Lower Dopamine Levels Research Articles

Fixing Pitx3 gene Mutation with CRISPR-Cas9 Intervention in Zygotic Aphakia-Prone Mice – A Research Protocol

Introduction: Despite the drawbacks of gene-editing, CRISPR-Cas9 remains a versatile tool for editing mutated genes. The mutated Pitx3 gene may cause aphakia in mice and Parkinsonism in humans. Pitx3 gene codes for the Pitx3 transcription factor involved in many tasks including the differentiation of dopaminergic neurons in the substantia nigra, tyrosine hydroxylase expression, dopamine transporter and lens development. We aim to edit mutated Pitx3 genes using CRISPR-Cas9 in embryonic-dopaminergic progenitor-neurons of mice and compare to wildtypes (WT) that do not undergo CRISPR-Cas9 intervention. Methods: We will use 5 female mice, 2 homozygous for mice aphakia/Pitx3 mutation (Ak) and 3 standard pseudo-pregnant females. 2-male homozygous (+/+ Ak) mice with Ak will mate with the aphakic females (+/+ Ak). Dopamine levels in both (aphakic/non-aphakic) mice will be determined. We will extract embryonic stem cells (ESC) from aphakic female’s uterus and treat with CRISPR-Cas9 and homology-directed repair (HDR). Both treated and untreated ESC will be divided between 3 pseudo-pregnant females. Post-parturition, intervention success will be assessed using presence of optical lens, dopamine levels and restriction sequence expression in treated/untreated progeny. Results: We expect to observe that untreated ESC zygotes (no CRISPR-Cas9 and HDR treatment) will not express normal Pitx3. This will result in low dopamine levels (inappropriate dopamine levels for their age group) and an aphakic mice progeny. Likewise, treated ESC zygotes will express normal Pitx3, hence have normal dopamine levels and non-aphakic phenotype. Discussion: Progeny of both groups (treated/non-treated) will be examined for aphakia, dopamine levels and restriction sequence. Dopamine levels of treated mice will be compared to dopamine levels of WT mice. Should none of the treated progeny develop lenses or have normal dopamine levels, these mice will be sacrificed to target the restriction sequence in the inserted gene — helping to evaluate why the inserted gene is unexpressed. Conclusion: This research examines CRISPR-Cas9 and HDR use on embryos with mutated genes that impair lens development and dopaminergic-neuron differentiation in humans and mice. It has potential of qualifying for clinical trials as the technique may be used to fix heritable disease-inducing genes that decrease longevity and quality of life in humans.

Studying the relationship between tobacco use and depression between Egyptian patients

Abstract Background Although much attention has been drawn to trends in smoking and smoking related diseases in the general population, increasing evidence suggests that patients with mental illness are at a high risk for tobacco use and nicotine addiction. Cigarette smokers usually state the antidepressant and anxiolytic effects of smoking, but evidence reports that cigarette smoking may promote negative effect, so that the causal direction of this association still mysterious. It was reported that there is a cause effect relationship between cigarette smoking and depression as multiple studies mentioned that tobacco use increases the risk of symptoms of depression. The relationship between smoking and depression was attributed to genetic predisposition, low level of dopamine, low self-esteem, and coping styles. Aim of the Work The current study aimed to study the pattern of tobacco use among patients with depression, to study the degree of motivation to quit in patients with depression, and to assess severity of suicidal behavior among patients with depression using tobacco. Patients and Methods This is a case control study conducted in patients with the diagnosis of depression attending the outpatient clinic or inpatient of the institute of psychiatry Ain Shams University Hospitals during the academic year 2018-2019. The sample size was consisted of 100 patients and the patients were selected randomly. The relationship between tobacco use and depression between Egyptian patients was assessed using Socioeconomic status scale (SES), Hamilton Rating scale for Depression (HRSD), FagerströmTest for Nicotine Dependence (FTND), Lebanon Waterpipe Dependence Scale-11 (LWDS-11), Reason for quitting scale (RFQ), Columbia–Suicide Severity Rating Scale (C-SSRS), and ICD-10 symptom checklist for mental disorders. Results The present study showed a statistical significant association between the following scales; Fagerstrom Test for Nicotine Dependence (FTND) and Hamilton depression rating scale (HDRS), Difference score of Reason for quitting scale (RFQ) and Hamilton depression rating scale (HDRS), and Fagerstrom Test for Nicotine Dependence (FTND) and Columbia–Suicide Severity Rating Scale (CSSRS). Conclusion Compared to non-depressive persons, the results showed that depressive groups were less desired for quitting smoking.

Parkin-deficient rats are resistant to neurotoxicity of chronic high-dose methamphetamine

Methamphetamine (METH) is a highly addictive and powerful central nervous system psychostimulant with no FDA-approved pharmacotherapy. Parkin is a neuroprotective protein and its loss of function contributes to Parkinson’s disease. This study used 3-month-old homozygous parkin knockout (PKO) rats to determine whether loss of parkin protein potentiates neurotoxicity of chronic METH to the nigrostriatal dopamine pathway. PKO rats were chronically treated with 10 mg/kg METH for 10 consecutive days and assessed for neurotoxicity markers in the striatum on the 5th and 10th day of withdrawal from METH. The PKO rats showed higher METH-induced hyperthermia; however, they did not display augmented deficits in dopaminergic and serotonergic neurotoxicity markers, astrocyte activation or decreased mitochondrial enzyme levels as compared to wild-type (WT) rats. Interestingly, saline-treated PKO rats had lower levels of dopamine (DA) as well as mitochondrial complex I and II levels while having increased basal levels of glial fibrillary acidic protein (GFAP), a marker of gliosis. These results indicate PKO display a certain resistance to METH neurotoxicity, possibly mediated by lowered DA levels and downregulated mitochondria.

Treating Parkinson Disease with Autologous Telomerase-Positive Stem Cells, Update 2021

Parkinson disease (PD) is the second most common progressive neurodegenerative disorder that affects older adults. PD is characterized by a low level of dopamine being expressed in the striatum and a deterioration of dopaminergic neurons and associated neural networks in the substantia nigra of the midbrain. Current medical, surgical, and rehabilitative treatments for PD have long-term side effects and do not halt the progression of the disease. Stem cell therapies generating dopaminergic neurons from fetal brain tissue, human embryonic stem cells, human induced pluripotent stem cells, mesenchymal stem cells, human neural stem cells, direct reprogramming of somatic cells and direct reprogramming of stem cells by either gene editing, and/or gene transfer have elicited keen interest as to eventual therapeutics for Parkinson disease. Unfortunately, thus far, these experimental therapies have proved to be of limited therapeutic value in clinical trials. Using a neurotoxin-induced animal model of PD, transplantation of a naïve telomerase positive pluripotent stem cell clone demonstrated reconstitution of dopaminergic neurons and associated neural networks when stereotactically injected into neurotoxin-lesioned substantia nigra pars compactum of the ventral midbrain. Two IRB-approved clinical trials in small cohort studies (n=8 & n=4), with a combined sample size of n=12, demonstrated that intranasal infusion of autologous telomerase positive totipotent cells followed by intravenous infusion of telomerase positive pluripotent stem cells and mesodermal stem cells had a positive influence on patient symptomology with Parkinson’s Disease. No adverse effects were reported by any participant or their respective caregiver for the entire combined small cohort study (n=12). Taken together as a 2021 update of this on-going clinical study, 33% (n=4) showed moderate to no benefit of telomerase positive stem cell treatment by demonstrating a continued decline in symptoms after treatment; 33% (n=4) remained in stasis after the first month after treatment; and 33% (n=4) resolved their symptoms. The results suggest that autologous telomerase positive stem cells, TSCs, PSCs, and MesoSCs, are safe and efficacious (66%) to reduce the symptoms in participants with Parkinson’s disease.

Molecular Docking Studies of Secondary Metabolites against Sequestosome-1 to Treat Parkinson Disease

Parkinson's disease (PD) is one of the major progressive neurological disorders. It occurs due to a low level of a chemical substance in the brain known as Dopamine, which controls the muscle movements of the body. In many cases, PD occurs due to a low level of dopamine. PD generally appears in persons between the ages of 50 & 60. Some common symptoms of Parkinson's are slow movements, tremors, change in voice, depression, anxiety, hallucinations, psychosis, etc. Diagnosis of PD is done by CAT (Computerized Axial Tomography) scan or MRI (Magnetic Resonance Imaging, and DAT (Dopamine Transporter) scan. No specific cure for PD but Medication, Surgery, Adequate rest, exercise, and a balanced diet, and Several different drugs may help to relieve Parkinson's Disease (PD). According to the in silico study, we found that Rosmarinic Acid (RA) was the compound, which may inhibit the activities of Sequestosome-1. After in vitro and in vivo studies, Rosmarinic Acid may be an effective drug to control Parkinson's disease (PD).

Contribution of M-opsin-based color vision to refractive development in mice

M-opsin, encoded by opn1mw gene, is involved in green-light perception of mice. The role of M-opsin in emmetropization of mice remains uncertain. To answer the above question, 4-week-old wild-type (WT) mice were exposed to white light or green light (460–600 nm, a peak at 510 nm) for 12 weeks. Refractive development was estimated biweekly. After treatment, retinal function was assessed using electroretinogram (ERG). Dopamine (DA) in the retina was evaluated by high-performance liquid chromatography, M-opsin and S-opsin protein levels by Western blot and ELISA, and mRNA expressions of opn1mw and opn1sw by RT-PCR. Effects of M-opsin were further verified in Opn1mw−/− and WT mice raised in white light for 4 weeks. Refractive development was examined at 4, 6, and 8 weeks after birth. The retinal structure was estimated through hematoxylin and eosin staining (H&E) and transmission electron microscopy (TEM). Retinal wholemounts from WT and Opn1mw−/− mice were co-immunolabeled with M-opsin and S-opsin, their distribution and quantity were then assayed by immunofluorescence staining (IF). Expression of S-opsin protein and opn1sw mRNA were determined by Western blot, ELISA, or RT-PCR. Retinal function and DA content were analyzed by ERG and liquid chromatography tandem-mass spectrometry (LC-MS/MS), respectively. Lastly, visual cliff test was used to evaluate the depth perception of the Opn1mw−/− mice. We found that green light-treated WT mice were more myopic with increased M-opsin expression and decreased DA content than white light-treated WT mice after 12-week illumination. No electrophysiologic abnormalities were recorded in mice exposed to green light compared to those exposed to white light. A more hyperopic shift was further observed in 8-week-old Opn1mw−/− mice in white light with lower DA level and weakened cone function than the WT mice under white light. Neither obvious structural disruption of the retina nor abnormal depth perception was found in Opn1mw−/− mice. Together, these results suggested that the M-opsin-based color vision participated in the refractive development of mice. Overexposure to green light caused myopia, but less perception of the middle-wavelength components in white light promoted hyperopia in mice. Furthermore, possible dopaminergic signaling pathway was suggested in myopia induced by green light.

Bifurcation analyses and potential landscapes of a cortex-basal ganglia-thalamus model.

The dynamics of cortical neuronal activity plays important roles in controlling body movement and is regulated by connection weights between neurons in a cortex–basal ganglia–thalamus (BGCT) loop. Beta‐band oscillation of cortical activity is closely associated with the movement disorder of Parkinson's disease, which is caused by an imbalance in the connection weights of direct and indirect pathways in the BGCT loop. In this study, the authors investigate how the dynamics of cortical activity are modulated by connection weights of direct and indirect pathways in the BGCT loop under low dopamine levels through bifurcation analyses and potential landscapes. The results reveal that cortical activity displays rich dynamics under different connection weights, including one, two, or three stable steady states, one or two stable limit cycles, and the coexistence of one stable limit cycle with one stable steady state or two stable ones. For a low dopamine level, cortical activity exhibits oscillation for larger connection weights of direct and indirect pathways. The stability of these stable dynamics is explored by the potential landscapes.

Spinal Dopaminergic Mechanisms Regulating the Micturition Reflex in Male Rats with Complete Spinal Cord Injury.

Traumatic spinal cord injury (SCI) often causes micturition dysfunction. We recently discovered a low level of spinally-derived dopamine (DA) that regulates recovered bladder and sphincter reflexes in SCI female rats. Considering substantial sexual dimorphic features in the lower urinary tract, it is unknown if the DA-ergic mechanisms act in the male. Histological analysis showed a similar distribution of tyrosine hydroxylase (TH)+ neurons in the lower cord of male rats and the number increased following thoracic SCI. Subsequently, focal electrical stimulation in slices obtained from L6/S1 spinal segments of SCI rats elicited detectable DA release with fast scan cyclic voltammetry. Using bladder cystometrogram and external urethral sphincter (EUS) electromyography in SCI male rats, intravenous (i.v.) administration of SCH 23390, a D1-like receptor (DR1) antagonist, induced significantly increased tonic EUS activity and a trend of increased residual volume, whereas activation of these receptors with SKF 38393 did not influence the reflex. Meanwhile, blocking spinal D2-like receptors (DR2) with remoxipride had no effect but stimulating these receptors with quinpirole elicited EUS bursting to increase voiding volume. Further, intrathecal delivery of SCH 23390 and quinpirole resulted in similar responses to those with i.v. delivery, respectively, which indicates the central action regardless of delivery route. In addition, metabolic cage assays showed that quinpirole increased the voiding frequency and total voiding volume in spontaneous micturition. Collectively, spinal DA-ergic machinery regulates recovered micturition reflex following SCI in male rats; spinal DR1 tonically suppress tonic EUS activity to enable voiding and activation of DR2 facilitates voiding.

Dopamine receptor agonist rotigotine-loaded microspheres ameliorates sexual function deteriorated by fluoxetine in depression rats.

Low dopamine levels may cause depressive symptoms. Dopamine is also involved in sexual behavior. Rotigotine is a nonergolinic dopamine agonist. Fluoxetine, an antidepressant that acts as a selective serotonin (5-HT) reuptake inhibitor, may cause moderate or severe sexual dysfunction. This study aims to investigate the effects of rotigotine-loaded microspheres (RoMS) and rotigotine on fluoxetine-induced impairment of sexual function and their efficacy in depression-model rats. Rats with depressive-like behavior, induced by bilateral olfactory bulbectomy, were treated intragastrically with fluoxetine and co-administered RoMS or rotigotine subcutaneously. Then, copulatory behavior and open field tests were conducted. Serum luteinizing hormone and testosterone levels were assayed with enzyme-linked immunosorbent assay kits. The concentrations of 5-HT, dopamine, and norepinephrine were measured in the raphe nucleus and amygdala. The results showed that sexual function was decreased in olfactory bulbectomy rats and significantly deteriorated by fluoxetine. Co-administration of RoMS partly reversed the fluoxetine-induced impairment of sexual function, but rotigotine administration did not produce any improvement. Hyperactivity in olfactory bulbectomy rats was significantly attenuated by fluoxetine but was not influenced by co-administration of RoMS. Compared with the fluoxetine group, RoMS increased the testosterone, luteinizing hormone, dopamine, and norepinephrine levels. These findings indicated that RoMS improved the fluoxetine-induced impairment of sexual function and did not affect its antidepressant efficacy in depressive rats, which provides a potential treatment for patients with depression that can reduce the possibility of sexual dysfunction. Additionally, co-administration of fluoxetine with RoMS may be beneficial for Parkinson's disease patients with depression.

Cognitive profile in Restless Legs Syndrome: A signal-to-noise ratio account.

Restless legs syndrome (RLS) is a common neurological disorder characterized by a sensorimotor condition, where patients feel an uncontrollable urge to move the lower limbs in the evening and/or during the night. RLS does not only have a profound impact on quality of life due to the disturbed night-time sleep, but there is growing evidence that untreated or insufficiently managed RLS might also cause cognitive changes in patients affected by this syndrome. It has been proposed that RLS is caused by alterations in the signal-to-noise ratio (SNR) and in dopamine (DA) neurotransmission in the nervous system. Based on this evidence, we propose the “SNR-DA hypothesis” as an explanation of how RLS could affect cognitive performance. According to this hypothesis, variations/reductions in the SNR underlie RLS-associated cognitive deficits, which follow an inverted U-shaped function: In unmedicated patients, low dopamine levels worsen the SNR, which eventually impairs cognition. Pharmacological treatment enhances DA levels in medicated patients, which likely improves/normalizes the SNR in case of optimal doses, thus restoring cognition to a normal level. However, overmedication might push patients past the optimal point on the inverted U-shaped curve, where an exaggerated SNR potentially impairs cognitive performance relying on cortical noise such as cognitive flexibility. Based on these assumptions of SNR alterations, we propose to directly measure neural noise via “1/f noise” and related metrics to use transcranial random noise stimulation (tRNS), a noninvasive brain stimulation method which manipulates the SNR, as a research tool and potential treatment option for RLS.

Catecholamine activity in delirium with and without pre‐existing dementia

AbstractBackgroundDelirium “acute confusion” is an unpleasant but common complication of acute illness in the aged population associated with prolonged hospitalization. Dementia is a substantial risk factor for delirium that may be apparent already in preclinical Alzheimer’s disease, but a delirium is also a risk factor for dementia. Effective agents for preventing and treating delirium are therefore searched. This include administration of antipsychotics targeting anticipated excessive dopaminergic activity in delirium and alpha‐2‐receptor (α2) agonists reducing noradrenergic activity. Data of noradrenergic and dopaminergic activity in delirium is however limited. We therefore aimed to characterize the cerebrospinal fluid (CSF) levels of dopamine and noradrenaline (norepinephrine) in delirium, with or without pre‐existing dementia.MethodCSF levels of dopamine and noradrenaline were determined by high‐performance‐liquid‐chromatography (HPLC) in: 1) cognitively healthy (controls; n=122) 2) Hip fracture patients (n=118) with and without delirium and pre‐fracture dementia 3) Patients with delirium precipitated by another medical condition (n=26). Non‐parametric statistical analyzes were applied.ResultPatients with delirium following a hip fracture and another medical condition had lower CSF dopamine levels relative to hip fracture patients without delirium and controls respectively. Stratified analyzes of hip fracture patients according to dementia status and separating patients with delirium before and after surgery showed differences in the two stratas. Interestingly there was a trend for higher levels of noradrenaline in incident delirium among those without pre‐fracture dementia, but there were few patients in this group (n=7).ConclusionThe lower levels of dopamine in CSF in delirium align with recent meta‐analyzes not recommending use of antipsychotics. Further evaluation of α2‐agonists for delirium prevention, in particular in those without pre‐existing dementia is supported, although the data should be reproduced in larger studies.

A novel idea for establishing Parkinson’s disease mouse model by intranasal administration of paraquat

ABSTRACT Background: In this study, we sought to provide an idea for establishing a novel mouse model for Parkinson’s disease (PD) through intranasal administration of paraquat instead of the conventional method of intraperitoneal injection. Intranasal administration has the potential to lower mortality caused by intraperitoneal paraquat administration. Methods: A paraquat-loaded thermosensitive hydrogel composed of poloxamer 407 and poloxamer 188 was prepared. The survival rate of the animals was monitored upon paraquat administration nasally and intraperitoneally. The animals’ behavior was also observed. Immunofluorescence staining of tyrosine hydroxylase (TH) – positive cells and western blotting of α-synuclein (α-syn)in striatum were performed. HPLC method with electrochemical detection was used to quantify monoamine neurotransmitters in striatum. Real-time RT-PCR analysis of type 1 collagen, type 3 collagen and fibronectin expression was used to evaluate pulmonary fibrosis in mice after paraquat administration. Results: The results indicated that intranasal administration of paraquat-loaded thermosensitive hydrogel can elicit Parkinsonism-like symptoms in mice. Relative to the conventional intraperitoneal injection, this strategy significantly improves survival when modeling PD and resulted in a higher loss of TH positive neurons in substantia nigra pars compacta (SNpc) and more aggregation of α-syn in striatum. Moreover, animals receiving paraquat hydrogel nasally exhibited motor disorder as well as lower levels of dopamine and dopamine metabolites in striatum when compared to those receiving paraquat intraperitoneally. The mRNA expression of collagen and fibronectinindicated that intranasal administration of paraquat was not associated with lung fibrosis. Conclusion: This strategy provides a new idea and more convenient operation for the future study of mouse model of PD.

Methylglyoxal-Mediated Dopamine Depletion, Working Memory Deficit, and Depression-Like Behavior Are Prevented by a Dopamine/Noradrenaline Reuptake Inhibitor.

Methylglyoxal (MGO) is an endogenous toxin, mainly produced as a by-product of glycolysis that has been associated to aging, Alzheimer's disease, and inflammation. Cell culture studies reported that MGO could impair the glyoxalase, thioredoxin, and glutathione systems. Thus, we investigated the effect of in vivo MGO administration on these systems, but no major changes were observed in the glyoxalase, thioredoxin, and glutathione systems, as evaluated in the prefrontal cortex and the hippocampus of mice. A previous study from our group indicated that MGO administration produced learning/memory deficits and depression-like behavior. Confirming these findings, the tail suspension test indicated that MGO treatment for 7days leads to depression-like behavior in three different mice strains. MGO treatment for 12days induced working memory impairment, as evaluated in the Y maze spontaneous alternation test, which was paralleled by low dopamine and serotonin levels in the cerebral cortex. Increased DARPP32 Thr75/Thr34 phosphorylation ratio was observed, suggesting a suppression of phosphatase 1 inhibition, which may be involved in behavioral responses to MGO. Co-treatment with a dopamine/noradrenaline reuptake inhibitor (bupropion, 10mg/kg, p.o.) reversed the depression-like behavior and working memory impairment and restored the serotonin and dopamine levels in the cerebral cortex. Overall, the cerebral cortex monoaminergic system appears to be a preferential target of MGO toxicity, a new potential therapeutic target that remains to be addressed.

Association between Chronic Pain and Alterations in the Mesolimbic Dopaminergic System

Chronic pain (pain lasting for >3 months) decreases patient quality of life and even occupational abilities. It can be controlled by treatment, but often persists even after management. To properly control pain, its underlying mechanisms must be determined. This review outlines the role of the mesolimbic dopaminergic system in chronic pain. The mesolimbic system, a neural circuit, delivers dopamine from the ventral tegmental area to neural structures such as the nucleus accumbens, prefrontal cortex, anterior cingulate cortex, and amygdala. It controls executive, affective, and motivational functions. Chronic pain patients suffer from low dopamine production and delivery in this system. The volumes of structures constituting the mesolimbic system are known to be decreased in such patients. Studies on administration of dopaminergic drugs to control chronic pain, with a focus on increasing low dopamine levels in the mesolimbic system, show that it is effective in patients with Parkinson’s disease, restless legs syndrome, fibromyalgia, dry mouth syndrome, lumbar radicular pain, and chronic back pain. However, very few studies have confirmed these effects, and dopaminergic drugs are not commonly used to treat the various diseases causing chronic pain. Thus, further studies are required to determine the effectiveness of such treatment for chronic pain.

A non-linear deterministic model of action selection in the basal ganglia to simulate motor fluctuations in Parkinson's disease.

Motor fluctuations and dyskinesias are severe complications of Parkinson's disease (PD), especially evident at its advanced stage, under long-term levodopa therapy. Despite their strong clinical prevalence, the neural origin of these motor symptoms is still a subject of intense debate. In this work, a non-linear deterministic neurocomputational model of the basal ganglia (BG), inspired by biology, is used to provide more insights into possible neural mechanisms at the basis of motor complications in PD. In particular, the model is used to simulate the finger tapping task. The model describes the main neural pathways involved in the BG to select actions [the direct or Go, the indirect or NoGo, and the hyperdirect pathways via the action of the sub-thalamic nucleus (STN)]. A sensitivity analysis is performed on some crucial model parameters (the dopamine level, the strength of the STN mechanism, and the strength of competition among different actions in the motor cortex) at different levels of synapses, reflecting major or minor motor training. Depending on model parameters, results show that the model can reproduce a variety of clinically relevant motor patterns, including normokinesia, bradykinesia, several attempts before movement, freezing, repetition, and also irregular fluctuations. Motor symptoms are, especially, evident at low or high dopamine levels, with excessive strength of the STN and with weak competition among alternative actions. Moreover, these symptoms worsen if the synapses are subject to insufficient learning. The model may help improve the comprehension of motor complications in PD and, ultimately, may contribute to the treatment design.

Development of dopamine biosensor based on polyaniline/carbon quantum dots composite

Low level of dopamine (DA) in human brain may lead to neurological diseases, therefore, detection of DA is necessary. This study aims to develop 2 types of DA biosensor, i.e., electrochemical and fluorescent biosensors based on conducting polymer and quantum dot composite. The polyaniline/carbon quantum dots (PANi/CQDs) composite was prepared and characterized by UV–Vis absorption spectroscopy, fluorescence spectroscopy, FT–IR spectroscopy, scanning electron microscopy (SEM) and X–ray photoelectron spectroscopy (XPS). For electrochemical biosensor, the electrospun nanofiber film of PANi/CQDs was fabricated on fluorine doped tin oxide (FTO)–coated glass substrate. Cyclic voltammetry and amperometry were performed to study the electrochemical activity of the PANi/CQDs film toward detection of DA in neutral solution. The obtained film showed good sensitivity for DA sensing with sensitivity of 8.025 nA.cm−2.μM−1 and linear range of 10–90 μM (R2 = 0.99) with detection limit of 0.1013 μM. In addition, for fluorescent biosensor, the fluorescent intensity of PANi/CQDs in PBS solution was quenched with increasing DA concentrations. The PANi/CQDs fluorescent biosensor presented the linear range of 0.1–100 μM (R2 = 0.94) with detection limit of 0.0801 μM. The prepared PANi/CQDs composite can be promising candidate material for future use as DA biosensor in real sample analysis.

The Role of the Dopamine D2 Receptor in Form-Deprivation Myopia in Mice: Studies With Full and Partial D2 Receptor Agonists and Knockouts.

PurposeThe purpose of this study was to explore the role and mechanism of D2 receptor (D2R) involvement in myopia development and the effects of the full D2R agonist quinpirole and partial D2R agonist aripiprazole on postnatal refractive development and form-deprivation myopia (FDM).MethodsC57BL/6 (“B6”) mice, raised either in a visually normal or unilateral form-deprivation environment, were divided into three subgroups, including an intraperitoneally injected (IP) vehicle group and two quinpirole (1 and 10 µg/g body weight) treatment groups. The effects of quinpirole on FDM were further verified in D2R-knockout (KO) mice and corresponding wild-type littermates. Then, the modulation of normal vision development and FDM by aripiprazole (1 and 10 µg/g body weight, IP) was assessed in C57BL/6 mice. All biometric parameters were measured before and after treatments, and retinal cyclic adenosine phosphate (cAMP) and phosphorylated ERK (pERK) levels were analyzed to assess D2R-mediated signal transduction.ResultsNeither quinpirole nor aripiprazole affected normal refractive development. FDM development was inhibited by quinpirole at low dose but enhanced at high dose, and these bidirectional effects were validated by D2R-specificity. FDM development was attenuated by the partial D2R agonist aripiprazole, at high dose but not at low dose. Quinpirole caused a dose-dependent reduction in cAMP levels, but had no effect on pERK. Aripiprazole reduced cAMP levels at both doses, but caused a dose-dependent increase of pERK in the form-deprived eyes.ConclusionsReduction of D2R-mediated signaling contributes to myopia development, which can be selectively attenuated by partial D2R agonists that activate D2Rs under the low dopamine levels that occur with FDM.

Silver nanoclusters and carbon dots based light-addressable sensors for multichannel detections of dopamine and glutathione and its applications in probing of parkinson's diseases

Parkinson's disease (PD) is a common neurological disease caused by nerve cells degradation which leads to extremely low level of dopamine (DA) in patients. Therefore, ultrasensitive DA detection is particularly important for the assessment and treatment of Parkinson's patients. In this research, photoelectrochemical (PEC) sensors based on Ag44(SR)30 nanoclusters (AgNCs) with 5-mercapto-2-nitrobenzoic acid (MNBA) ligands were first developed for ultrasensitive and selective detection of DA. Then, hybrid nanomaterials by introducing graphene oxide (GO) and silver nanoparticles (AgNPs) into AgNCs were used to enhance sensing properties. AgNCs/AgNPs/GO based PEC sensors achieved high sensitivity (7.476 nA/μM) and low limit of detection (LOD, S/N = 3, 53 nM) in the linear range 0.16–6 μM DA concentration. Besides DA, PD causes the concentration change of other analytes, such as glutathione (GSH). Multichannel detections of different analytes can provide more information in studying PD. Therefore, carbon dots (CDs) based PEC sensors were designed and achieved high sensing performances on GSH detection. Then, AgNCs/AgNPs/GO and CDs based PEC sensors were combined and extended into light-addressable sensors for multichannel detections of DA and GSH. Algorithms were used to solve interference problems to improve the measurement accuracy of DA and GSH in complex solution. Finally, PD biological model samples from mice were measured by light-addressable sensors. The relationships between the DA and GSH concentration and the PD stage were proved. Our designed light-addressable sensors exhibited advantages of multichannel detection, high sensitivity, fast response and so on. In the future, it can be expanded to detect more biological molecules to provide more information on studying PD.

Individual susceptibility or resistance to posttraumatic stress disorder-like behaviours

The aim of this study was to explore the neurobiological background of individual susceptibility and resistance to the development of posttraumatic stress disorder (PTSD)-like behaviours. Rats were divided into susceptible, PTSD(+), and resistant, PTSD(-), groups based on freezing duration during exposure to aversive context and the time spent in the central area in open field test one week after threefold stress experience (modified single prolonged stress). PTSD(-) rats showed increased concentrations of corticosterone in plasma and changes in GAD67 expression: decreased in the infralimbic cortex (IL) and increased in the lateral amygdala (LA), dentate gyrus (DG), and CA1 area of the hippocampus. Moreover, in this group, we found an increase in the number of CRF-positive nuclei in the parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN). The PTSD(+) group, compared to PTSD(-) rats, had decreased concentrations of corticosterone in plasma and reduced CRF expression in the pPVN, higher CRF expression in the CA1, increased expression of CRF-positive nuclei and GR receptors in the CA3 area of the hippocampus, and increased expression of GR receptors in the DG and the central amygdala (CeA). Biochemical analysis showed higher concentrations of noradrenaline, glutamic acid in the dorsal hippocampus and amygdala and lower levels of dopamine and its metabolites in the amygdala of the PTSD(+) group than in the PTSD(-) group. The study revealed different behavioural and biochemical profiles of PTSD(+) and PTSD(-) rats and suggested that individual differences in hypothalamic-pituitary-adrenal (HPA) axis activity may determine hippocampal- and amygdala-dependent memory and fear processing.

Autoantibodies to thyroid antigens levels in the population of the Russian Arctic at different levels of blood dopamine.

Neuroimmunoendocrine regulation of the thyroid gland involves the use of autoantibodies as regulatory molecules to stimulate or reduce the activity of the tissues of the organ itself. A huge number of regulatory signal molecules and factors, acting directly or indirectly, often plays a much more significant role, both in ensuring normal activity and in pathological processes. In this regard, it was interesting for us to determine the possible effect of dopamine at its various concentrations in the blood on the levels of thyroglobulin and antibodies to thyroid antigens. A survey of 110 men and 206 women aged 22 to 75 years who were born and lived in the Arctic zone of the Russian Federation and had no diseases of the endocrine and immune system was conducted. Dopamine concentrations were determined in blood plasma, thyroid stimulating hormone (TSH), thyroglobulin (TG), antibodies to thyroperoxidase (at-TPO) and thyroglobulin (at-TG) in serum. Higher concentrations of thyrotropin and thyroglobulin and lower concentrations of at-TG and at-TPO were shown with increasing dopamine levels from undetectable values to normative and excess levels. We explain this by the influence of dopamine on a-adrenoreceptors of antibody-producing cells and changes in the secretion of immunoglobulins class G, subclasses of which include at-TG and at-TPO. The appearance of different from zero values of autoantibodies concentrations in themselves, we associate with the negative impact of the conditions of the North and the prenosological state of the organism. Their higher values in women with low levels of dopamine can be explained by the lack of its immunomodulatory activity.