Ability Of Dopamine Research Articles

Mechanism of SDBS functionalized PPy enhancing the electrochemical sensitivity of SPGE to dopamine and uric acid: Experimental and DFT investigations

A novel approach to enhance the electrochemical sensitivity of screen-printed graphene electrode (SPGE) to dopamine (DA) and uric acid (UA) utilizing sodium dodecylbenzene sulfonate (SDBS) functionalized polypyrrole (PPy) is presented. The functionalized PPy nanosheets (SDBS/PPy) were synthesized via low-temperature polymerization. The introduced dodecylbenzene sulfonate (DBS-) facilitated the dispersion of functionalized PPy nanosheets, resulting in a notably increased specific surface area. DA and UA adsorption behavior on PPy and SDBS/PPy surface was investigated using density functional theory (DFT). The adsorption energy of DA and UA on SDBS/PPy was 0.15 eV and 0.05 eV higher than that on PPy. The adsorption ability of DA and UA was greatly improved after doping DBS- in PPy. The electrochemical response of SDBS/PPy-modified SPGE (SDBS/PPy/SPGE) to different concentrations of DA and UA was evaluated. Compared with SPGE, the oxidation current sensitivity of SDBS/PPy/SPGE to DA increased from 0.08 μA·μM−1 to 0.13 μA·μM−1, the oxidation current sensitivity of SDBS/PPy/SPGE to UA increased from 0.01 μA·μM−1 to 0.04 μA·μM−1. Electrochemical measurement demonstrated that PPy doping with DBS- caused a unique improvement in DA and UA performance of SPGE.

Dopamine alters phage morphology to exert an anti-infection effect.

Antiviral drug development is important for human health, and the emergence of novel COVID-19 variants has seriously affected human lives and safety. A bacteriophage-a bacterial virus with a small and simple structure-is an ideal experimental candidate for studying the interactions between viruses and their hosts. In this study, the effects and mechanisms of catecholamines on phages were explored, and dopamine (DA) was found to have general and efficient anti-infection effects. A clear dose-dependent effect was observed when different phages were treated with DA, with higher DA concentrations exhibiting stronger anti-phage activity. The half maximal inhibitory concentration values of DA for vB-EcoS-IME167, T4 Phage, and VMY22 were determined as 0.26, 0.12, and 0.73 mg mL-1, respectively. The anti-phage effect of DA increased with treatment duration. In addition, the anti-infection activities of DA against vB-EcoS-IME167, T4 Phage, and VMY22 were increased by 105, 104, and 104 folds compared to that of the control. This ability of DA was observed only in phages and not in the host bacteria. Morphological changes of phages were observed under transmission electron microscopy following their treatment with DA, and considerable changes in adsorption were confirmed via quantitative reverse transcription polymerase chain reaction. These results suggest that the anti-phage effect of DA is primarily due to the destruction of the external structure of the phage. This study, to the best of our knowledge, is the first to report the universal anti-phage infection effect of dopamine, which provides novel information regarding DA and forms a basis for further research and development of antiviral drugs. Moreover, it provides a new perspective for the research about the defense and counter-defense of bacteria and bacteriophages.

Dopaminergic inhibition of human neutrophils is exerted through D1-like receptors and affected by bacterial infection.

Dopamine (DA) affects immune functions in healthy subjects (HS) and during disease by acting on D1-like (D1 and D5) and D2-like (D2, D3 and D4) dopaminergic receptors (DR); however, its effects on human polymorphonuclear leukocytes (PMN) are still poorly defined. We investigated DR expression in human PMN and the ability of DA to affect cell migration and reactive oxygen species (ROS) production. Experiments were performed on cells from HS and from patients (Pts) with bacterial infections as well, during the acute phase and after recovery. Some experiments were also performed in mice knockout (KO) for the DRD5 gene. PMN from HS express both D1-like and D2-like DR, and exposure to DA results in inhibition of activation-induced morphological changes, migration and ROS production which depend on the activation of D1-like DR. In agreement with these findings, DA inhibited migration of PMN obtained from wild-type mice, but not from DRD5KO mice. In Pts with bacterial infections, during the febrile phase D1-like DRD5 on PMN were downregulated and DA failed to affect PMN migration. Both D1-like DRD5 expression and DA-induced inhibition of PMN migration were however restored after recovery. Dopaminergic inhibition of human PMN is a novel mechanism which is likely to play a key role in the regulation of innate immunity. Evidence obtained in Pts with bacterial infections provides novel clues for the therapeutic modulation of PMN during infectious disease.

Bile Acids Gate Dopamine Transporter Mediated Currents.

Bile acids (BAs) are molecules derived from cholesterol that are involved in dietary fat absorption. New evidence supports an additional role for BAs as regulators of brain function. Sterols such as cholesterol interact with monoamine transporters, including the dopamine (DA) transporter (DAT) which plays a key role in DA neurotransmission and reward. This study explores the interactions of the BA, obeticholic acid (OCA), with DAT and characterizes the regulation of DAT activity via both electrophysiology and molecular modeling. We expressed murine DAT (mDAT) in Xenopus laevis oocytes and confirmed its functionality. Next, we showed that OCA promotes a DAT-mediated inward current that is Na+-dependent and not regulated by intracellular calcium. The current induced by OCA was transient in nature, returning to baseline in the continued presence of the BA. OCA also transiently blocked the DAT-mediated Li+-leak current, a feature that parallels DA action and indicates direct binding to the transporter in the absence of Na+. Interestingly, OCA did not alter DA affinity nor the ability of DA to promote a DAT-mediated inward current, suggesting that the interaction of OCA with the transporter is non-competitive, regarding DA. Docking simulations performed for investigating the molecular mechanism of OCA action on DAT activity revealed two potential binding sites. First, in the absence of DA, OCA binds DAT through interactions with D421, a residue normally involved in coordinating the binding of the Na+ ion to the Na2 binding site (Borre et al., J. Biol. Chem., 2014, 289, 25764–25773; Cheng and Bahar, Structure, 2015, 23, 2171–2181). Furthermore, we uncover a separate binding site for OCA on DAT, of equal potential functional impact, that is coordinated by the DAT residues R445 and D436. Binding to that site may stabilize the inward-facing (IF) open state by preventing the re-formation of the IF-gating salt bridges, R60-D436 and R445-E428, that are required for DA transport. This study suggests that BAs may represent novel pharmacological tools to regulate DAT function, and possibly, associated behaviors.

Перспектива местного применения регуляторов дофаминергической системы для снижения внутриглазного давления

Dopaminergic system takes part in regulation of intraocular pressure (IOP) and other elements of the pathogenesis of glaucoma. Development of new drugs for the glaucoma treatment remains an actual problem in modern ophthalmology. Purpose. To estimate the perspective of topical use of dopaminergic system regulators as ocular hypotensive agents. Matherials and methods. The investigation was carried out on healthy Shinshilla rabbits and knock-out mice with γ-sinuclein gene deletion (γ-KO) that served for a model of ocular hypertension. IOP was measured before 10% dopamine instillation and every 30 minutes after it for 2 hours totally. Results. Single instillation of 10% dopamine caused a mean IOP decrease of 4-5 mm Hg after 1,5-2 hours. In γ-KO mice IOP decreased significantly on 5-6 mm Hg after 30 min and remained lower than the initial level for 2 hours. Conclusion. Single instillation of 10% dopamine cause a statistically significant decrease of IOP in healthy rabbits and γ-KO mice that initially have ocular hypertension. The ability of dopamine and D2 receptor agonists to decrease IOP denote the prospectivity of their use for the therapy of glaucoma. Key words: glaucoma, intraocular pressure, dopaminergic system, dopamine, γ-sinuclein knock-out mice.

A study of the dopamine transporter using the TRACT assay, a novel in vitro tool for solute carrier drug discovery

Members of the solute carrier (SLC) transporter protein family are increasingly recognized as therapeutic drug targets. The majority of drug screening assays for SLCs are based on the uptake of radiolabeled or fluorescent substrates. Thus, these approaches often have limitations that compromise on throughput or the physiological environment of the SLC. In this study, we report a novel application of an impedance-based biosensor, xCELLigence, to investigate dopamine transporter (DAT) activity via substrate-induced activation of G protein-coupled receptors (GPCRs). The resulting assay, which is coined the ‘transporter activity through receptor activation’ (TRACT) assay, is based on the hypothesis that DAT-mediated removal of extracellular dopamine directly affects the ability of dopamine to activate cognate membrane-bound GPCRs. In two human cell lines with heterologous DAT expression, dopamine-induced GPCR signaling was attenuated. Pharmacological inhibition or the absence of DAT restored the apparent potency of dopamine for GPCR activation. The inhibitory potencies for DAT inhibitors GBR12909 (pIC50 = 6.2, 6.6) and cocaine (pIC50 = 6.3) were in line with values from reported orthogonal transport assays. Conclusively, this study demonstrates the novel use of label-free whole-cell biosensors to investigate DAT activity using GPCR activation as a readout. This holds promise for other SLCs that share their substrate with a GPCR.

Double molecular recognition strategy based on boronic acid-diol and NHS ester-amine for selective electrochemical detection of cerebral dopamine.

Electrochemical detection of dopamine (DA) usually depends on electrochemical oxidation of DA. This conventional method can hardly provide sufficient sensitivity and selectivity in the determination of the cerebral DA down to nanomolar level, because the ability of DA to be electrochemically oxidized is limited and many electroactive interferents are also oxidized at a similar potential with DA. Here, an electrochemical assay based on a double molecular recognition strategy has been proposed and proved to be of high sensitivity and selectivity for DA measurement in the cerebral system. 3,3'-Dithiodipropionic acid di(N-hydroxysuccinimide ester) (DSP) was anchored on the electrode surface to capture DA target through the specific reaction between N-hydroxysuccinimide (NHS) ester and amine. The captured DA endowed the electrode with a layer of diol groups, which further reacted with the boronic acid to trap of 4-mercaptophenylboronic acid (MBA) molecules, thus leading to the conjunction of electroactive thionine (Th) molecules on the electrode for signal readout. In addition, an Au nanostructure was employed to enhance signal amplification and facilitate the double molecular recognition process. As a consequence, this method was able to quantify DA from 1 to 300nM with a detection limit of 0.74nM, which exhibited a high specificity against cerebral interferents. Furthermore, the practicability of this platform was successfully demonstrated through determination of the dynamics of cerebral DA in the events of high K+ and nomifensine retromicrodialysis. Graphical abstract.

G protein‐coupled receptor kinase 2 can enhance beta‐arrestin recruitment to the D2 dopamine receptor in the absence of receptor phosphorylation

Dopamine (DA) receptors (DARs) regulate diverse physiological functions and are classified as either D1‐like (D1R and D5R) or D2‐like (D2R, D3R, and D4R) based on structural homology and pharmacological properties. DARs can signal through two main pathways: activation of G proteins and recruitment of β‐arrestin, a multivalent scaffolding protein that coordinates downstream signaling events. Upon agonist binding to the receptor, an active state is formed that activates G proteins and facilitates receptor phosphorylation by one or more members of the G protein‐coupled receptor kinase (GRK) family. GRK‐mediated receptor phosphorylation is widely believed to enhance GPCR‐β‐arrestin interactions, but the precise mechanism remains unclear for the D2R. We recently identified a single amino acid (F189 (5.38 using Ballesteros‐Weinstein numbering)) within the ligand binding site of the D2R that acts as a micro‐switch for regulating D2R interactions with β‐arrestin. When F189 is mutated to alanine, the mutant D2R (D2R‐F1895.38A) is capable of activating G proteins, but is unable to recruit β‐arrestin, i.e., D2R‐F1895.38A is a G protein‐biased mutant. To investigate the mechanisms underlying the biased signaling of D2R‐F1895.38A, its interactions with GRK2 were explored using a variety of bioluminescence resonance energy transfer (BRET) assays. GRK2 has been shown to phosphorylate the D2R‐WT in response to agonist stimulation and its overexpression can enhance the ability of DA to promote β‐arrestin recruitment to the receptor. Importantly, we found that the G protein‐biased D2R‐F1895.38A mutant does not recruit GRK2 upon agonist stimulation. This finding suggests that the absence of D2R‐F1895.38A ‐GRK2 interactions may underlie the receptor’s inability to recruit β‐arrestin. To test this hypothesis, we examined DA‐stimulated β‐arrestin and GRK2 recruitment using a phosphorylation‐defective D2R mutant (Namkung et. al., JBC 284:34103, 2009), a catalytically inactive GRK2 mutant (GRK2‐K220R), and compound 101, a GRK2/3 inhibitor. Strikingly, the phosphorylation‐defective D2R mutant was not impaired in its ability to recruit either GRK2 or β‐arrestin. In addition, overexpression of GRK2‐K220R, or treatment with compound 101, resulted in a decrease, but not elimination of DA‐stimulated β‐arrestin recruitment to the D2R, suggesting that, while GRK2 kinase activity is required for enhancement of β‐arrestin recruitment, phosphorylation of the D2R is not involved. We further examined the role of GRK2 using a cell line in which GRK2 was knocked out and found that, while β‐arrestin recruitment to the D2R was diminished, it was not eliminated. Taken together, these data suggest that while GRK2 plays a facilitatory role in regulating β‐arrestin recruitment to the D2R, and thus can potentially mediate receptor signaling bias, receptor phosphorylation itself does not appear to be involved.Support or Funding InformationNINDS Intramural Research Program

Loss of β-arrestin2 in D2 cells alters neuronal excitability in the nucleus accumbens and behavioral responses to psychostimulants and opioids.

Psychostimulants and opioids increase dopamine (DA) neurotransmission, activating D1 and D2 G protein-coupled receptors. β-arrestin2 (βarr2) desensitizes and internalizes these receptors and initiates G protein-independent signaling. Previous work revealed that mice with a global or cell-specific knockout of βarr2 have altered responses to certain drugs; however, the effects of βarr2 on the excitability of medium spiny neurons (MSNs), and its role in mediating the rewarding effects of drugs of abuse are unknown. D1-Cre and D2-Cre transgenic mice were crossed with floxed βarr2 mice to eliminate βarr2 specifically in cells containing either D1 (D1βarr2-KO ) or D2 (D2βarr2-KO ) receptors. We used slice electrophysiology to characterize the role of βarr2 in modulating D1 and D2 nucleus accumbens MSN intrinsic excitability in response to DA and tested the locomotor-activating and rewarding effects of cocaine and morphine in these mice. Eliminating βarr2 attenuated the ability of DA to inhibit D2-MSNs and altered the DA-induced maximum firing rate in D1-MSNs. While D1βarr2-KO mice had mostly normal drug responses, D2βarr2-KO mice showed dose-dependent reductions in acute locomotor responses to cocaine and morphine, attenuated locomotor sensitization to cocaine, and blunted cocaine reward measured with conditioned place preference. Both D2βarr2-KO and D1βarr2-KO mice displayed an enhanced conditioned place preference for the highest dose of morphine. These results indicate that D1- and D2-derived βarr2 functionally contribute to DA-induced changes in MSN intrinsic excitability and behavioral responses to psychostimulants and opioids dose-dependently.

Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors.

The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, Autism Spectrum Disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine to methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e. anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous dopamine efflux. Here we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation display impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.

Elucidation of self‐mediated enhancement of dopamine transport by the dopamine transporter which can be modulated by extracellular gate and N‐terminal residues

The dopamine (DA) and serotonin (5‐HT) transporters (DAT and SERT respectively) are members of the SLC6 family of neurotransmitter:sodium symporters (NSSs). DAT and SERT clear substrate from perisynaptic spaces by the generally accepted alternating access mechanism in which the transporters transition between outward‐facing and inward‐facing conformational states. This mechanism involves a sequential closing and opening of extracellular (EC) and intracellular (IC) gates along the permeation pathway. The EC and IC gates are almost exclusively composed of acidic and basic residues capable of interacting through salt bridge formation, closing the primary substrate binding site to the intracellular and extracellular milieus. Previously, we identified that the human SERT acidic/basic residue pair is critical for the recognition of 3,4‐methylenedioxymethamphetamine (MDMA) as a substrate. In contrast, mutations in the EC gate had no effect on 5‐HT recognition. Our current efforts focus on determining if the EC gate of the human DAT has similar mechanistic characteristics for substrate selectivity. While investigating that possibility, we identified a previously unreported phenomenon of self‐mediated enhancement of DA transport in hDAT expressing cells. In homologous competitive uptake experiments utilizing [3H]DA, a 200% to 300% increase in [3H]DA uptake is observed upon addition of micromolar concentrations of unlabeled DA. This enhancement is further modulated by the identity of the acidic EC gate residue. Substituting the Asp with the polar amino acid Asn (D476N) produces a 600% increase in [3H]DA uptake. Experiments utilizing heterologous competition with [3H]DA and the known hDAT substrates 1‐methyl‐4‐phenylpyridinium (MPP+), 4‐(4‐dimethylamino)phenyl‐1‐methylpyridinium(APP+) and tyramine indicate that the enhancement effect is not exclusive to DA nor is it observed with all DAT substrates. Notably, elimination of phosphorylation at N‐terminal residue Thr53 virtually eliminates the DA self‐enhancement phenotype. The apparent ability of DA to enhance its own uptake is consistent with reports proposing a second substrate binding site (S2) that can act as a trigger for release of substrate from the primary DA binding site (S1). However, the presence of this S2 site remains controversial. Continued investigation of this phenomenon may provide insight into molecular determinants on both the substrate and transporter that are important for substrate identification and translocation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Murine genetic variance in muscarinic cholinergic receptor antagonism of sucrose and saccharin solution intakes in three inbred mouse strains

Nutritive (e.g., sucrose) and non-nutritive (e.g., saccharin) sweeteners stimulate intake in inbred mouse strains. BALB/c, SWR and C57BL/6 mice differ in the ability of dopamine (DA) D1 (SCH23390) and opioid (naltrexone) receptor antagonism to alter sucrose intake. Whereas SCH23390 comparably reduced cumulative sucrose intake in all three strains, naltrexone reduced cumulative sucrose intake maximally in C57/BL/6 mice, in intermediate fashion in BALB/c mice, but not in SWR mice. Whereas cumulative saccharin intake was reduced by DA D1 receptor antagonism in BALB/c and SWR mice, naltrexone was more potent in SWR relative to BALB/c mice. The present study first examined whether SCH23390 (50–1600nmol/kg) and naltrexone (0.01–5mg/kg) altered saccharin intake in C57BL/6 mice. Given that scopolamine (SCOP), a muscarinic cholinergic receptor antagonist, reduces sweet intake in outbred rats, a second experiment examined whether SCOP (0.1–10mg/kg) altered 0.2% saccharin and 10% sucrose intakes in BALB/c, SWR and C57BL/6 mice. Cumulative saccharin intake was significantly reduced by SCH23390 (200–1600nmol/kg; ID40=175nmol/kg) and naltrexone (0.1–5mg/kg; ID40>5mg/kg) in C57BL/6 mice. Cumulative sucrose intake was significantly reduced following SCOP in C57BL/6 (0.1–10mg/kg; ID40=2.32mg/kg) and BALB/c (2.5–10mg/kg; ID40=0.52mg/kg) mice. In contrast, SWR mice (ID40=41.61mg/kg) only displayed transient (15min) reductions in sucrose intake following SCOP (2.5–10mg/kg). Cumulative saccharin intake was significantly reduced following SCOP in C57BL/6 and BALB/c mice (0.1–10mg/kg; ID40<0.1mg/kg). In contrast, SWR mice (ID40=2.28mg/kg) displayed smaller significant reductions in saccharin intake following SCOP (0.1–10mg/kg). These data indicate that although both nutritive and non-nutritive sweet intakes are governed by muscarinic cholinergic receptor signaling, this process is subject to murine genetic variance with greater sensitivity observed in C57BL/6 and BALB/c relative to SWR inbred mouse strains.

Evidence for Noncanonical Neurotransmitter Activation: Norepinephrine as a Dopamine D2-Like Receptor Agonist

The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression patterns prompts the question of a possible noncanonical action by norepinephrine. In fact, previous studies have suggested that norepinephrine can functionally interact with D4R. To our knowledge, significant interactions between norepinephrine and D2R or D3R receptors have not been demonstrated. By using radioligand binding and bioluminescent resonance energy transfer (BRET) assays in transfected cells, the present study attempted a careful comparison between dopamine and norepinephrine in their possible activation of all D2-like receptors, including the two D2R isoforms and the most common D4R polymorphic variants. Functional BRET assays included activation of G proteins with all Gαi/o subunits, adenylyl cyclase inhibition, and β arrestin recruitment. Norepinephrine acted as a potent agonist for all D2-like receptor subtypes, with the general rank order of potency of D3R > D4R ≥ D2SR ≥ D2L. However, for both dopamine and norepinephrine, differences depended on the Gαi/o protein subunit involved. The most striking differences were observed with Gαi2, where the rank order of potencies for both dopamine and norepinephrine were D4R > D2SR = D2LR >> D3R. Furthermore the results do not support the existence of differences in the ability of dopamine and norepinephrine to activate different human D4R variants. The potency of norepinephrine for adrenergic α2A receptor was only about 20-fold higher compared with D3R and D4R across the three functional assays.

Staff acceptability of contingency management to promote longer breastfeeding duration at WIC

Staff acceptability of contingency management to promote longer breastfeeding duration at WIC

Impedimetric DNA-biosensor for the study of dopamine induces DNA damage and investigation of inhibitory and repair effects of some antioxidants

A simple and inexpensive methodology was used to develop a new method in order to inspect the DNA damage due to dopamine and some ionic metals. In addition, the inhibitory and repair effects of some antioxidant such as glutathione and ascorbic acid were studied and compared with each other using electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry (DPV). In this work a pencil graphite electrode (PGE) was modified with multiwall carbon nanotubes (MWCNTs) and chitosan (CHIT), then it was decorated with a ds-DNA (ds-DNA/CHIT–MWCNTs/PGE). Due to interaction of ds-DNA and the damaging agents (dopamine+metallic ions), electrochemical and spectroscopy properties of ds-DNA at the surface of the modified electrode was changed, and these changes are followed with EIS and DPV methods. Our study showed that dopamine, Cu(II) and Fe(III) alone could not destroy DNA, but dopamine+Cu(II) and dopamine+Fe(III) can damage DNA. In addition, the ability of dopamine–Cu(II) was greater than dopamine–Fe(III). Moreover, some antioxidant such as glutathione and ascorbic acid can overcome and/or minimize the influence of these damaging interactions.

Redox potentials of dopamine and its supramolecular complex with aspartic acid

Dopamine (DA) can be oxidized to dopamine quinone (DAquinone) through a one-step, two-electron redox reaction. The electron transfer property of DA and its supramolecular complex with aspartic acid (Asp) has been investigated by the theoretical calculations. We calculated the standard redox potentials (E o) of DA/DAquinone at the MP2/6-31G(d,p)//B3LYP/6-31G(d,p), MP2/6-31+G(d,p)//B3LYP/6-31+G(d,p), MP2/6-31G(d,p)//B3LYP/6-311G(d,p), and MP2/6-311+G(d,p)//B3LYP/6-311+G(d,p) levels. Comparing the experimental value, the redox potentials of DA/DAquinone obtained at MP2//B3LYP/6-311G(d,p) and MP2//B3LYP/6-311+G(d,p) levels can be considered as the upper and lower estimates. DA can form supramolecular complex (DA-Asp) with Asp through hydrogen bond (H-bond). Therefore, the values of 0.631 and 0.628 V obtained at MP2//B3LYP/6-311G(d,p) and MP2//B3LYP/6-311+G(d,p) levels for DA-Asp/DAquinone-Asp can be proposed as the upper and lower estimates of a probable (about 0.630 V) value of the corresponding redox potential. The calculated E o values of DA-Asp/DAquinone-Asp at the four theoretical levels are upper than those of DA/DAquinone, which indicates that the formation of H-bonds weaken the electron-donating ability of DA.

Chapter 6 - The multilingual nature of dopamine neurons

The ability of dopamine (DA) neurons to release other transmitters in addition to DA itself has been increasingly recognized, hence the concept of their multilingual nature. A subset of DA neurons, mainly found in the ventral tegmental area, express VGLUT2, allowing them to package and release glutamate onto striatal spiny projection neurons and cholinergic interneurons. Some dopaminergic axon terminals release GABA. Glutamate release by DA neurons has a developmental role, facilitating axonal growth and survival, and may determine in part the critical contribution of the ventral striatum to psychostimulant-induced behavior. Vesicular glutamate coentry may have synergistic effects on vesicular DA filling. The multilingual transmission of DA neurons across multiple striatal domains and the increasing insight into the role of glutamate cotransmission in the ventral striatum highlight the importance of analyzing DA neuron transmission at the synaptic level.

Restricted Diffusion of Dopamine in the Rat Dorsal Striatum

Recent evidence has shown that the dorsal striatum of the rat is arranged as a patchwork of domains that exhibit distinct dopamine kinetics and concentrations. This raises the pressing question of how these distinct domains are maintained, especially if dopamine is able to diffuse through the extracellular space. Diffusion between the domains would eliminate the concentration differences and, thereby, the domains themselves. The present study is a closer examination of dopamine's ability to diffuse in the extracellular space. We used voltammetry to record dopamine overflow in dorsal striatum while stimulating the medial forebrain bundle over a range of stimulus currents and frequencies. We also examined the effects of drugs that modulated the dopamine release (raclopride and quinpirole) and uptake (nomifensine). Examining the details of the temporal features of the evoked profiles reveals no clear evidence for long-distance diffusion of dopamine between fast and slow domains, even though uptake inhibition by nomifensine clearly prolongs the time that dopamine resides in the extracellular space. Our observations support the conclusion that striatal tissue has the capacity to retain dopamine molecules, thereby limiting its tendency to diffuse through the extracellular space.

Inhibiting effect of dopamine adsorption and polymerization on hydrated swelling of montmorillonite

This paper aims at evaluating the inhibition performance of dopamine (DA) on hydrated swelling of montmorillonite (MMT) and exploring the inhibitive mechanism. The inhibition performance of DA was evaluated through the combination of linear swelling and mud making tests, and compared with three commonly used inhibitors in the field. The results show that DA performs extremely well on inhibiting the MMT swelling, within a broad temperature range even at 200°C. Based on a combined use of FT-IR, XPS, XRD, zeta potential and TEM analysis, the probable inhibition mechanism was determined due to the identification of the structure of polydopamine (pDA) polymerized in the MMT interlayer. The results indicate that the forming of interlayered pDA that composed of bilayer planer 5, 6-dihydroxyindole (DHI) oligomers is primarily responsible for the excellent inhibition ability of DA. In addition to this, the collapse of MMT colloidal particle diffuse double layers due to the adsorption of positive charged DA monomers also contributed considerably to the inhibition effect on hydrated swelling.

Dopamine prevents lipid peroxidation-induced accumulation of toxic α-synuclein oligomers by preserving autophagy-lysosomal function

The formation of Lewy bodies containing α-synuclein (α-syn), prominent loss of dopaminergic neurons and dopamine (DA) deficiency in substantia nigra and striatum are histopathological and biochemical hallmarks of Parkinson’s disease (PD). Multiple lines of evidence have indicated that a critical pathogenic factor causing PD is enhanced production of reactive oxygen species (ROS), which reacts readily with polyunsaturated fatty acids to cause lipid peroxidation (LPO). LPO products have been shown to facilitate assembly of toxic α-syn oligomers in in vitro studies. Since DA is prone to autoxidation and cause ROS, it has been suggested that interactions among DA, LPO, and α-syn play an important role in neuronal loss in PD. However, the exact mechanism(s) remains unclear. We addressed this issue using a neuronal cell model which inducibly expresses human wild-type α-syn by the tetracycline off (Tet-Off) mechanism and stably expresses high levels of DA transporter. Under retinoic acid elicited neuronal differentiation, cells with or without overexpressing α-syn and with or without exposure to LPO inducer-arachidonic acid (AA), plus 0–500 μM of DA were assessed for the levels of LPO, α-syn accumulation, cell viability, and autophagy. AA exposure elicited similar LPO levels in cells with and without α-syn overexpression, but significantly enhanced the accumulation of α-syn oligomers and monomers only in cultures with Tet-Off induction and decreased cell survival in a LPO-dependent manner. Surprisingly, DA at low concentrations (<50 μM) protected cells from AA cytotoxicity and α-syn accumulation. Such effects were attributed to the ability of DA to preserve autophagic-lysosomal function compromised by the AA exposure. At high concentrations (>100 μM), DA exposure enhanced the toxic effects of AA. To our knowledge, this is the first report showing biphasic effects of DA on neuronal survival and α-syn accumulation.