopamine and serotonin receptors: preliminary results from a prospective study on schizophrenia and bipolar disorder

IntroductionCariprazine (CAR) is a D2, D3, 5HT1A receptor partial agonist and a 5HT2A, 5HT2B antagonist, used to treat Schizophrenia and Bipolar disorder. Interindividual variability in therapeutic and side effects of antipsychotics is difficult to predict, due to non-genetic and genetic factors. Single nucleotide polymorphisms (SNPs) are the main source of genetic variability, the ones in dopamine and serotonin receptors to which CAR binds are indeed likely to determine response to treatment.ObjectivesThe aim of the study is to define a relationship between CAR clinical efficacy and SNPs in dopamine and serotonin receptors genes of patients affected by schizophrenia and bipolar disorder.MethodsWe recruited 16 patients starting a monotherapy with CAR, evaluated at baseline and after 2, 4 and 8 weeks through BPRS rating scale. We selected a panel of SNPs in DR2, DR3, 5HT1A and 5HT2A receptors, with a frequency higher that 10% in Caucasians and functionally characterized. Cut-off for response to treatment was a 50% reduction of BPRS score. Statistical analysis was performed with one-way ANOVA followed by the test for linear trend between columns.ResultsAll subjects achieved response after 8 weeks of treatment, but 6 patients after 4 weeks. Early responders have a genetic profile associated with increased dopamine and serotonin receptor expression and/or binding affinity for their specific ligands. The association don’t reach statistical significance, probably due to low number of patients.ConclusionsPreliminary results suggest that an array of dopamine and serotonin receptors SNPs could predict time to respond to CAR in schizophrenia and bipolar disorder.DisclosureThe study is founded by Recordati AG, that commercialize the drug under study (Cariprazine) in Switzerland. Funding covers the costs for genetic analysis and other procedures of the study, no financial compensation is planned for investigators/authors.

Evaluating the conformational space of the active site of D2 dopamine receptor. Scope and limitations of the standard docking methods.

We report here for the first time the potential energy surfaces (PES) of phenyletilamine (PEA) and meta-tyramine (m-OH-PEA) at the D2 dopamine receptor (D2DR) binding site. PESs not only allow us to observe all the critical points of the surface (minimums, maximums, and transition states), but also to note the ease or difficulty that each local minima have for their conformational inter-conversions and therefore know the conformational flexibility that these ligands have in their active sites. Taking advantage of possessing this valuable information, we analyze how accurate a standard docking study is in these cases. Our results indicate that although we have to be careful in how to carry out this type of study and to consider performing some extra-simulations, docking calculations can be satisfactory. In order to analyze in detail the different molecular interactions that are stabilizing the different ligand-receptor (L-R) complexes, we carried out quantum theory of atoms in molecules (QTAIM) computations and NMR shielding calculations. Although some of these techniques are a bit tedious and require more computational time, our results demonstrate the importance of performing computational simulations using different types of combined techniques (docking/MD/hybrid QM-MM/QTAIM and NMR shielding calculations) in order to obtain more accurate results. Our results allow us to understand in details the molecular interactions stabilizing and destabilizing the different L-R complexes reported here. Thus, the different activities observed for dopamine (DA), m-OH-PEA, and PEA can be clearly explained at molecular level.

Is styrene competitive for dopamine receptor binding?

The potential role of styrene oxide in altering the dopaminergic pathway in the ear is investigated by means of molecular docking and molecular dynamics simulations. We estimate the binding affinity of both styrene oxide and dopamine to the dopaminergic receptor DrD2 by computing the free-energy difference, ∆G, between the configuration where the ligand is bound to the receptor and the situation in which it is "infinitely" far away from it. The results show that the styrene oxide has a somewhat lower affinity for binding with respect to dopamine, which, however, may not be enough to prevent exogenous high concentration styrene oxide to compete with endogenous dopamine for DrD2 binding.

Proteomic Analysis of Swertiamarin-treated BV-2 Cells and Possible Implications in Neuroinflammation.

The purpose of this study was to explore the neuroprotective role of swertiamarin on neuro-inflammation, and analyzed its potential mechanism by proteomics. We used LPS to induce a inflammatory model on BV-2 cells, then 10, 25, 50 μg/mL swertiamarin was used to treat the LPS pretreated BV-2 cells. We used ELISA to detect the effect of swertiamarin on the expression of inflammation related indicators such as IL-1β, il-6, IL-18 and TNF-α. The proteomics based on TMT-LC-MS/MS analysis was performed to explore the anti-inflammatory effects of swertiamarin by bioinformatics analysis. We found swertiamain was able to inhibit pro-inflammatory cytokines secretion in a does dependent manner, including IL-1β, IL-6, IL-18 and TNF-α. These results were further verified by western blot. The proteomics analysis results suggested that the potential bioprocessings which regulated by swertiamarin mainly involved in cellular response to carbon monoxide, strand displacement, palmitoleoyltransferase activity, D2 dopamine receptor binding, RNA polymerase II transcription cofactor activity. The present study may provide a promising approach to treat and prevent neuro-inflammation diseases. It is preliminarily indicated that swertiamarin will play an important role in clinical anti-neuroinflammation process in the future.

Comparing common and unique disruptions in transposable elements and gene networks in two humanized mouse models of AD.

Alzheimer's Disease (AD) is an widespread neurodegenerative disorder, most common in elderly and Veteran populations, culminating in dementia with additional non-cognitive behavioral and metabolic symptomatology, such as hyperactivity and disrupted sleep/wake patterns, that promote weight loss. Weight loss In demented patients is associated with adverse outcomes like accelerated AD progression and institutionalization. Mouse models of tau deposition, such as Tg4510 mice, and both tau and amyloidosis, such as 3X Tg, develop both cognitive and non-cognitive symptoms. To identify early common and unique factors affecting gene networks in these different molecular models of AD, we analyzed RNA-seq data from young Tg4510 and 3X Tg mice to compare the common and unique transcripts and transposable elements (TE) expression changes that may initiate the behavioral and metabolic derangements in AD. We analyzed RNA-seq from two month old Tg4510 mice (n=5) vs. controls (n=6) and 3X Tg (n=3) and controls (n=3). Using our established bioinformatics TTESA pipeline, reads were aligned to reference genome and measured gene expression or TEs with featureCounts. Pathway enrichment analysis using Visual Annotation Display was used to discover common functional and disease pathways using Gene Ontology, Mammalian Phenotype Ontology, and Protein Ontology. TTESA results detected significantly differentially expressed TEs in both models (p<0.001) albeit 3X Tg expressed four times more TEs. The majority of significantly differentially expressed TEs were retrotransposons (68-85%), mainly of long terminal repeats (LTRs; 50-70%), and some LINE retroelements (10-30%) and a few SINEs (5%) in either transgenic model. VLaD pathway analysis revealed many biological processes upregulated in transgenic mice, including non-cognitive behavioral pathways were downregulated, such as the regulation of circadian and sleep/wake behavior, however with different genes altered within these networks (e.g., Tg3x p<0.032; Ncor1, Rasd1, Rgs16; Tg4510 Ciart, Dbp, Per2, Per3 p<0.0165). There were also unique pathways to each model, e.g., 3X Tg: subcellular organelle structure, cytoskeleton, tubulin and actin binding, whereas Tg4510 dopamine receptor binding and bHLH transcription factor binding. Based on our data, early dysregulation of TEs may be involved altered neural gene expression networks underlying neurogenesis, behavioral changes, and molecular function in two different mouse models of AD.

Synthesis and dopamine receptor binding of dihydrexidine and SKF 38393 catecholamine-based analogues

Dopamine is an important neurotransmitter that regulates numerous essential functions, including cognition and voluntary movement. As such, it serves as an important scaffold for synthesis of novel analogues as part of drug development effort to obtain drugs for treatment of neurodegenerative diseases, such as Parkinson's disease. To that end, similarity search of the ZINC database based on two known dopamine-1 receptor (D1R) agonists, dihydrexidine (DHX) and SKF 38393, respectively, was used to predict novel chemical entities with potential binding to D1R. Three compounds that showed the highest similarity index were selected for synthesis and bioactivity profiling. All main synthesis products as well as the isolated intermediates, were properly characterized. The physico-chemical analyses were performed using HRESIMS, GC/MS, LC/MS with UV-Vis detection, and FTIR, 1H NMR and 13C NMR spectroscopy. Binding to D1 and D2 receptors and inhibition of dopamine reuptake via dopamine transporter were measured for the synthesized analogues of DHX and SKF 38393.

Reading abilities and dopamine D2/D3 receptor availability: An inverted U-shaped association in subjects with schizophrenia

Reading impairments are prominent trait-like features of cognitive deficits in schizophrenia, predictive of overall cognitive functioning and presumably linked to dopaminergic abnormalities. To evaluate this, we used 18F-fallypride PET in 19 healthy and 21 antipsychotic-naïve schizophrenia subjects and correlated dopamine receptor binding potentials in relevant AFNI-derived regions and voxelwise with group performance on WRAT4 single-word reading subtest. Healthy subjects’ scores were positively and linearly associated with D2/D3 receptor availability in the rectus, orbital and superior frontal gyri, fusiform and middle temporal gyri, as well as middle occipital gyrus and precuneus, all predominantly in the left hemisphere and previously implicated in reading, hence suggesting that higher dopamine receptor density is cognitively advantageous. This relationship was weakened in schizophrenia subjects and in contrast to healthy participants followed an inverted U-shaped curve both in the cortex and dorsal striatum, indicating restricted optimal range of dopamine D2/D3 receptor availability for cognitive performance in schizophrenia.

Factors Governing Selectivity of Dopamine Receptor Binding Compounds for D2R and D3R Subtypes

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.

11C- and 18F-Radiotracers for In Vivo Imaging of the Dopamine System: Past, Present and Future.

The applications of positron emission tomography (PET) imaging to study brain biochemistry, and in particular the aspects of dopamine neurotransmission, have grown significantly over the 40 years since the first successful in vivo imaging studies in humans. In vivo PET imaging of dopaminergic functions of the central nervous system (CNS) including dopamine synthesis, vesicular storage, synaptic release and receptor binding, and reuptake processes, are now routinely used for studies in neurology, psychiatry, drug abuse and addiction, and drug development. Underlying these advances in PET imaging has been the development of the unique radiotracers labeled with positron-emitting radionuclides such as carbon-11 and fluorine-18. This review focuses on a selection of the more accepted and utilized PET radiotracers currently available, with a look at their past, present and future.

Impact of hypoxia-ischemia and dopamine treatment on dopamine receptor binding density in the preterm fetal sheep brain.

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 (n = 6) or exposed to severe HI using umbilical cord occlusion and saline infusion (UCO + saline, n = 8) or to HI with dopamine infusion (UCO + dopamine, 10 µg/kg/min, n = 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.NEW & NOTEWORTHY 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.

The effect of 17β-estradiol on maternal immune activation-induced changes in prepulse inhibition and dopamine receptor and transporter binding in female rats

Maternal immune activation (MIA) during pregnancy is associated with an increased risk of development of schizophrenia in later life. 17β-estradiol treatment may improve schizophrenia symptoms, but little is known about its efficacy on MIA-induced psychosis-like behavioural deficits in animals. Therefore, in this study we used the poly(I:C) neurodevelopmental model of schizophrenia to examine whether MIA-induced psychosis-like behavioural and neurochemical changes can be attenuated by chronic treatment (2–6 weeks) with 17β-estradiol. Pregnant rats were treated with saline or the viral mimetic, poly(I:C), on gestational day 15 and adult female offspring were tested for changes in prepulse inhibition (PPI) and density of dopamine D1 and D2 receptors and dopamine transporters in the forebrain compared to control offspring. Poly(I:C)-treated offspring exhibited significantly disrupted PPI, an effect which was reversed by chronic treatment with 17β-estradiol. In control offspring, but not poly(I:C) offspring, PPI was significantly reduced by acute treatment with either the dopamine D1/D2 receptor agonist, apomorphine, or dopamine releaser, methamphetamine. 17β-estradiol restored the effect of apomorphine, but not methamphetamine, on PPI in poly(I:C) offspring. There was a strong trend for a dopamine D2 receptor binding density increase in the nucleus accumbens core region in poly(I:C) offspring, and this was reversed by chronic 17β-estradiol treatment. No changes were found in the nucleus accumbens shell, caudate putamen or frontal cortex or in the density of dopamine D1 receptors or transporters. These findings suggest that 17β-estradiol may improve some symptoms of schizophrenia, an effect that may be mediated by selective changes in dopamine D2 receptor density.

Changes in Stereotypical Behavior Following Chlorpromazine Termination: Polypharmcy Effects on Response Class Membership.

A paucity of information exists relating to the possible biological and environmental interactions influencing the occurrence of stereotypical behavior. In particular, there is limited research on the effects of psychotropic medication use on stereotypy presentation in individuals diagnosed with developmental disabilities such as intellectual disability and autism spectrum disorder. We studied the stereotypy of a man with autism spectrum disorder and intellectual disability across 2 years. The topographies of stereotypical behavior included walking in circles, head tapping, arm flinging, and object stereotypy. These behaviors were observed weekly while the participant received daily dosages of 25 mg of chlorpromazine, 1.5 mg of lorazepam, and 2,500 mg of divalproex. At Week 75, chlorpromazine was discontinued while the other drugs and dosages were maintained. We observed a statistically significant decrease in walking in circles, but no changes in the other topographies of stereotypy. The results suggest that the gross motor activity was differentially affected by the chlorpromazine discontinuation and also suggests that alterations in dopamine receptor binding may have selectively influenced changes in stereotypical responding.

Acute cocaine treatment enhances the antagonistic allosteric adenosine A2A-dopamine D2 receptor\u2013receptor interactions in rat dorsal striatum without increasing significantly extracellular dopamine levels

BackgroundAntagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor–receptor interactions have previously been demonstrated in A2AR–D2R heteroreceptor complexes in the rat dorsal striatum. They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A2AR by an A2AR agonist. Upon cocaine self-administration, this antagonistic A2AR–D2R interaction disappeared in the dorsal striatum.MethodsIn the current experiments, it was tested whether such modifications in the antagonistic A2AR–D2R receptor–receptor interactions can develop also after an acute systemic injection of a low cocaine dose (1 mg/kg; sc).ResultsMicrodialysis experiments indicated that acute cocaine did not significantly alter the extracellular dopamine levels in the dorsal striatum of the awake Wistar rats. Competition dopamine receptor binding experiments demonstrated that in the acute cocaine group, the A2AR agonist CGS-21680 produced significantly larger increases in the D2R Ki, High values (reduction of high-affinity) versus the saline-injected (i.e. control) group. Furthermore, in the dorsal striatum membrane preparation from acute cocaine-injected rats, CGS-21680 also produced significant increases in the D2R Ki, Low values (reduction of low-affinity) and in the proportion of D2Rs in the high-affinity state (RH). Such significant effects were not observed with CGS-21680 in the control group.ConclusionsThe molecular mechanism involved in the acute cocaine-induced increase in the antagonistic allosteric A2AR–D2R receptor–receptor interactions may be an increased formation of higher-order complexes A2AR–D2R-sigma1R in which cocaine by binding to the sigma1R protomer also allosterically enhances the inhibitory A2AR–D2R interaction in this receptor complex.

Abundance Compensates Kinetics: Similar Effect of Dopamine Signals on D1 and D2 Receptor Populations.

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.SIGNIFICANCE STATEMENT 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.