Search

Tetrodotoxin (TTX) inhibits neurotransmission in animals, and there is no specific antidote. In clinical practice in China, Althaea rosea ( A. rosea flower) extract has been used to treat TTX poisoning. In this work, the efficacy of the ethyl acetate fraction extract of A. rosea flower in treating TTX poisoning in rats was investigated. A high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to determine nine neurotransmitters in rat brain tissue, including γ-aminobutyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT), noradrenaline (NE), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-3-acetic acid (5-HIAA), epinephrine (E), and tyramine (Tyn). The detoxifying effect of A. rosea flower was verified by comparing the changes in neurotransmitters' content in brain tissue before and after poisoning in rats. The assay was performed in multiple reaction monitoring mode. The quantification method was performed by plotting an internal-standard working curve with good linearity (R 2 > 0.9941) and sensitivity. Analyte recoveries were 94.04-107.53% (RSD < 4.21%). Results indicated that the levels of 5-HT, DA, E, and NE in the brains of TTX-intoxicated rats decreased, whereas the levels of GABA, Tyn, and 5-HIAA showed an opposite trend, and HVA and DOPAC were not detected. The levels of all seven neurotransmitters returned to normal after the gavage administration of ethyl acetate extract of A. rosea flower to prove that the ethyl acetate extract of A. rosea flower had a therapeutic effect on TTX poisoning. The work provided new ideas for studies on TTX detoxification.

Purpose: To study the effectiveness of high-dose atropine for reducing eye growth in Mendelian myopia in children and mice., Methods: We studied the effect of high-dose atropine in children with progressive myopia with and without a monogenetic cause. Children were matched for age and axial length (AL) in their first year of treatment. We considered annual AL progression rate as the outcome and compared rates with percentile charts of an untreated general population. We treated C57BL/6J mice featuring the myopic phenotype of Donnai-Barrow syndrome by selective inactivation of Lrp2 knock out (KO) and control mice (CTRL) daily with 1% atropine in the left eye and saline in the right eye, from postnatal days 30-56. Ocular biometry was measured using spectral-domain optical coherence tomography. Retinal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured using high-performance liquid chromatography., Results: Children with a Mendelian form of myopia had average baseline spherical equivalent (SE) -7.6 ± 2.5D and AL 25.8 ± 0.3 mm; children with non-Mendelian myopia had average SE -7.3 ± 2.9 D and AL 25.6 ± 0.9 mm. During atropine treatment, the annual AL progression rate was 0.37 ± 0.08 and 0.39 ± 0.05 mm in the Mendelian myopes and non-Mendelian myopes, respectively. Compared with progression rates of untreated general population (0.47 mm/year), atropine reduced AL progression with 27% in Mendelian myopes and 23% in non-Mendelian myopes. Atropine significantly reduced AL growth in both KO and CTRL mice (male, KO: -40 ± 15; CTRL: -42 ± 10; female, KO: -53 ± 15; CTRL: -62 ± 3 μm). The DA and DOPAC levels 2 and 24 h after atropine treatment were slightly, albeit non-significantly, elevated., Conclusions: High-dose atropine had the same effect on AL in high myopic children with and without a known monogenetic cause. In mice featuring a severe form of Mendelian myopia, atropine reduced AL progression. This suggests that atropine can reduce myopia progression even in the presence of a strong monogenic driver., (© 2023 The Authors. Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.)

DOPAC, a relevant scaffold in dopamine metabolism, was probed in the gas phase and interrogated by high-resolution rotational spectroscopy. Herein, three distinct conformers were isolated in a supersonic jet and identified for the first time through an examination of the trend of the rotational constants and the dipole moment selection rules. Additionally, we examined the plausible relaxation pathways of the low-energy conformers of DOPAC, which helped us to claim the indirect detection of two additional conformers, providing conclusive experimental evidence of the flexible nature of this biomolecule. The current investigation sheds some light on the differences between jet-cooled rotational experiments and matrix-isolation infrared spectroscopy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Since dietary flavonoid glycosides, including quercetin 4′-glucoside from onion, are poorly absorbed from the gastrointestinal tract, they are converted into smaller phenolic acids, which can be absorbed into the circulation. The purpose of this study was to compare the effects of the major phenolic acid catabolites of quercetin 4′-glucoside, including 3,4-dihydroxyphenylacetic acid (DOPAC), 3-hydroxyphenylacetic acid, 3,4-dihydroxybenzoic acid (protocatechuic acid) and hippuric acid, on the antioxidant activity and phase II cytoprotective enzyme induction in vitro . Both DOPAC and protocatechuic acid, having a catechol moiety, exhibited both DPPH radical scavenging and superoxide dismutase-like activities, whereas 3-hydroxyphenyl acetic acid and hippuric acid did not. DOPAC also more potently enhanced the gene expression of several phase II drug-metabolizing enzymes than the other phenolic acid catabolites. DOPAC significantly inhibited the hydrogen peroxide-induced cytotoxicity in hepatocytes with the enhancement of the total glutathione S-transferase activity. In conclusion, DOPAC may play a key role in the antioxidative potential of the colonic lumen after the ingestion of the quercetin glycoside-rich onion. [ABSTRACT FROM AUTHOR]

1. Acetaminophen (APAP) overdose leads to severe hepatotoxicity. 3,4-dihydroxyphenylacetic acid (DOPAC) is a scarcely studied microbiota-derived metabolite of quercetin. The aim of this study was to determine the protective effect of DOPAC against APAP-induced liver injury. 2. Mice were treated intragastrically with DOPAC (10, 20 or 50 mg/kg) for 3 days before APAP (300 mg/kg) injection. APAP alone caused increase in serum aminotransferase levels and changes in hepatic histopathology. APAP also promoted oxidative stress by increasing lipid peroxidation and decreasing anti-oxidant enzyme activities. These events led to hepatocellular necrosis and reduced liver function. DOPAC increased nuclear factor erythroid 2-related factor 2 (Nrf-2) translocation to the nucleus and enhanced the expression of phase II enzymes and anti-oxidant enzymes, and thereby reduced APAP hepatotoxicity and enhanced anti-oxidant ability. 3. Our data provide evidence that DOPAC protected the liver against APAP-induced injury, which is involved in Nrf-2 activation, implying that DOPAC can be considered as a potential natural hepatoprotective agent. [ABSTRACT FROM AUTHOR]

l -DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson’s disease (PD). With prolonged treatment (⩾5 years) the majority of patients will develop abnormal involuntary movements as a result of l -DOPA treatment, known as l -DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of l -DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kg s.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non-dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after l -DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In l -DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate l -DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence. [ABSTRACT FROM AUTHOR]

Since the discovery of the role of the ubiquitin–proteasome system (UPS) in the pathogenesis of Parkinson’s disease, UPS inhibitors, such as lactacystin have been used to investigate the relationship between UPS impairment and degeneration of dopamine (DA) neurons. However, mostly long-term neurotoxic effects of lactacystin have been studied in animal models. Therefore, the aim of our study was to investigate behavioral and biochemical changes related to the DA system during the first week following unilateral intranigral injection of lactacystin to rats. We found that lactacystin produced early spontaneous contralateral rotations which were inhibited by combined administration of DA D1 and D2 receptor antagonists. Simultaneously, an increase in the extracellular level of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) was found in the ipsilateral striatum. In contrast, one week after lesion, when turning behavior was no longer visible, a decrease in the extracellular level of DA, DOPAC and HVA was demonstrated. It was accompanied by a substantial reduction in the tissue levels of DA and its metabolites in the lesioned substantia nigra and striatum. We concluded that unilateral intranigral administration of lactacystin produces an early increase in DA neurotransmission which precedes a decrease in the striatal and nigral tissue DA content. It is manifested by the appearance of spontaneous contralateral rotations and an elevation of the extracellular DA level in the ipsilateral striatum. Since similar behavior was previously observed after intranigral administration of rotenone and MPP + but not 6-hydroxydopamine (6-OHDA), it may indicate a common mechanism of action shared by these neurotoxins. [ABSTRACT FROM AUTHOR]

Hierarchical nanoporous AuAg (HNP-AuAg) alloy with bimodal ligament/pore size distributions is fabricated by means of selective dealloying of Al and redealloying of Ag from AuAgAl source alloy combined with annealing operation. The as-made HNP-AuAg alloy consists of interconnected hierarchical nanoporous architecture with two order ligament/pore size distributions around 100 and 10 nm in all three dimensions. Characterized by such the specific nanoporous architecture, HNP-AuAg alloy exhibits excellent electrocatalytic activities towards the simultaneous and individual oxidation of dopamine (DA) and uric acid (UA) in the absence and presence of ascorbic acid. The electrochemical sensing towards DA and UA on HNP-AuAg alloy displays fast response and low detection limit of 0.2 μM and 1.0 μM in a wide linear range of 5–335 μM and 5–425 μM, respectively. More importantly, the as-made HNP-AuAg alloy behaves long-term stability and reproducibility towards the detection of DA and UA. Along with these attractive features, HNP-AuAg shows great application potential for constructing electrochemical sensors to the detection of DA and UA. [ABSTRACT FROM AUTHOR]

Acid-activated clays KSF and KSF/0 were successfully used in the hydrogen peroxide conversion of phenyl acetic acid to high-added phenolic compounds: p -hydroxyphenyl acetic acid and 3,4-dihydroxyphenyl acetic acid, endowed with a powerful antioxidant capacity. The catalytic conversion enhancement could be correlated to the total surface acidity and the high iron content of the catalysts KSF/0 and KSF, respectively. The synthetic route described here was conducted under mild conditions with very low degree of mineralization and without significant Fe ion leaching observations. The synthesis reaction is operationally simple and could find application for industrial purposes. [ABSTRACT FROM AUTHOR]

The ability to generalize previously learned information to novel situations is fundamental for adaptive behavior. However, too wide or too narrow generalization is linked to neuropsychiatric disorders. Previous research suggests that interactions between the dopaminergic system and the hippocampus may play a role in generalization, but whether and how the degree of generalization can be modulated via these pathways is currently unknown. Here, we addressed this question in humans using pharmacology, functional magnetic resonance imaging, and computational modeling. Blocking dopamine D2-receptors (D2R) altered generalization behavior as revealed by an increased kurtosis of the generalization gradient, and a decreased width of model-derived generalization parameters. Moreover, D2R-blockade modulated similarity-based responses in the hippocampus and decreased midbrain-hippocampal connectivity, which in turn correlated with individual differences in generalization. These results suggest that dopaminergic activity in the hippocampus may relate to the degree of generalization and highlight a potential target for treatment. [ABSTRACT FROM AUTHOR]

Impulsivity, which can be subdivided into impulsive action and impulsive choice, is implicated as a factor underlying drug abuse vulnerability. Although previous research has shown that dopamine (DA) systems in prefrontal cortex are involved in impulsivity and substance abuse, it is not known if inherent variation in DA transporter (DAT) function contributes to impulsivity. The current study determined if individual differences in either impulsive action or impulsive choice are related to DAT function in orbitofrontal (OFC) and/or medial prefrontal cortex (mPFC). Rats were first tested both for impulsive action in a cued go/no-go task and for impulsive choice in a delay-discounting task. Following behavioral evaluation, in vitro [ 3 H]DA uptake assays were performed in OFC and mPFC isolated from individual rats. V max in OFC, but not mPFC, was correlated with performance in the cued go/no-go task, with decreased OFC DAT function being associated with high impulsive action. In contrast, V max in OFC and mPFC was not correlated with performance in the delay-discounting task. The current results demonstrate that impulsive behavior in cued go/no-go performance is associated with decreased DAT function in OFC, suggesting that hyperdopaminergic tone in this prefrontal subregion mediates, at least in part, increased impulsive action. [ABSTRACT FROM AUTHOR]

A silica/gold (SiO 2 /Au) cavity array microelectrode was fabricated on a gold film-coated glass slide by using highly ordered monodispersed polystyrene spheres as a template. The surface of the silica, as the upper part of the cavity, was sulfonated by 1,3-propanesultone, providing negative charges on the surface of the cavities in a media with pH > 2. The ion selectivity of the sulfonated SiO 2 /Au cavities was revealed by voltammetric response of potassium ferricyanide and methyl viologen dichloride as the electrochemical probes. Due to the electrostatic interaction, the positively charged methyl viologen cations can transport through the negatively charged SiO 2 gate and react on active sites at the bottom of the cavities, whereas the diffusion access of the negatively charged ferricyanide anions into the cavities is blocked by the SiO 2 gate. The ion selective gate of the cavities enables the electrode to selectively detect dopamine in the presence of ascorbic acid and uric acid, giving a linear range from 15 μM to 160 μM and a low detection limit of 85 nM. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc) region of brain. Oxidative stress and inflammation plays important role in the neurodegeneration and development of PD. Ursolic Acid (UA: 3β-hydroxy-urs-12-en-28-oic acid) is a natural pentacyclic triterpenoid found in various medicinal plants. Its anti-inflammatory and antioxidant activity is a well-established fact. In this paper, the neuroprotective efficiency of UA in MPTP induced PD mouse model has been explored. For this purpose, we divided 30 mice into 5 different groups; first was control, second was MPTP-treated, third, fourth and fifth were different doses of UA viz., 5 mg/kg, 25 mg/kg, and 50 mg/kg body weight (wt) respectively, along with MPTP. After 21 days of treatment, different behavioral parameters and biochemical assays were conducted. Tyrosine hydroxylase (TH) immunostaining of SN dopaminergic neurons as well as HPLC quantification of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) were also performed. Our results proved that, UA improves behavioral deficits, restored altered dopamine level and protect dopaminergic neurons in the MPTP intoxicated mouse. Among three different doses, 25 mg/kg body wt was the most effective dose for the PD. This work reveals the potential of UA as a promising drug candidate for PD treatment. [ABSTRACT FROM AUTHOR]

3,4-Dihydroxyphenylacetic acid (DHPAA), a catechol derivative with proposed beneficial human health applications, was synthesized in this work from 4-hydroxyphenylacetic acid (HPAA) using an unpurified, tyrosinase-containing, cell preparation from the fruiting body of the edible mushroom Agaricus bisporus which were immobilized in silica alginate matrix capsules. The formation of DHPAA was equimolar to the conversion of HPAA, as long as ascorbic acid was present in amounts sufficient for reduction of o -quinones generated by oxidation of DHPAA. With a concentration of 5 mM HPAA and 5, 10, or 25 mM ascorbic acid, the maximum yields of DHPAA were 26, 36, or 56%, respectively. When aluminum oxide, pretreated with ammonium acetate, was added for an in situ adsorption of DHPAA, the yield obtained with 5 or 10 mM ascorbic acid was increased to 42 or 52%, respectively, with a reaction time reduced by ∼25%. In contrast to experiments without in situ adsorption, the yield remained almost constant after depletion of ascorbic acid. After desorption, the concentration of DHPAA in the eluent was up to 32 times higher than the concentration of HPAA. The results presented here will be useful for the design of production and purification processes for DHPAA. [ABSTRACT FROM AUTHOR]

This study aims to investigate whether 3,4-dihydroxyphenylacetic acid (DHAA) can improve gut barrier function by inhibiting the mitogen-activated protein kinase (MAPK) - myosin light-chain kinase (MLCK) signaling pathway in type 2 diabetes (T2D) mice. T2D mice were induced by a high-fat diet combined with streptozotocin. T2D mice were intragastrically administered with DHAA at 75 and 150 mg kg/body weight per day for 4 weeks. Blood glucose, insulin level, oxidative stress and inflammatory cytokines were measured. TJ (tight junction) protein and MAPK-MLCK pathway-related proteins were analyzed by western blot. DHAA alleviated hyperglycemia and decreased insulin resistance of T2D mice. It also decreased oxidative stress via increased glutathione (GSH) and total superoxide dismutase (T-SOD) activities and reduced containing malondialdehyde (MDA). DHAA exhibited a significant anti-inflammatory effect by decreasing the level of pro-inflammatory cytokines lipopolysaccharide (LPS) and interleukin (IL)-6 and increasing that of anti-inflammatory cytokine IL-10. More importantly, DHAA improved gut barrier function by enhancing tight junction protein expression and inhibiting the MAPK-MLCK signaling pathway. DHAA could reduce oxidative stress, decrease inflammatory response, and improve intestinal function in T2D mice, which may help to relieve the symptoms of T2D. [Display omitted] • 3,4-Dihydroxyphenylacetic acid (DHAA) alleviates the symptoms of T2D mice. • DHAA reduces inflammatory response and enhances antioxidant defense. • DHAA reduces colonic intestinal permeability by the MAPK/MLCK pathway. • DHAA mitigates T2D symptoms via positive effects on the intestinal tract. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S) is a toxin affecting the cardiovascular, respiratory, and central nervous systems. Acute H 2 S exposure is associated with a high rate of mortality and morbidity. The precise pathophysiology of H 2 S-induced death is a controversial topic; however, inhibition of the respiratory center in the brainstem is commonly cited as a cause of death. There is a knowledge gap on toxicity and toxic mechanisms of acute H 2 S poisoning on the brainstem, a brain region responsible for regulating many reflective and vital functions. Serotonin (5-HT), dopamine (DA), and γ-aminobutyric acid (GABA) play a role in maintaining a normal stable respiratory rhythmicity. We hypothesized that the inhibitory respiratory effects of H 2 S poisoning are mediated by 5-HT in the respiratory center of the brainstem. Male C57BL/6 mice were exposed once to an LCt 50 concentration of H 2 S (1000 ppm). Batches of surviving mice were euthanized at 5 min, 2 h, 12 h, 24 h, 72 h, and on day 7 post-exposure. Pulmonary function, vigilance state, and mortality were monitored during exposure. The brainstem was analyzed for DA, 3,4-dehydroxyphenyl acetic acid (DOPAC), 5-HT, 5-hydroxyindoleatic acid (5-HIAA), norepinephrine (NE), GABA, glutamate, and glycine using HPLC. Enzymatic activities of monoamine oxidases (MAO) were also measured in the brainstem using commercial kits. Neurodegeneration was assessed using immunohistochemistry and magnetic resonance imaging. Results showed that DA and DOPAC were significantly increased at 5 min post H 2 S exposure. However, by 2 h DA returned to normal. Activities of MAO were significantly increased at 5 min and 2 h post-exposure. In contrast, NE was significantly decreased at 5 min and 2 h post-exposure. Glutamate was overly sensitive to H 2 S-induced toxicity manifesting a time-dependent concentration reduction throughout the 7 day duration of the study. Remarkably, there were no changes in 5-HT, 5-HIAA, glycine, or GABA concentrations. Cytochrome c oxidase activity was inhibited but recovered by 24 h. Neurodegeneration was observed starting at 72 h post H 2 S exposure in select brainstem regions. We conclude that acute H 2 S exposure causes differential effects on brainstem neurotransmitters. H 2 S also induces neurodegeneration and biochemical changes in the brainstem. Additional work is needed to fully understand the implications of both the short- and long-term effects of acute H 2 S poisoning on vital functions regulated by the brainstem., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Despite the extensive investigation of the nanozymes exhibit their favorable performance compared to natural enzymes, nevertheless, the highly specific nanozyme still needs to be developed so that it can meet the requirements of exploring the mechanism as well as administration of related diseases and selective monitoring in biological system. In this study, self-assembled glutathione-Cu/Cu 2 O nanoparticles (GSH-Cu/Cu 2 O NPs) that exhibits specific ascorbic acid (AA) oxidase-like catalytic activity were constructed for AA-activated and H 2 O 2 -reinforced cancer cell proliferation inhibition and selective neurochemical monitoring. Cu/Cu 2 O NPs demonstrates effective AA oxidase-like activity and no common characteristics of other redox mimic enzymes often present in nanozyme. In particular, we found that the AA oxidase-like activity of GSH-Cu/Cu 2 O nanozyme was significantly improved by about 40% by improving the activation ability toward oxygen. The synthesized nanozyme can induce the generation of active oxygen by accelerating the oxidation of AA, which effectively suppresses the proliferation of cancer cells. We constructed an online electrochemical system (OECS) though loading nanozyme with enhanced ascorbate oxidase activity into a microreactor and setting it in the upstream of the detector. This GSH-Cu/Cu 2 O NPs-integrated microreactor can completely eliminate AA interference of the physical level toward 3,4-dihydroxy phenylacetic acid (DOPAC) electrochemical measurement, and the nanozyme-based OECS is able to continuously capture DOPAC alteration in rat brain acidosis model. Our findings may inspire rational design of nanozymes with high specificity as well as nanozyme-based selectivity solution for in vivo detection and show promising opportunities for their involvement in neurochemistry investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

In the present study, we investigated the effects of physical exercise in the presence of Vitamin D3 (VD3), on 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. The animals were divided into sham-operated (SO), 6-OHDA-lesioned, and 6-OHDA-lesioned plus VD3 (1 µg/kg, 21 days), in the absence (no exercise, NE) and presence (with exercise, WE) of physical exercise on a treadmill (30 min, speed of 20 cm/s, once a day/21 days). This procedure started, 24 h after the stereotaxic surgery (injections of 6-OHDA into the right striatum). The animals were then subjected to behavioral (rotarod, open field, and apomorphine tests) and their brain areas were dissected for neurochemical, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) determinations, and immunohistochemical studies for tyrosine hydroxylase (TH), dopamine transporter (DAT), and vitamin D receptor (VD3R). The effects on the brain oxidative stress: nitrite/nitrate, glutathione (GSH), and malondialdehyde (MDA) measurements were also evaluated. Behavioral changes of the 6-OHDA lesioned group were improved by exercise plus VD3. Similar results were observed in dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations increased by exercise and VD3, compared with SO groups. Additionally, tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoexpressions were decreased in the 6-OHDA-lesioned groups, with values normalized after exercise and VD3. The VD3 receptor immunoexpression decreased in the 6-OHDA (NE) group, and this was attenuated by exercise, especially after VD3. While 6-OHDA lesions increased, VD3 supplementation decreased the oxidative stress, which was intensified by exercise. VD3 showed neuroprotective properties that were intensified by physical exercise. These VD3 actions on hemiparkinsonian rats are possibly related to its antioxidant and anti-inflammatory effects., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cocaine dependence is characterized by compulsive drug taking and reduced involvement in social, occupational, or recreational activities. Unraveling the diverse mechanisms contributing to the loss-of-interest in these 'non-drug' pursuits is essential for understanding the neurobiology of addiction and could provide additional targets for treating addiction. The study objectives were to examine changes in cocaine-induced dopamine (DA) overflow in the nucleus accumbens (NAc) over the course of self-administration and determine the roles of α1- and β-adrenergic receptors (AR) in the loss-of-interest in food rewards following the development of an addicted phenotype in male and female rats. Subjects were given access to cocaine and palatable food pellets in a choice self-administration paradigm to identify 'addicted' cocaine-preferring (CP) individuals and resistant pellet-preferring (PP) individuals based on their patterns of self-administration over 7 weeks. Cocaine-induced DA overflow in the NAc was examined with microdialysis early and late during self-administration (weeks 2 and 7). Subjects were treated in counter-balanced order with propranolol (β-AR antagonist), terazosin (α1-AR antagonist), or vehicle for an additional 3 weeks of self-administration. CP rats displayed increased motivation for cocaine and attenuated motivation for pellets following the development of cocaine preferences. In females, the estrous cycle affected pellet, but not cocaine, self-administration. CP rats displayed attenuated cocaine-induced DA overflow in the NAc. Propranolol enhanced cocaine reinforcement and reduced pellet intake, whereas terazosin enhanced motivation for pellets and reversed preferences in a subset of CP rats. The implications of these results for the treatment of addiction are discussed. [ABSTRACT FROM AUTHOR]

Agitated shoot cultures of three Hypericum perforatum cultivars: 'Elixir', 'Helos' and 'Topas' were established and maintained on Linsmaier and Skoog (LS) and Murashige and Skoog (MS) media containing varying concentrations (0.1-3.0 mg l) of α-naphthaleneacetic acid (NAA) and 6-benzyladenine (BA). In methanolic extracts of the biomass, the amount s of free phenolic acids and cinnamic acid were determined by HPLC. Six of the seventeen compounds analyzed were detected in all the extracts: 3,4-dihydroxyphenylacetic acid, p-coumaric acid, protocatechuic acid, syringic acid, and two depsides-chlorogenic and neochlorogenic acids. The amounts of individual compounds and the total amount of phenolic acids depended on the media variants used and the increases ranged from 1.2- to 15.0-fold and from 1.2- to 1.9-fold, respectively. The maximum total amounts in the biomass of 'Elixir', 'Helos' and 'Topas' were 212, 222, and 191 mg 100 g DW, respectively. The main metabolites in all the cultivars were neochlorogenic acid (max. 118.81 mg 100 g DW) and 3,4-dihydroxyphenylacetic acid (max. 129.29 mg 100 g DW). Three metabolites that also accumulated in high amounts were protocatechuic acid (max. 21.43 mg 100 g DW), syringic acid (max. 23.63 mg 100 g DW) and chlorogenic acid (max. 18.79 mg 100 g DW). The richest s ource of the estimated compounds and hence a potential biotechnological platform were the shoots of 'Helos' cultivated on LS and MS media containing low concentrations of NAA and BA (0.1-1.0 mg l). [ABSTRACT FROM AUTHOR]

The development of the effective procedure to recover the potentially high-added-value phenolic compound, 3,4-dihydroxyphenylacetic acid (3,4-DHPAA) was investigated using electrochemical conversion of phenylacetic acid (PAA). The proposed mechanism is based on the hypothesis of two-electron oxidation of PAA molecule leading to 3-hydroxyphenyl acetic acid. The latter underwent a second bi-electronic transfer by means of a radical cation, thus leading to the formation of the 2,5 dihydroxyphenylacetic (2,5-DHPAA) acid and 3,4-DHPAA as major products. The 3,4-DHPAA was synthesized by anodic oxidation of PAA at lead dioxide electrode and identified by cyclic voltammetry and spectrophotometry UV-visible. It was also confirmed by mass spectrophotometry using LC-MS/MS apparatus. According to their voltammetric behavior during electrolysis, the oxidation potential of 3,4-DHPAA was lower than that of PAA. The antioxidant activity was measured by DPPH assay, showing that the strongest antiradical activity was detected when the 3,4-DHPAA concentration was higher during electrolysis experiments. [ABSTRACT FROM AUTHOR]

In this study, a nanocomposite of 3, 4, 9, 10-perylenetetracarboxylic acid and L-cysteine (PTCA-Cys) with satisfactory water-solubility and film-forming ability was prepared and worked as substrate for modifying the glassy carbon electrode. Then, gold nanoparticles (AuNPs) were immobilized to achieve a PTCA-Cys-AuNPs modified electrode which provided more reaction positions on the sensor. Scanning electron microscopy, transmission electron microscopy, cyclic voltammetry and different pulse voltammetry were employed to characterize the assembly process of the sensor. The constructed sensor displayed desirable sensitivity, selectivity and stability towards the simultaneous detection of ascorbic acid (AA), dopamine (DA) and uric acid (UA). Under the optimal experimental conditions, the oxidation peaks of AA, DA and UA appeared at 64, 240 and 376 mV, respectively. The corresponding linear response ranges were 3.2-435, 0.04-100 and 0.80-297 μM, and the detection limits were 1.1, 0.010 and 0.27 μM (S/N=3), respectively. [ABSTRACT FROM AUTHOR]

In Pavlovian conditioning, sign- and goal-tracking behaviors represent different approaches towards the conditioned stimulus. These behavioral patterns have been associated with predictive or incentive properties of the conditioned stimulus, with a crucial involvement of the mesolimbic dopamine system. As it is possible that sign tracking behavior is more sensitive to dopamine modulation, we evaluated the dopamine-dependence of sign- and goal-tracking behavior. We assessed responses to both a D2 agonist and an antagonist, and tested performance in a behavioral paradigm known to activate dopamine projections and in an animal model that affects mesolimbic and mesocortical function. Sign trackers displayed a greater sensitivity to a D2 agonist and smaller prepulse inhibition of the acoustic startle response than goal trackers, suggesting a reduced inhibitory ability. In addition, a neonatal ventral hippocampal lesion resulted in the loss of incentive salience of cues in sign trackers. Overall, these data indicate that sign-tracking behavior is more heavily controlled by dopamine than goal tracking. [ABSTRACT FROM AUTHOR]

The temporal control of action is a highly conserved and critical mammalian behavior. Here, we investigate the neuronal basis of this process using an interval timing task. In rats and humans, instructional timing cues triggered spectral power across delta and theta bands (2-6 Hz) from the medial frontal cortex (MFC). Humans and rodents with dysfunctional dopamine have impaired interval timing, and we found that both humans with Parkinson's disease (PD) and rodents with local MFC dopamine depletion had attenuated delta and theta activity. In rodents, spectral activity in this range could functionally couple single MFC neurons involved in temporal processing. Without MFC dopamine, these neurons had less functional coupling with delta/theta activity and less temporal processing. Finally, in humans this 2- to 6-Hz activity was correlated with executive function in matched controls but not in PD patients. Collectively, these findings suggest that cue-evoked low-frequency rhythms could be a clinically important biomarker of PD that is translatable to rodent models, facilitating mechanistic inquiry and the development of neurophysiological biomarkers for human disease. [ABSTRACT FROM AUTHOR]

On the basis of between subjects monitoring of in vivo dopamine (DA) transmission in the rat nucleus accumbens (NAc) shell and core during response-contingent and non-contingent sucrose feeding we have hypothesized that long term, daily exposure to sucrose feeding results in the acquisition of conditioned/discriminative stimuli capable of activating accumbens shell DA transmission in a non-habituating fashion. In order to verify this hypothesis we have now monitored within the same subject the changes in accumbens shell and core DA during acquisition of fixed ratio 1 (FR1) nose-poking for sucrose pellets. Once full training was obtained, dialysate DA was monitored in the same rat on three different sessions: responding for sucrose, extinction and non-contingent sucrose presentation. Dialysate DA steadily increased in the shell during operant sessions as training progressed but was activated in the core only early and transiently in training (5th session). After full training, reinforced as well as non-reinforced responding for sucrose activated DA selectively in the NAc shell. Non-contingent sucrose feeding activated DA in the shell and in the core. No habituation of shell DA responsiveness was observed under contingent and non-contingent sucrose feeding. These observations are consistent with the hypothesis that learning of FR1 nose-poking for sucrose involves acquisition of conditioned activation of DA transmission in the shell and active suppression in the core and that loss of habituation of shell DA responsiveness is related to change from primary-rewarding to conditioned/discriminative as driving stimuli of DA transmission in this area. [ABSTRACT FROM AUTHOR]

Psychostimulant substances have been found to either increase or inhibit impulsive choice (preference to choose small immediate reward over large delayed reward) in laboratory animals. Although central dopamine transmission has been demonstrated to be involved in impulsivity and drug addiction, little is known regarding dopaminergic neurotransmission in addictive drug-induced alteration of impulse control. In this study, we used a delay discounting model to measure impulsive choice in rats and found that acute cocaine dose-dependently decreased impulsive choice in rats. Intraperitoneal injection (i.p.) of D1 receptor antagonist SCH23390 (0.02 mg/kg) could increase the impulsive choice but had no effect on the inhibition of impulsive choice induced by acute cocaine exposure. D2 receptor antagonist eticlopride (0.06 mg/kg) had no effect on the choice behavior itself, but it reversed acute cocaine-induced impulse inhibition. Moreover, bilateral microinjection of eticlopride (1 μg/side) into the basolateral amygdala (BLA) but not the nucleus accumbens (NAc) core reversed the inhibitory effect of acute cocaine on impulsive choice. These data suggest important but dissociable roles of dopamine D1 and D2 receptors in impulse control. The preference of delayed rewards depends on D1 receptors, whereas acute cocaine inhibited impulsive choice by activating D2 receptors in the BLA. [ABSTRACT FROM AUTHOR]

There are ∼1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA-approved pharmacotherapies. Amphetamine-based dopamine-releasing drugs have shown efficacy in reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels. Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine-naive animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day × 5 days). Dopamine kinetics were measured 1 and 24 h after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine-naive animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals. Here, for the first time, we demonstrate pharmacologically induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high-dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid timescale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy. [ABSTRACT FROM AUTHOR]

Medium spiny neurons (MSNs) are the major striatal neuron and receive synaptic input from both glutamatergic and dopaminergic afferents. These synapses are made on MSN dendritic spines, which undergo density and morphology changes in association with numerous disease and experience-dependent states. Despite wide interest in the structure and function of mature MSNs, relatively little is known about MSN development. Furthermore, most in vitro studies of MSN development have been done in simple striatal cultures that lack any type of non-autologous synaptic input, leaving open the question of how MSN development is affected by a complex environment that includes other types of neurons, glia, and accompanying secreted and cell-associated cues. Here we characterize the development of MSNs in striatal-cortical co-culture, including quantitative morphological analysis of dendritic arborization and spine development, describing progressive changes in density and morphology of developing spines. Overall, MSN growth is much more robust in the striatal-cortical co-culture compared to striatal mono-culture. Inclusion of dopamine (DA) in the co-culture further enhances MSN dendritic arborization and spine density, but the effects of DA on dendritic branching are only significant at later times in development. In contrast, exogenous Brain Derived Neurotrophic Factor (BDNF) has only a minimal effect on MSN development in the co-culture, but significantly enhances MSN dendritic arborization in striatal mono-culture. Importantly, inhibition of NMDA receptors in the co-culture significantly enhances the effect of exogenous BDNF, suggesting that the efficacy of BDNF depends on the cellular environment. Combined, these studies identify specific periods of MSN development that may be particularly sensitive to perturbation by external factors and demonstrate the importance of studying MSN development in a complex signaling environment. [ABSTRACT FROM AUTHOR]