Brain Dopamine Research Articles

α-Viniferin, a dietary phytochemical, inhibits Monoamine oxidase and alleviates Parkinson's disease associated behavioral deficits in a mice model

Parkinson's disease (PD) is one of the most prevalent age-related neurodegenerative disorders. Behavioral complexities worsen over time due to progressive dopaminergic (DArgic) neuronal loss at substantia nigra region of brain. Available treatments typically aim to increase dopamine (DA) levels at striatum. DA is degraded by Monoamine oxidase (MAO), thus dietary phytochemicals with MAO inhibitory properties can contribute to elevate DA levels and reduce the ailment. Characterization of naturally occurring dietary MAO inhibitors is inadequate. Based on available knowledge, we selected different classes of molecules and conducted a screening process to assess their potential as MAO inhibitors. The compounds mostly derived from food sources, broadly belonging to triterpenoids (ursane, oleanane and hopane), alkaloid, polyphenolics, monoterpenoids, alkylbenzene, phenylpropanoid and aromatic alcohol classes. Among all the molecules, highest level of MAO inhibition is offered by α-viniferin, a resveratrol trimer. Cell viability, mitochondrial morphology and reactive oxygen species (ROS) generation remained unaltered by 50 μM α-viniferin treatment in-vitro. Toxicity studies in Drosophila showed unchanged gross neuronal morphology, ROS level, motor activity or long-term survival. α-Viniferin inhibited MAO in mice brain and elevated striatal DA levels. PD-related akinesia and cataleptic behavior were attenuated by α-viniferin due to increase in striatal DA. Our study implies that α-viniferin can be used as an adjunct phytotherapeutic agent for mitigating PD-related behavioral deterioration.

Effects of cannabidiol in post-stroke mood disorders in neonatal rats.

Neonatal rats can manifest post-stroke mood disorders (PSMD) following middle cerebral artery occlusion (MCAO). We investigated whether cannabidiol (CBD) neuroprotection, previously demonstrated in neonatal rats after MCAO, includes prevention of PSMD development. Seven-day-old Wistar rats (P7) underwent MCAO and received either vehicle or 5 mg/kg CBD treatment. Brain damage was quantified by MRI, and neurobehavioral and histological (TUNEL) studies were performed at P14 and P37. PSMD were assessed using the tail suspension test, forced swimming test, and open field tests. The dopaminergic system was evaluated by quantifying dopaminergic neurons (TH+) in the Ventral Tegmental Area (VTA), measuring brain dopamine (DA) concentration and DA transporter expression, and assessing the expression and function D2 receptors (D2R) through [35S]GTPγS binding. Animals without MCAO served as controls. CBD reduced MCAO-induced brain damage and improved motor performance. At P14, MCAO induced depressive-like behavior, characterized by reduced TH+ cell population and DA levels, which CBD did not prevent. However, CBD ameliorated hyperactivity observed at P37, preventing increased DA concentration by restoring D2R function. These findings confirm the development of PSMD following MCAO in neonatal rats and highlight CBD as a neuroprotective agent capable of long-term functional normalization of the dopaminergic system post-MCAO. MCAO in neonatal rats led to post-stroke mood disorders consisting in a depression-like picture in the medium term evolving towards long-term hyperactivity, associated with an alteration of the dopaminergic system. The administration of CBD after MCAO did not prevent the development of depressive-like behavior, but reduced long-term hyperactivity, normalizing dopamine receptor function. These data point to the importance of considering the development of depression-like symptoms after neonatal stroke, a well-known complication after stroke in adults. Our work confirms the interest of CBD as a possible treatment for neonatal stroke.

Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats.

Schizophrenia (SCZ) response to pharmacological treatment is highly variable. Quetiapine (QTP) administered as QTP lipid core nanocapsules (QLNC) has been shown to modulate drug delivery to the brain of SCZ phenotyped rats (SPR). In the present study, we describe the brain concentration-effect relationship after administrations of QTP as a solution or QLNC to SPR and naïve animals. A semimechanistic pharmacokinetic (PK) model describing free QTP concentrations in the brain was linked to a pharmacodynamic (PD) model to correlate the drug kinetics to changes in dopamine (DA) medial prefrontal cortex extracellular concentrations determined by intracerebral microdialysis. Different structural models were investigated to fit DA concentrations after QTP dosing, and the final model describes the synthesis, release, and elimination of DA using a pool compartment. The results show that nanoparticles increase QTP brain concentrations and DA peak after drug dosing to SPR. To the best of our knowledge, this is the first study that combines microdialysis and PK/PD modeling in a neurodevelopmental model of SCZ to investigate how a nanocarrier can modulate drug PK and PD, contributing to the development of new treatment strategies for SCZ.

The neuromodulatory role of dopamine in improved reaction time by acute cardiovascular exercise.

Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n=16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n=18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.

Parkinson’s New Advancements in Diagnosis and Treatment: A Review

Parkinsonism Disease (PD) is a progressive neurological disorder. Although PD is associated with a variety of Non-motor symptoms (NMS) in virtually all patients including hyposmia, constipation, pain and sleep disturbances. It is age related disorder and affects more than 6 million population every year. It is associated with neuronal degeneration in substantia nigra and to lesser extent, in the globus pallidus, putamen and caudate nucleus. The degeneration of the neurons of the substantia nigra that send their axons to the corpus striatum results in reduction in the release of neurotransmitter dopamine with in corpus striatum. This leads to hypersensitivity of the dopamine receptors in the post synaptic neurons in the striatum. Individuals have characteristics signs and symptoms tremors, bradykinesia, postural instabilities, rigidity. Neither loss of sense nor muscle power is usually seen in such cases. Deep tendon, Superficial and Abdominal reflexes are well retained on evaluation. There has been various types of classification in Parkinsonism which are described later. Together with aging, genetics, environment and the role of biological sex as important factor in development of PD has been widely discussed in the past decade. Investigations in PD remains a challenge, recent studies included 7 Tesla MRI, PET and SPECT have proved to be confirmatory in diagnosis of PD. Parkinsonism disease treatment includes increasing the levels of dopamine in brain by giving its immediate precursor L-dopa which can easily cross blood brain barrier unlike dopamine. Evidence of slowing the process of degeneration has been seen with drug selegiline. Other than drugs surgical options include pallidotomy

Au@Ag nanoparticles: an analytical tool to study the effect of tyrosine on dopamine levels.

The neurotransmitter dopamine (DA) plays important roles in the human body, including regulatory functions, movement, memory and motivational control. The direct intake of DA is impossible as it cannot cross the blood-brain barrier (BBB) efficiently. Notably, l-tyrosine works as a precursor of DA in the human brain. Herein, we report an analytical method that strongly supports the hypothesis that the intake of tyrosine (Tyr)-rich food enhances DA levels. For this analysis, citrate-coated gold-core silver-shell nanoparticles (Au@Ag NPs) were synthesized. The interaction of DA with the Au@Ag NPs was investigated using multiple spectroscopic techniques, and different thermodynamic parameters were evaluated to assign the binding mechanism. Real sample analysis with Tyr-rich food was also conducted to study the effect of Tyr on DA levels. Analytical studies were performed to verify the outcomes of the present work. The limit of detection of the Au@Ag NPs-DA system for Tyr was found to be 1.64 mM. This study can contribute to development in the fields of medicine and pharmaceuticals, particularly in regard to neuromedicine. One of the major advantages of this investigation is that it will fuel research interest in the supplementation of neurotransmitters and help categorize Tyr as a dietary precursor of dopamine.

Neurovascular coupling of striatal dopamine D2/3 receptor availability and perfusion using simultaneous PET/MR in humans

The midbrain dopamine system contributes to important neural functions in the basal ganglia, and is involved in aspects of pathological processes in schizophrenia. In preclinical and clinical studies, pharmacological blockade or stimulation of brain dopamine receptors alters cerebral perfusion, which is a surrogate marker of metabolic activity. However, there is scant documentation of this neurofunctional coupling in relation to individual differences in the dopamine system of healthy humans. We therefore tested the hypothesis that baseline dopamine D2/3 receptor availability predicts individual blood flow responses to challenge with a dopamine agonist.We used [18F]fallypride positron emission tomography (PET) imaging to quantify dopamine D2/3 receptor availability as binding potential (BPND) in nine healthy subjects. Using simultaneous perfusion-weighted functional magnetic resonance imaging (fMRI), we measured perfusion at baseline and after challenge with the dopamine agonist apomorphine.Results of this multimodal imaging study revealed a strong negative association between baseline D2/3 dopamine receptor availability and apomorphine-induced perfusion changes in the human basal ganglia. There was considerable intra-individual variation in the neurovascular response to the apomorphine challenge, which may call for further investigation of the dopaminergic regulation of cerebral perfusion in patients with schizophrenia.This study describes a novel paradigm for assessing dopamine sensitivity, facilitating an exploration of the dopamine supersensitivity hypothesis.

A Simple Immunofluorescence Method to Characterize Neurodegeneration and Tyrosine Hydroxylase Reduction in Whole Brain of a Drosophila Model of Parkinson's Disease.

Dopaminergic (DAergic) neurodegeneration in the substantia nigra pars compacta of the human brain is the pathological feature associated with Parkinson's disease (PD). Drosophila also exhibits mobility defects and diminished levels of brain dopamine on exposure to neurotoxicants mimicking PD. Our laboratory demonstrated in a Drosophila model of sporadic PD that there is no decrease in DAergic neuronal number; instead, there is a significant reduction in tyrosine hydroxylase (TH) fluorescence intensity (FI). Here, we present a sensitive assay based on the quantification of FI of the secondary antibody (ab). As the FI is directly proportional to the amount of TH synthesis, its reduction under PD conditions denotes the decrease in the TH synthesis, suggesting DAergic neuronal dysfunction. Therefore, FI quantification is a refined and sensitive method to understand the early stages of DAergic neurodegeneration. FI quantification is performed using the ZEN 2012 SP2 single-user software; a license must be acquired to utilize the imaging system to interactively control image acquisition, image processing, and analysis. This method will be of good use to biologists, as it can also be used with little modification to characterize the extent of degeneration and changes in the level of degeneration in response to drugs in different cell types. Unlike the expensive and cumbersome confocal microscopy, the present method will be an affordable option for fund-constrained neurobiology laboratories. Key features • Allows characterizing the incipient DAergic and other catecholaminergic neurodegeneration, even in the absence of loss of neuronal cell body. • Great alternative for the fund-constrained neurobiology laboratories in developing countries to utilize this method in different cell types and their response to drugs/nutraceuticals.

High intensity interval training exercise increases dopamine D2 levels and modulates brain dopamine signaling.

Previous research has outlined the health benefits of exercise including its therapeutic potential for substance use disorders (SUD). These data have already been utilized and it is now common to find exercise as part of SUD treatment and relapse prevention programs. However, we need to better understand different exercise regimens and determine which would be the most beneficial for SUDs. Recently, high intensity interval training (HIIT) has gained attention in comparison with aerobic and resistance exercise. Little is known regarding the neurobiological mechanisms of HIIT, including its effects on dopamine signaling and receptor levels in the brain. The present study examined the effects of chronic HIIT exercise on dopamine signaling as measured by dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and tyrosine hydroxylase (TH) quantification in the brains of male and female rats as measured by [3H] SCH 23390 and [3H] spiperone autoradiography, and TH-immunoreactive optical density values. Rats were separated in two groups: sedentary and HIIT exercise. Exercise was on a treadmill for 30 min daily (10 3 min cycles) for six weeks with progressive speed increased up to 0.8 mph (21.5 m/min). Results showed for D2R-like binding, a significant effect across the ventral caudate putamen (V CPU) between sexes, such that mean D2R-like binding was 14% greater for males than females. In the nucleus accumbens shell (Nac Shell), the HIIT Exercise rats showed 16% greater D2R-like binding as compared to the sedentary rats. No significant effects of HIIT exercise were found across groups for brain D1R-like binding levels or TH expression. These results suggest that HIIT exercise can modulate dopamine signaling by way of increased D2R. These findings support the premise that HIIT exercise plays an important role in dopamine signaling and, may provide a potential mechanism for how HIIT exercise can impact the brain and behavior.

Neurochemical Effects of the Adipokinetic Hormone/Red Pigment Concentrating Hormone Family of Peptides in MK-801-Induced Schizophrenia Rat Model

Objective: Adipokinetic hormone (AKH) plays a role in sugar and lipid metabolism in insects. Previous studies of AKH showed memory improvements in a schizophrenia rat model that displayed memory impairment and reduced depression in a rat olfactory bulbectomy model. In this study, we investigated the effects of the adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides on brain neurotransmitter levels and brain neurochemistry in a schizophrenia rat model. Materials and Methods: We administered AKH/RPCH peptides for 4 days sub-chronically, both in naive rats and also in the MK-801-induced schizophrenia rat model. Liquid chromatography-mass spectrometry apparatus was used for targeted and untargeted analysis of rat neurochemistry. Results: Increased brain glutamate levels characteristic of MK-801 peptide-treated rats were significantly reduced by AKH. Furthermore, AKH also increased brain dopamine levels in both naive and MK-801 rats. Metabolomic studies have shown that AKH affects lipid and glutamate metabolism, while hypertrehalosaemic hormone plays a role in sugar metabolism and inflammation. Conclusion: According to our results, AKH might affect dopaminergic and glutamatergic systems and reverse the effects of MK-801, possibly affecting NMDA receptors.

Synergistic Effect of Lovastatin and Selegiline on the Differentiation of Bone Marrow Stromal Cells Into Neuron-Like Cells

Background: The effect of selegiline as an oxidase inhibitor on cell differentiation into neuron-like cells has been demonstrated by altering gene expression. Based on the results of studies on the role of statins in neurotrophin regulation, in this study, we examined the effect of lovastatin (HMG-CoA reductase inhibitor) on the differentiation of bone marrow mesenchymal cells (BMSCs) into neuron-like cells. Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) type B. Since dopamine in the human brain is metabolized primarily by MAO-B, selegiline increases dopamine levels in the central nervous system. In addition to inhibiting MAO-B, selegiline also inhibits the uptake of dopamine and norepinephrine into presynaptic nerves and increases dopamine turnover. Methods: Bone marrow mesenchymal cells were collected from 28-day-old rats and cultured under standard conditions on the medium. The experimental groups in this study were as follows: BMSCs (control); BMSCs induced with 20 µM selegiline for 24 hours (experiment 1); BMSCs induced with 6 µM lovastatin for 24 hours (experiment 2); BMSCs were induced with 20 µM selegiline for 24 hours and 6 µM lovastatin for the next 24 hours (experiment 3). Real-time RT-PCR was performed to determine the mRNA levels of the nestin and NF-68 genes. Results: Real-time RT-PCR results showed that nestin and NF-68 mRNA levels were significantly increased in the co-treatment group (experiment 3) compared to the other experimental groups (P < 0.05). Conclusions: Based on the increased expression of nestin and NF-68 genes, the presence of lovastatin has a synergistic effect on neuronal differentiation and optimization of stem cell therapeutic approaches.

Effect of perinatal dietary protein deficiency on some neurochemicals and cytoarchitectural balance, in F1 and F2 generations of rats

ABSTRACT Protein deficiency, characterized by an inadequate intake of protein in the diet that fails to meet the body’s physiological requirements across various stages, can lead to detrimental outcomes. This is of interest due to the persistent low protein content in staple foods and suboptimal dietary patterns. The study sought to assess the intergenerational repercussions of dietary protein deficiency on specific neurochemicals and the cytoarchitecture of the brain within the F1 and F2 generations of rats. The rats were categorized into four groups based on the protein content percentage in their diets: 21% protein diet (21%PD), 10% protein diet (10%PD), 5% protein diet (5%PD), and control diet. Neurobehavior was assessed, while brain serotonin and dopamine levels were measured using HPLC. BDNF and GDNF expression in the hippocampal and prefrontal (PFC) sections, Immunohistochemical investigations of the morphological impact on the hippocampus and PFC, were also analyzed. The protein-deficient groups displayed anxiety, loss of striatal serotonin and increased dopamine levels, degenerated pyramidal cells in the hippocampus, and a prominent reduction in cellular density in the PFC. BDNF and GDNF levels in the PFC were reduced in the 5%PD group. GFAP astrocyte expression was observed to be increased in the prefrontal cortex (PFC) and hippocampal sections, indicating heightened reactivity. The density of hypertrophied cells across generations further suggests the presence of neuroinflammation. Changes in brain structure, neurotransmitter levels, and neurotrophic factor levels may indicate intergenerational alterations in critical regions, potentially serving as indicators of the brain’s adaptive response to address protein deficiency across successive generations.

Brain dopamine receptor system is not altered in obesity: Bayesian and frequentist meta-analyses.

Feeding induces dopamine release in the striatum, and a dysfunction of the dopaminergic reward system can lead to overeating, and obesity. Studies have reported inconsistent findings of dopamine receptor (DR) positron emission tomography scans in obesity. Here we investigated the association between DR availability and overweight/obesity using Bayesian and frequentist meta-analysis. We performed a systematic search of Embase, Medline, Scopus and Web of Science for studies that compared striatal DR availability between lean subjects and overweight/obese subjects. The standardized mean difference (Hedge's g) of DR availability was calculated after extraction of data from each study. Studies were divided into two groups according to the definition of overweight/obese subjects (body mass index [BMI] cutoff of 25 and 30 kg/m2 ). Both Bayesian and frequentist meta-analysis was done in R Statistical Software version 4.2.2 (The R Foundation for Statistical Computing). Nine studies were eligible for inclusion in this study. Three studies with C11-raclopride, one with C11-PNHO, two with F18-fallypride, one with I123-IBZM, one with C11-NMB and one with both C11-raclopride and C11-PNHO were included. In Bayesian meta-analysis, the standardized mean difference of DR availability between lean and overweight/obese subjects markedly overlapped with zero regardless of BMI cutoff for obesity. In frequentist meta-analysis, the pooled standardized mean difference of DR availability did not show the significant difference between lean and overweight/obese subjects. There was an effect of the radiopharmaceutical on the standardized mean difference of DR availability in meta-analysis of BMI cutoff of 25 kg/m2 . In conclusion, brain DR availability is not different between lean and overweight/obese subjects. However, the effect is dependent on the radiopharmaceutical and the degree of obesity. Further studies with multi-radiopharmaceutical in the same individuals are needed to understand the association between DR and obesity.

Bioassays guided isolation of berberine from Berberis lycium and its neuroprotective role in aluminium chloride induced rat model of Alzheimer's disease combined with insilico molecular docking.

Berberis lycium is an indigenous plant of Pakistan that is known for its medicinal properties. In the current study, we investigated the anti-Alzheimer's effect of berberine isolated from Berberis lycium. Root extract of B. lycium was subjected to acetylcholinesterase inhibition assay and column chromatography for bioassays guided isolation of a compound. The neuroprotective and memory improving effects of isolated compound were evaluated by aluminium chloride induced Alzheimer's disease rat model, elevated plus maze (EPM) and Morris water maze (MWM) tests., Levels of dopamine and serotonin in rats brains were determined using HPLC. Moreover, western blot and docking were performed to determine interaction between berberine and β-secretase. During fractionation, ethyl acetate and methanol (3:7) fraction was collected from solvent mixture of ethyl acetate and methanol. This fraction showed the highest anti-acetylcholinesterase activity and was alkaloid positive. The results of TLC and HPLC analysis indicated the presence of the isolated compound as berberine. Additionally, the confirmation of isolated compound as berberine was carried out using FTIR and NMR analysis. In vivo EPM and MWM tests showed improved memory patterns after berberine treatment in Alzheimer's disease model. The levels of dopamine, serotonin and activity of antioxidant enzymes were significantly (p<0.05) enhanced in brain tissue homogenates of berberine treated group. This was supported by decreased expression of β-secretase in berberine treated rat brain homogenates and good binding affinity of berberine with β-secretase in docking studies. Binding energies for interaction of β-secretase with berberine and drug Rivastigmine is -7.0 kcal/mol and -5.8 kcal/mol respectively representing the strong interactions. The results of docked complex of secretase with berberine and Rivastigmine was carried out using Gromacs which showed significant stability of complex in terms of RMSD and radius of gyration. Overall, the study presents berberine as a potential drug against Alzheimer's disease by providing evidence of its effects in improving memory, neurotransmitter levels and reducing β-secretase expression in the Alzheimer's disease model.

COF-Coated Microelectrode for Space-Confined Electrochemical Sensing of Dopamine in Parkinson's Disease Model Mouse Brain.

Parkinson's disease (PD) is a progressive neurodegenerative disorder causing the loss of dopaminergic neurons in the substantia nigra and the drastic depletion of dopamine (DA) in the striatum; thus, DA can act as a marker for PD diagnosis and therapeutic evaluation. However, detecting DA in the brain is not easy because of its low concentration and difficulty in sampling. In this work, we report the fabrication of a covalent organic framework (COF)-modified carbon fiber microelectrode (cCFE) that enables the real-time detection of DA in the mouse brain thanks to the outstanding antibiofouling and antichemical fouling ability, excellent analytical selectivity, and sensitivity offered by the COF modification. In particular, the COF can inhibit the polymerization of DA on the electrode (namely, chemical fouling) by spatially confining the molecular conformation and electrochemical oxidation of DA. The cCFE can stably and continuously work in the mouse brain to detect DA and monitor the variation of its concentration. Furthermore, it was combined with levodopa administration to devise a closed-loop feedback mode for PD diagnosis and therapy, in which the cCFE real-time monitors the concentration of DA in the PD model mouse brain to instruct the dose and injection time of levodopa, allowing a customized medication to improve therapeutic efficacy and meanwhile avoid adverse side effects. This work demonstrates the fascinating properties of a COF in fabricating electrochemical sensors for in vivo bioanalysis. We believe that the COF with structural tunability and diversity will offer enormous promise for selective detection of neurotransmitters in the brain.

Tailoring Efficient Fluorogenic Tactic for Ultrasensitive Detection of Dopamine in Urine and Rat Brain through Real-Time and In Situ Formation of High-Performance Fluorophore.

Owing to the predominance of dopamine (DA) in controlling mental health, planning an innovative method for DA detection with simplicity and high efficacy is conducive to the assessment of neurological disorders. Herein, an efficient fluorogenic tactic has been elaborated for ultrasensitive detection of DA with remarkably enhanced turn-on response. Utilizing a twisted intramolecular charge-transfer (TICT)-suppressing strategy, a highly emissive azocine derivative 11-hydroxy-2,3,6,7,11,12,13,14-octahydro-1H,5H,10H-11,14a-methanoazocino[5',4':4,5]furo[2,3-f]pyrido[3,2,1-ij]quinolin-10-one (J-Aza) is generated via a one-step reaction between DA and 8-hydroxyjulolidine. It is marvelous that J-Aza not only possesses ideal fluorescence quantum yield (ΦF) as high as 0.956 but also exhibits bathochromic shifted fluorescence (green emissive) and stronger anti-photobleaching capacity superior to traditional azocine-derived 1,2,3,4-tetrahydro-5H-4,11a-methanobenzofuro[2,3-d]azocin-5-one (Aza) with moderate ΦF, blue fluorescence, and poor photostability. By confining the TICT process, the detection limit to DA can be reduced to 80 pM, which is competitive in contrast to previously reported fluorescence methods. Encouraged by the instant response (within 90 s), wide linear range (0.1-500 nM), great selectivity, and excellent sensitivity, this fluorogenic method has been used for the real-time measurement of DA contents in practical urine samples with satisfactory results. Furthermore, the cerebral DA level in the reserpine-induced depression rat model has also been evaluated by our designed method, demonstrating its potent analytical applicability in the biosensing field.

The role of dopamine in visual imagery-An experimental pharmacological study.

Mental imagery enables people to simulate experiences in their minds without the presence of an external stimulus. The underlying biochemical mechanisms are poorly understood but there is vague evidence that dopamine may play a significant role. A better understanding at the biochemical level could help to unravel the mechanisms of mental imagery and related phenomena such as aphantasia (= lack of voluntary mental imagery), but also opens up possibilities for interventions to enhance or restore mental imagery. To test the hypothesis that acute dopamine depletion leads to a decrease in the strength of mental imagery, N = 22 male participants will be administered an amino acid mixture containing branched-chain amino acids (BCAAs) and tryptophan (TRP) to transiently reduce dopamine synthesis and further N = 22 male participants will receive a placebo. Plasma prolactin (PRL) levels are determined as a peripheral marker of brain dopamine function. The strength of mental imagery will be measured before and after ingestion of the BCAA/TRP mixture using the method of mental imagery priming. Additional exploratory analyses will use genetic data to investigate possible effects of variations on dopaminergic gene loci (e.g., DAT1) on dopamine levels and strength of mental imagery. The results show […].

Increased depression-like behaviors with altered brain dopamine metabolisms in male mice housed in large cages are alleviated by bupropion

Psycho-environmental stress-based animal models of anxiety and depression are useful for investigating pathological mechanisms and drug development. Although several rodent-based studies have reported the beneficial effects of environmental enrichment (EE) on brain plasticity and anxiety- and depression-like behaviors, other studies have reported inverse effects. Here, we found that housing male mice in EE involving large cages and other EE materials increased anxiety- and depression-like behaviors in open field and tail suspension tests (TST). We further confirmed that housing in large cages was sufficient to induce increased depression-like behaviors in the TST and reduce the saccharine preference percentage, a sign of anhedonia, in male mice. In these experiments, the number of animals per cage was equivalent to that in standard cage housing, suggesting that low density in large cages may be a determining factor for behavioral alteration. In mice housed in large cages, sex-specific dysregulation of brain monoamine systems was observed; dopamine turnover to homovanillic acid or norepinephrine in the prefrontal cortex was elevated in males, while serotonin turnover to 5-hydroxyindoleacetic acid in the amygdala was increased in females. Finally, we demonstrated that daily intraperitoneal injections of bupropion, a dopamine and norepinephrine reuptake inhibitor, counteracted large-cage housing-induced changes in depression- and anhedonia-like behaviors in male mice. Our results suggest that housing in large cages with a low density of mice is a novel paradigm to clarify the mechanisms of environmental stress-induced emotional dysregulation and to identify drugs or food factors to alleviate the dysregulation.

Koumine supplementation positively affects growth, circadian rhythms, and stress levels in Cyprinus carpio

This study evaluated the effects of koumine on growth performance, brain transcriptional response, expression of genes associated with circadian rhythms, and physiological stress indicators in carp (5.21 ± 0.05 g). Fish were fed four different koumine levels (0, 0.2, 2, and 20 mg/kg) of diet (crude protein 29.71%, crude lipid 3.68%) for 10 weeks in a RAS (26.0–28.0 ℃, pH 7.3–7.5, and DO 5.5–6.1 mg/L). Each type of feed was administered to three replicate tanks (50 L, 12 cycles per day), each containing 30 fish, with feeding occurring twice daily. The results showed that koumine supplementation improved the growth performance of carp. Significant enrichment of circadian rhythm, memory, and behavior-related pathways in the brain of the koumine-supplemented group of fish. The circadian rhythm positive feedback-related genes MKP5, ATP1A, ATP2A, and CRY2 were significantly upregulated (P < 0.05), and the negative feedback-related genes REV-ERBA were significantly downregulated (P < 0.05) in the koumine supplementation group. The fish in the koumine group showed a significant increase in brain dopamine concentrations (P < 0.05) and a significant decrease in 5-hydroxytryptamine concentrations (P < 0.05). Overall, our study showed that koumine supplementation improved growth performance and reduced stress levels during rearing of carp, which may be related to the regulation of expression of circadian rhythm-related pathways.

OR06-03 Intergenerational Exposure To Endocrine-disrupting Chemicals (Edcs) Affects Dopamine-mediated Behaviors In A Sex-Specific Manner In Rats

Abstract Disclosure: E.N. Hilz: None. C. Schnurer: None. S. Bhamidipati: None. L. Thompson: None. E. Morales-Ledesma: None. A.C. Gore: None. Polychlorinated biphenyls (PCBs) are a weakly estrogenic class of ubiquitous environmental EDCs that affect a range of sex-specific neuroendocrine and reproductive outcomes. Furthermore, these effects can extend intergenerationally via epigenetic changes carried down the germline. In humans, PCBs are associated with sexually dimorphic and hormone sensitive neurobehavioral disorders including attention deficit hyperactivity disorder (ADHD) and mood disorders such as depression; however, little preclinical work has modeled these cognitive changes in rats and none has determined if they extend intergenerationally via endocrine-mediated changes to the brain dopamine system. In the current work, three generations of male and female Sprague-Dawley rats were exposed to the PCB mixture Aroclor 1221 (A1221) at different life stages: as adults; through perinatal exposure via mother's diet; or preconceptionally, as the germ cells within the exposed fetus. Adults of each generation underwent a battery of behavioral tasks to assess attentional phenotype, cognitive flexibility, and affect as measured by attentional set-shifting, conditioned orienting, and sucrose preference tests. These outcomes were correlated with both serum estradiol concentrations and dopamine cell quantity in the midbrain. Results revealed that A1221 treatment had sex- and generation-specific effects: in adult-exposed females, decreased conditioned orienting suggested a hyporesponsive attentional phenotype; in males, preconceptional exposure reduced cognitive flexibility via impaired attentional set-shifting. All rats showed a strong preference for sucrose solution; however, A1221 treatment decreased the total amount of sucrose solution consumed (indicating anhedonia) regardless of sex or timing of exposure. Dopamine cell numbers were inversely affected by A1221 between the sexes: decreased in females and increased in males, which correlates well with the cognitive changes observed. Relationships among estradiol concentration, cognitive changes, and dopamine cell quantity will be ascertained using a multilevel model that accounts for endocrine-mediated disruptions at the brain, body, and behavioral levels. These data show that the PCB mixture A1221 impairs different aspects of cognitive behavior between the sexes depending on timing of exposure, while having a broader effect of increased anhedonia, in a manner potentially mediated by hypo- or hyper-availability of midbrain dopamine and serum estradiol. Supported by RO1 ES029464. Presentation: Thursday, June 15, 2023