Dopamine D2 Receptor Binding Research Articles

Selenoprotein P in a Rodent Model of Exercise; Theorizing Its Interaction with Brain Reward Dysregulation, Addictive Behavior, and Aging.

Exercise promotes health and wellness, including its operation as a protective factor against a variety of psychological, neurological, and chronic diseases. Selenium and its biomarker, selenoprotein P (SEPP1), have been implicated in health, including cancer prevention, neurological function, and dopamine signaling. SEPP1 blood serum levels were compared with a one-way ANOVA between sedentary (SED), moderately exercised (MOD) [10 m/min starting at 10 min, increasing to 60 min], and high-intensity interval training (HIIT) exercised rats [30 min in intervals of 2-min followed by a 1-min break, speed progressively increased from 10 to 21 m/min]. HIIT rats showed significantly higher serum SEPP1 concentrations compared to MOD and SED. More specifically, HIIT exercise showed an 84% increase in SEPP1 levels compared to sedentary controls. MOD rats had greater serum SEPP1 concentrations compared to SED, a 33% increase. The results indicated that increased exercise intensity increases SEPP1 levels. Exercise-induced increases in SEPP1 may indicate an adaptive response to the heightened oxidative stress. Previous studies found a significant increase in dopamine D2 receptor (D2R) binding in these same rats, suggesting a potential association between SEPP1 and dopamine signaling during exercise. Modulating antioxidants like SEPP1 through personalized therapies, including exercise, has broad implications for health, disease, and addiction.

Effects of deep brain stimulation on dopamine D2 receptor binding in patients with treatment-refractory depression

BackgroundDepression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD. MethodsSix patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [11C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [11C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BPND) with the cerebellum as reference tissue. ResultsDepression and anxiety symptoms improved after 3–6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [11C]raclopride BPND in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01). LimitationsThis study was limited to the small sample size and lack of a healthy control group. ConclusionsChronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.

Discovery of a Small Molecule Activator of Slack (Kcnt1) Potassium Channels That Significantly Reduces Scratching in Mouse Models of Histamine-Independent and Chronic Itch.

Various disorders are accompanied by histamine-independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, KNa1.1), a potassium channel highly expressed in itch-sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack-activating antipsychotic drug, loxapine, a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles is designed that enables to validate Slack as a pharmacological target in vivo. One of these new Slack activators, compound 6, exhibits negligible dopamine D2 and D3 receptor binding, unlike loxapine. Notably, compound 6 displays potent on-target antipruritic activity in multiple mouse models of acute histamine-independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack.

Relationship between antipsychotic medication and aggressive events in patients with a psychotic disorder hospitalized for treatment

BackgroundDisruptive and aggressive behavior is frequent in patients with a psychotic disorder; furthermore, it is a recurrent reason for compulsory admission. Even during treatment, many patients continue to show aggressive behavior. Antipsychotic medication is posed to have anti-aggressive properties; its prescription is a common strategy for the treatment (and prevention) of violent behavior. The present study aims to investigate the relation between the antipsychotic class, according to the dopamine D2-Receptor binding affinity (i.e., “loose” – “tight binding”), and aggressive events perpetrated by hospitalized patients with a psychotic disorder.MethodsWe conducted a four-year retrospective analysis of legally liable aggressive incidents perpetrated by patients during hospitalization. We extracted patients’ basic demographic and clinical data from electronic health records. We used the Staff Observation Aggression Scale (SOAS-R) to grade the severity of an event. Differences between patients with a “loose” or “tight-binding” antipsychotic were analyzed.ResultsIn the observation period, there were 17,901 direct admissions; and 61 severe aggressive events (an incidence of 0.85 for every 1,000 admissions year). Patients with a psychotic disorder perpetrated 51 events (incidence of 2.90 for every 1,000 admission year), with an OR of 15.85 (CI: 8.04–31.25) compared to non-psychotic patients. We could identify 46 events conducted by patients with a psychotic disorder under medication. The mean SOAS-R total score was 17.02 (2.74). The majority of victims in the “loose-binding” group were staff members (73.1%, n = 19), while the majority of victims in the “tight-binding” group were fellow patients (65.0%, n = 13); (X2(3,46) = 19.687; p < 0.001). There were no demographic or clinical differences between the groups and no differences regarding dose equivalents or other prescribed medication.ConclusionsIn aggressive behaviors conducted by patients with a psychotic disorder under antipsychotic medication, the dopamine D2-Receptor affinity seems to have a high impact on the target of aggression. However, more studies are needed to investigate the anti-aggressive effects of individual antipsychotic agents.

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.

Characterization and Chemical Optimization of the D2 Dopamine Receptor‐Selective Antagonist, ML321, Identifies Lead Compounds for the Clinical Treatment of Neuropsychiatric Disorders

Schizophrenia is a devastating illness characterized by both positive (hallucinations, delusions) and negative (flat affect, decreased motivation) symptoms coupled with cognitive impairment. Current antipsychotic medications are effective in treating the positive symptoms through antagonism of the D2 dopamine receptor (D2R). However, antipsychotic treatment is also hindered by side‐effects due to off‐target activities at other GPCRs and unfavorable binding kinetics at the D2R. We have identified and characterized a novel D2R antagonist with high selectivity against other GPCRs – ML321. In functional profiling screens of up to 168 different GPCRs, ML321 showed little activity beyond potent inhibition of the D2R, and to a lesser extent the D3R, demonstrating exceptional GPCR selectivity. Schild‐type functional assays revealed that ML321 acts as a competitive antagonist of the D2R while kinetic studies showed that ML321 exhibits slow‐on and fast‐off receptor binding rates; properties that are believed to limit extrapyramidal side‐effects that are commonly observed with antipsychotics. In fact, using doses that were maximally effective in antipsychotic‐predictive behavioral assays in rodents, ML321 promoted little to no catalepsy, suggesting that ML321 may produce less extrapyramidal side‐effects in patients. Importantly, no other D2R antagonist exhibits this pharmacological and behavioral profile supporting its development into an advanced drug lead. While a promising therapeutic, ML321 has a short metabolic half‐life, impeding its clinical development. A metabolite study revealed that the primary site of metabolism involves oxidation of the alkyl‐thiophene portion of ML321. To create more metabolically stable derivatives, we iteratively designed and synthesized over 100 analogs with modifications focused on the alkyl‐thiophene moiety. These analogs were pharmacologically characterized for both D2R binding affinity and function, and were also tested for metabolic stability, permeability, and solubility. These efforts have led to the optimization of ML321 into a collection of lead candidates that show similar pharmacological characteristics of ML321, but with marked increases in metabolic stability and ADME properties. Molecular docking and mutagenesis studies have led to a better understanding of how ML321 binds to the D2R, which will further assist in analog design and development. Together, these findings have advanced our understanding of ML321 structure‐activity relationships, particularly around the alkyl‐thiophene moiety, and have identified lead candidates for in vivo pharmacokinetic studies, thus representing substantial progress in the development of a new antipsychotic treatment.

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.

Thalamic dopamine D2-receptor availability in schizophrenia: a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis

Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [11C]FLB457. The main outcome was D2-R binding potential (BPND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen’s dz = −0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BPND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen’s dz = −0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen’s d = −0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.

Interaction of clozapine with metformin in a schizophrenia rat model

The low efficacy of antipsychotic drugs (e.g., clozapine) for negative symptoms and cognitive impairment has led to the introduction of adjuvant therapies. Because previous data suggest the procognitive potential of the antidiabetic drug metformin, this study aimed to assess the effects of chronic clozapine and metformin oral administration (alone and in combination) on locomotor and exploratory activities and cognitive function in a reward-based test in control and a schizophrenia-like animal model (Wisket rats). As impaired dopamine D1 receptor (D1R) function might play a role in the cognitive dysfunctions observed in patients with schizophrenia, the second goal of this study was to determine the brain-region-specific D1R-mediated signaling, ligand binding, and mRNA expression. None of the treatments affected the behavior of the control animals significantly; however, the combination treatment enhanced D1R binding and activation in the cerebral cortex. The Wisket rats exhibited impaired motivation, attention, and cognitive function, as well as a lower level of cortical D1R binding, signaling, and gene expression. Clozapine caused further deterioration of the behavioral parameters, without a significant effect on the D1R system. Metformin blunted the clozapine-induced impairments, and, similarly to that observed in the control animals, increased the functional activity of D1R. This study highlights the beneficial effects of metformin (at the behavioral and cellular levels) in blunting clozapine-induced adverse effects.

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.

Investigating the role of striatal dopamine receptor 2 in motor coordination and balance: Insights into the pathogenesis of DYT1 dystonia

DYT1 or DYT-TOR1A dystonia is early-onset, generalized dystonia. Most DYT1 dystonia patients have a heterozygous trinucleotide GAG deletion in DYT1 or TOR1A gene, with a loss of a glutamic acid residue of the protein torsinA. DYT1 dystonia patients show reduced striatal dopamine D2 receptor (D2R) binding activity. We previously reported reduced striatal D2R proteins and impaired corticostriatal plasticity in Dyt1 ΔGAG heterozygous knock-in (Dyt1 KI) mice. It remains unclear how the D2R reduction contributes to the pathogenesis of DYT1 dystonia. Recent knockout studies indicate that D2R on cholinergic interneurons (Chls) has a significant role in corticostriatal plasticity, while D2R on medium spiny neurons (MSNs) plays a minor role. To determine how reduced D2Rs on ChIs and MSNs affect motor performance, we generated ChI- or MSN-specific D2R conditional knockout mice (Drd2 ChKO or Drd2 sKO). The striatal ChIs in the Drd2 ChKO mice showed an increased firing frequency and impaired quinpirole-induced inhibition, suggesting a reduced D2R function on the ChIs. Drd2 ChKO mice had an age-dependent deficient performance on the beam-walking test similar to the Dyt1 KI mice. The Drd2 sKO mice, conversely, had a deficit on the rotarod but not the beam-walking test. Our findings suggest that D2Rs on Chls and MSNs have critical roles in motor control and balance. The similarity of the beam-walking deficit between the Drd2 ChKO and Dyt1 KI mice supports our earlier notion that D2R reduction on striatal ChIs contributes to the pathophysiology and the motor symptoms of DYT1 dystonia.

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.

Characterization of dopamine D2 receptor binding, expression and signaling in different brain regions of control and schizophrenia-model Wisket rats

In previous studies we have shown that a three-hit animal model of schizophrenia (Wisket rat) has several behavioral impairments related to the disorder along with altered mu-opioid (MOP) and cannabinoid (CB1) receptor signaling. As the dopamine hypothesis of schizophrenia is central to research in the field, the goal of the present study was to investigate dopaminergic D2 receptor (D2R) functions (binding capacity, G-protein activation and expression) in several brain regions (hippocampus, prefrontal cortex, striatum, olfactory bulb, cerebellum, brainstem, cortex and diencephalon) of control (Wistar) and Wisket rats.It was found that the D2R mediated maximal activation of G-proteins was substantially higher in hippocampus, striatum and olfactory bulb membranes prepared from the Wisket than in control animals, which was accompanied with lower potency of the D2R-mediated G-protein activation. In contrast, enhanced potency was detected in the prefrontal cortex without changes in the maximal activation. In saturation binding assays the maximal binding capacity of D2Rs was higher in the model animals in cerebral cortex, striatum and lower in the brainstem, while no changes in the dissociation constant values were detected. The D2R mRNA expression showed a trend for greater level in the investigated areas, while the D2R protein expression was significantly higher of Wisket rats compared to Wistar animals in the hippocampus and in the prefrontal cortex but not in the cerebellum.This study proved that the Wisket animals show altered D2 receptor expression and function which might be related to the schizophrenia-like symptoms.

Binding of Dopamine D1 Receptor and Noradrenaline Transporter in Individuals with Autism Spectrum Disorder: A PET Study.

Although previous studies have suggested the involvement of dopamine (DA) and noradrenaline (NA) neurotransmissions in the autism spectrum disorder (ASD) pathophysiology, few studies have examined these neurotransmissions in individuals with ASD in vivo. Here, we investigated DA D1 receptor (D1R) and noradrenaline transporter (NAT) binding in adults with ASD (n = 18) and neurotypical controls (n = 20) by utilizing two different PET radioligands, [11C]SCH23390 and (S,S)-[18F]FMeNER-D2, respectively. We found no significant group differences in DA D1R (striatum, anterior cingulate cortex, and temporal cortex) or NAT (thalamus and pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex and temporal cortex) and the "attention to detail" subscale score of the Autism Spectrum Quotient. Further, there was a significant positive correlation between DA D1R binding (temporal cortex) and emotion perception ability assessed by the neurocognitive battery. Associations of NAT binding with empathic abilities and executive function were found in controls, but were absent in the ASD group. Although a lack of significant group differences in binding might be partly due to the heterogeneity of ASD, our results indicate that central DA and NA function might play certain roles in the clinical characteristics of ASD.

Effects of exposure to chronic uncertainty and a sensitizing regimen of amphetamine injections on locomotion, decision-making, and dopamine receptors in rats.

Gambling disorder (GD) is a behavioral addiction that may be linked to alterations in dopamine (DA) systems. Gambling involves chronic exposure to uncertain reward, which can sensitize the activity of DA systems. Here we explored how combinations of Pavlovian and instrumental uncertainty impact DA sensitization and risky decision-making. Experiment 1: 40 rats underwent 66 uncertainty exposure (UE) sessions during which they responded for saccharin. Animal responding was reinforced according to a fixed or variable (FR/VR) ratio schedule that turned on a conditioned stimulus (CS; light), which predicted saccharin on 50% or 100% of trials. Animals responded under one of the four conditions: FR-CS100% (no uncertainty), VR-CS100%, FR-CS50%, and VR-CS50% (maximal uncertainty). DA sensitization was inferred from an enhanced locomotor response to d-amphetamine (d-AMPH; 0.5 mg/kg) challenge. The rat gambling task (rGT) was used to assess decision-making. Experiment 2: 24 rats received 5 weeks of sensitizing d-AMPH or saline doses, followed by locomotor activity and rGT testing. Experiment 3: Effects of UE and a sensitizing d-AMPH regimen on DA D1, D2, and D3 receptor binding were assessed in 44 rats using autoradiography. Compared to FR-CS100%, VR-CS100% and VR-CS50% rats displayed a greater locomotor response to d-AMPH, and VR-CS50% rats demonstrated riskier decision-making. Chronic d-AMPH-treated rats mirrored the effects of VR-CS50% groups on these two indices. Both VR-CS50% and d-AMPH-treated groups had increased striatal DA D2 receptor binding. These results suggest that chronic uncertainty exposure, similar to exposure to a sensitizing d-AMPH regimen, sensitized the function of DA systems and increased risky decision-making.

The interactions of dopamine and oxidative damage in the striatum of patients with neurodegenerative diseases.

The striatum with a number of dopamine containing neurons, receiving projections from the substantia nigra and ventral tegmental area; plays a critical role in neurodegenerative diseases of motor and memory function. Additionally, oxidative damage to nucleic acid may be vital in the development of age‐associated neurodegeneration. The metabolism of dopamine is recognized as one of the sources of reactive oxygen species through the Fenton mechanism. The proposed interactions of oxidative insults and dopamine in the striatum during the progression of diseases are the hypotheses of most interest to our study. This study investigated the possibility of significant interactions between these molecules that are involved in the late‐stage of Alzheimer's disease (AD), Parkinson disease (PD), Parkinson disease dementia, dementia with Lewy bodies, and controls using ELISA assays, autoradiography, and mRNA in situ hybridization assay. Interestingly, lower DNA/RNA oxidative adducts levels in the caudate and putamen of diseased brains were observed with the exception of an increased DNA oxidative product in the caudate of AD brains. Similar changes were found for dopamine concentration and vesicular monoamine transporter 2 densities. We also found that downstream pre‐synaptic dopamine D1 Receptor binding correlated with dopamine loss in Lewy body disease groups, and RNA damage and β‐site APP cleaving enzyme 1 in the caudate of AD. This is the first demonstration of region‐specific alterations of DNA/RNA oxidative damage which cannot be viewed in isolation, but rather in connection with the interrelationship between different neuronal events; chiefly DNA oxidative adducts and density of vesicular monoamine transporter 2 densities in AD and PD patients.

Membrane proteomic analysis reveals the intestinal development is deteriorated by intrauterine growth restriction in piglets.

The alterations of the intestinal proteome were observed in intrauterine growth restriction (IUGR) piglets during early life by gel-based approaches. Nevertheless, how IUGR affects the intestinal membrane proteome during neonatal development remains unclear. Here, we applied the iTRAQ-based proteomics technology and biochemical analysis to investigate the impact of IUGR on the membrane proteome of the jejunal mucosa in the piglets. Three hundred sixty-one membrane proteins were screened by functional prediction. Among them, eight, five, and one differentially expressed membrane proteins were identified between IUGR and NBW piglets at day 0, day 7, and day 21 after birth, respectively. Differentially expressed membrane proteins (DEMPs) including F1SBL3, F1RRW8, F1S539, F1S2Z2, F1RIR2, F1RUF2 I3LP60, Q2EN79, and F1SIH8 were reduced while the relative abundance of I3L6A2, F1SCJ1, F1RI18, I3LRJ7, and F1RNN0 were increased in IUGR piglets than NBW piglets. From the aspects of function, F1RRW8, F1S539, F1S2Z2, and F1RIR2 are mainly associated with D2 dopamine receptor binding, transmembrane transport of small molecules, signal transduction, and translocation of GLUT4, respectively, and F1SIH8, I3LRJ7, and F1RNN0 are related to autophagy, metabolism of vitamins, and intracellular protein transport. Additionally, IUGR decreased the level of proteins (F1RRW8, Q2EN79, and F1RI18) that are involved in response to oxidative stress.

The Universal 3D QSAR Model for Dopamine D2 Receptor Antagonists.

In order to search for novel antipsychotics acting through the D2 receptor, it is necessary to know the structure–activity relationships for dopamine D2 receptor antagonists. In this context, we constructed the universal three-dimensional quantitative structure–activity relationship (3D- QSAR) model for competitive dopamine D2 receptor antagonists. We took 176 compounds from chemically different groups characterized by the half maximal inhibitory concentration (IC50)from the CHEMBL database and docked them to the X-ray structure of the human D2 receptor in the inactive state. Selected docking poses were applied for Comparative Molecular Field Analysis (CoMFA) alignment. The obtained CoMFA model is characterized by a cross-validated coefficient Q2 of 0.76 with an optimal component of 5, R2 of 0.92, and an F value of 338.9. The steric and electrostatic field contributions are 67.4% and 32.6%, respectively. The statistics obtained prove that the CoMFA model is significant. Next, the IC50 of the 16 compounds from the test set was predicted with R2 of 0.95. Finally, a progressive scrambling test was carried out for additional validation. The CoMFA fields were mapped onto the dopamine D2 receptor binding site, which enabled a discussion of the structure–activity relationship based on ligand–receptor interactions. In particular, it was found that one of the desired steric interactions covers the area of a putative common allosteric pocket suggested for some other G protein-coupled receptors (GPCRs), which would suggest that some of the known dopamine receptor antagonists are bitopic in their essence. The CoMFA model can be applied to predict the potential activity of novel dopamine D2 receptor antagonists.

Which Dopamine Polymorphisms Are Functional? Systematic Review and Meta-analysis of COMT, DAT, DBH, DDC, DRD1–5, MAOA, MAOB, TH, VMAT1, and VMAT2

BackgroundMany polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear. MethodsWe conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product. ResultsWe screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the Val158Met polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine β-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH–STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5′ VNTR polymorphism. Dopamine D2 receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing. ConclusionsSome widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as “markers” of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.

D1-Dopamine Receptor Availability in First-Episode Neuroleptic Naive Psychosis Patients.

BackgroundPositron emission tomography studies examining differences in D1-dopamine receptor binding between control subjects and patients with schizophrenia have been inconsistent, reporting higher, lower, and no difference in the frontal cortex. Exposure to antipsychotic medication has been suggested to be a likely source of this heterogeneity, and thus there is a need for studies of patients at early stages of the disorder who have not been exposed to such drugs.MethodsHere, we compared 17 healthy control subjects and 18 first-episode neuroleptic naive patients with schizophrenia or schizophreniform psychosis using positron emission tomography and the D1-dopamine receptor radioligand [11C]SCH23390.ResultsWe observed a statistically significant difference in the dorsolateral prefrontal cortex. Contrary to our expectations, patients had less D1-dopamine receptor availability with a moderate effect size. In a Bayesian analysis, we show that the data are over 50 times more likely to have occurred under the decrease as opposed to the increase hypothesis. This effect was not global, as our analysis showed that the null hypothesis was preferred over either hypothesis in the striatum.ConclusionsThis investigation represents the largest single sample of neuroleptic-naive patients examined for D1-dopamine receptor availability using PET and suggests a reduction of prefrontal D1-dopamine receptor density in the pathophysiology of schizophrenia. However, further work will be required to reach a consensus.