Chaihu Shugan San exerts antidepressant effects by driving microglial M2 polarization via inhibition of the IL-1β/JNK signaling pathway.

Polygenic modulations of decoy and compromise effects by dopaminergic and serotonergic systems.

Changes in choroidal thickness are currently used to predict future refractive error development but there is incomplete knowledge about the communication between choroid and sclera. We studied how choroidal thickness changes interact with scleral thickness changes and how the abundance of dopamine (DA)- and all-trans retinoic acid (atRA)-synthetizing choroidal cells varies when choroidal thickness is altered by drugs. Changes in choroidal thickness were induced by a single intravitreal injection in the morning of the muscarinic antagonist atropine, the DA agonist apomorphine or the DA antagonist spiperone. Thickness of the choroid and the scleral layers was measured by spectral domain optical coherence tomography (SD-OCT). Immunocytochemistry was used to study the distribution of dopamine-synthetizing structures in the choroid and their colocalisation with retinaldehyde dehydrogenase 2 (RADLH2), the key synthetizing enzyme of atRA. (1) Both atropine and apomorphine increased choroidal thickness over the day while spiperone resulted in a decrease. (2) For apomorphine and spiperone, choroidal thickness changes were positively correlated with thickness changes in both the cartilaginous and fibrous layers of the sclera. With atropine, only the cartilaginous layer thickened. (3) DA was co-localized with RALDH2 in stromal cells in the choroid in a few cases but the numbers of double-stained cells increased massively after drug injections. (4) RALDH2-immunoreactivity (indicating atRA activity) increased, no matter whether the choroid and the sclera thickened or thinned. Following drug injections, thickness changes of choroid and sclera were correlated and occurred without phase delay. Numbers of DA and RALDH2 co-expressing cells in the choroid increased. Choroidal dopaminergic cells that synthesize atRA appear to act as activators of scleral metabolic activity during both scleral growth stimulation and inhibition.

Bifunctional fluorescent silver-based peroxidase-mimetic nanozymes: A novel ratiometric fluorescence/colorimetric dual-signal system for dopamine detection.

Orexin-A signaling modulates dopamine neurons and palatable food seeking: potential involvement of μ-opioid receptor signaling pathway.

The retinal nerve fiber layer mean thickness in patients with early Parkinson's disease reflects striatal dopamine function.

Antibacterial metal-organic framework thin films on cellulose fibers via dopamine-mediated ultrafast assembly.

A self-calibrating fluorescence / colorimetric dual-mode sensor based on MIL-101(Fe) for specifical dopamine detection in human serum.

Multiple microRNAs analysis based on DNAzyme cascade DNA fiber barcodes for cell typing.

Glial cell-specific proteomic data from the substantia nigra of a rat 6-OHDA and fluorocitrate model of astrocyte death and microglial activation.

Classic theories propose opponent functions for striatal dopamine (DA) and serotonin (5-hydroxytryptamine; 5HT), with DA promoting approach and 5HT promoting patience or avoidance. How these neuromodulators regulate downstream circuits to achieve such antagonistic effects remains mysterious. Here, we mapped striatal 5HT receptor expression in mice to reveal preferential enrichment of putatively excitatory, Gq-coupled 5HT receptors on medium spiny neurons expressing inhibitory D2 DA receptors (D2-MSNs). Acute slice recordings from genetically identified striatal neurons showed that DA and 5HT inversely regulate D2-MSN firing and confirmed that 5HT's excitatory effect on these cells is blocked by 5HT2a and 5HT2c receptor antagonists. Pharmacologically upregulating striatal 5HT release preferentially induced cfos expression in D2-MSNs, validating that 5HT's excitatory effect on these cells also occurs in vivo. Finally, 5HT2c receptor loss-of-function in D2-MSNs, but not D1-MSNs, enhanced animals' sensitivity to the behavioral effects of cocaine - a potent releaser of DA and 5HT - showing that 5HTergic excitation of D2-MSNs counteracts the reinforcing effects of striatal DA release. Altogether these results demonstrate that DA and 5HT inversely modulate D2-MSN activity to regulate cocaine reward, identifying a key circuit mechanism underlying the opponent behavioral effects of these important neuromodulators.

Our memories do not simply keep time - they distort it, stretching and compressing the past to reflect the structure of experience. Here, we combined functional magnetic resonance imaging (fMRI; n = 32) with eye-tracking (n = 28) to test whether activation of the dopaminergic system, known to influence encoding and time perception, expands mnemonic representations of time between contextually distinct events. Participants encoded item sequences while listening to tones that typically repeated over time, but occasionally changed, creating salient event boundaries. We found that tone switches significantly activated the ventral tegmental area (VTA), and the magnitude of these responses predicted greater time dilation between item pairs spanning those switches. At a longer timescale, increased blinking also predicted greater time dilation in memory, but only for boundary-spanning item pairs. Together, these findings suggest that dopaminergic processes are sensitive to event structure and contribute to distortions of remembered time that may help segment continuous experience into distinct episodic memories.

Metal-organic frameworks (MOFs) have shown major promise for electrochemical dopamine (DA) sensing owing to their high surface area, tunable pores, and abundant active sites. In this work, iron-tetra(4-carboxyphenyl)porphyrin-coordinated assembly metal-organic framework (Fe-TCPP MOF material) capable of effectively catalyzing the oxidation of DA was synthesized. Subsequently, it was combined with reduced graphene oxide (rGO) with excellent electrical conductivity and perfluorosulfonic acid polymer (Nafion) with cation selectivity to construct an electrochemical sensor that could synergistically enhance the sensitivity of DA detection. The resulting Fe-TCPP/rGO/Nafion electrode detected DA from 0.1 to 3200μM with a detection limit of 0.021μM, outperforming most reported sensors. It also maintained high stability, selectivity, and interference resistance over repeated cycles, and achieved recoveries of 84.84-110.76% in real samples. Mechanistically, the porous Fe-TCPP MOF increased accessibility of catalytic sites; rGO improved charge transport and π-π adsorption; and Nafion provided cation-exchange selectivity and electrostatic preconcentration. These complementary roles yielded synergistic gains in catalytic oxidation, preconcentration, selectivity, and anti-interference. The integrated strategy offered a practical route to high-performance MOF-based DA sensors and a useful reference for developing efficient analytical materials.

The continual emergence of novel synthetic cathinones poses significant public health concerns due to their unpredictable pharmacological profiles and potential for abuse. Among these, 4-F-3-Me-α-PVP-a newly identified analogue of α-PVP-has recently surfaced on the illicit drug market, yet its biological effects remain uncharacterized. To provide the first comprehensive pharmacological evaluation of 4-F-3-Me-α-PVP. In vitro transporter inhibition was assessed using HEK293 cells expressing human dopamine (DA), norepinephrine, and serotonin transporter (DAT, NET, or SERT). In male rodents, locomotor activity was measured after i.p. (mice) or s.c. (rats) administration. In vivo microdialysis in rats quantified extracellular DA in the nucleus accumbens. Rewarding and reinforcing effects were evaluated using conditioned place preference (CPP) in mice and intravenous self-administration (IVSA) in rats under fixed-ratio and progressive-ratio schedules. In vitro assays revealed that 4-F-3-Me-α-PVP acts as a potent DAT and NET inhibitor, with additional, though weaker, activity at SERT. In vivo, 4-F-3-Me-α-PVP significantly increased locomotor activity in male rodents (10 and 30 mg/kg in mice; 3 mg/kg in rats). Importantly, 4-F-3-Me-α-PVP also increased extracellular DA levels in the rat nucleus accumbens (3 mg/kg, s.c.), pointing to its potential for abuse. Behavioral assays further demonstrated rewarding and reinforcing effects in rodents, with significant CPP in mice at all doses tested and dose-dependent IVSA in rats observed under both fixed-ratio and progressive-ratio schedules. Collectively, these findings indicate that 4-F-3-Me-α-PVP possesses substantial psychostimulant and abuse-related effects in rodents, underscoring the need for regulatory vigilance and continued investigation into emerging synthetic cathinones.

Dopamine (DA), a neurotransmitter released by the hypothalamus, plays a significant role in maintaining mental well-being. Abnormal DA level leads to neurological disorders such as depression and schizophrenia. Consequently, DA is commonly monitored in urine using various analytical methods as a non‑invasive approach for assessing its physiological status. The available methods for DA detection are laborious and time-consuming. To circumvent this issue, we developed a Quantum dot-based enzyme biosensor for the rapid, sensitive detection of DA. Fluorescence quenching of QDs was in proportion with the DA concentration and was found to be linear with an R2 = 0.99, with p < 0.05. The biosensor used to detect DA in urine samples in the range of 1.2 µM-8 µM, with R² = 0.97 and p < 0.05, and a limit of detection (LOD) of 1.2 µM in a urine sample (1:100). Spiking and recovery analysis in urine showed 94-98% recovery with p < 0.05. The developed method showed specificity towards detecting DA in the presence of common interfering factors such as uric acid and ascorbic acid. The results show that dopamine-specific quenching is consistent and concentration-dependent, effectively distinguishing the target from background components in complex samples. This approach provides a promising platform for reliable DA monitoring in clinical diagnostics.

Dopamine (DA) in the central nervous system is considered a master regulator of mobility performance and vigor, but its mechanistic relationship with skeletal muscle energetics is unclear. We tested the cross-sectional association of striatal DA and skeletal muscle mitochondrial function in 146 older adults participating in the Study of Muscle, Mobility and Aging (75.4 years old, 54% women). Striatal DA was measured using (+)-a-[11C] dihydrotetrabenazine (DTBZ) PET imaging for the limbic, sensorimotor, and executive control subregions. Mitochondrial capacity to produce ATP (ATPmax, mM ATP/s) was measured in vivo using 31P magnetic resonance spectroscopy after repeated voluntary muscle contractions. Ex-vivo respirometry assays from biopsies of resting muscle captured complementary aspects of mitochondrial function under optimal conditions. In multivariable linear regression models, [11C]DTBZ in the limbic striatum, but not other subregions, was positively associated with greater ATPmax in vivo, independent of demographics, muscle volume, leg power, white matter hyperintensities, gray matter atrophy, moderate-to-vigorous physical activity and diabetes (β = 0.275, standard error 0.108, p = .019). [11C]DTBZ was not associated with the ex-vivo mitochondrial respiration markers (p > .2). The role of striatal limbic DA and the energetic capacity of skeletal muscles should be further investigated in older adults.

Osteoarthritis (OA) is driven by a vicious cycle of inflammation and reactive oxygen species (ROS). While cobalt-based metal-organic framework (MOF) nanozymes are potent catalase (CAT) mimics, their therapeutic efficacy is crippled by an inherently weak superoxide dismutase (SOD)-like activity that prevents full-chain ROS scavenging. Here, we resolve this imbalance through an innovative "pre-embedding/activation" strategy. This approach involves pre-embedding Zn2+ into a cobalt-based framework to create a stable yet activatable precursor. The subsequent dopamine (DA)-driven "activation" then remodels the latent Zn/Co-N coordination sites, unlocking an efficient SOD-to-CAT catalytic relay by synergistically amplifying the SOD-like activity for seamless elimination of the entire ROS cascade. This powerful scavenging capability restores mitochondrial function and reprograms macrophages toward an anti-inflammatory M2 phenotype by inhibiting the ROS-mediated S100A8/NF-κB signaling axis and its destructive positive feedback loop. The resulting immunomodulation translates to profound therapeutic outcomes in a rat OA model, where it simultaneously promotes chondrocyte anabolism to achieve significant cartilage repair while suppressing peripheral nerve sensitization to provide sustained pain relief. Our work thus establishes nanoscale interfacial reconstruction as a powerful and rational platform for engineering sophisticated catalytic relays within nanozymes for advanced biomedical applications.

Tralopyril is an emerging antifouling biocide widely used in hull coatings. However, tralopyril is neurotoxic and a potential olfactory toxicant. Additionally, it is not easily biodegradable and poses a threat to nontarget aquatic organisms. In this study, marine medaka were exposed to environmentally relevant concentrations of tralopyril from the embryonic stage for 180 days. Olfactory behavior was assessed, and histopathological damage to the olfactory epithelium, olfactory bulb, and brain was observed. The results showed impaired olfactory behavior, thickening of the olfactory epithelium, and an increase in damaged cells and tissue vacuolation in both the olfactory bulb and brain. Measurement of cAMP levels, ion channel protein activity, and related gene expression in the olfactory epithelium indicated disruption of the olfactory signal transduction pathway. Further proteomic analysis of the brain revealed abnormalities in the complement and coagulation cascades, with a significant inhibition of the complement alternative pathway. Brain neurotransmitter-targeted metabolomics showed abnormalities in dopamine synthesis and metabolism, with a significant reduction in dopamine content. ELISA analysis also confirmed decreased C3 and dopamine levels in the olfactory epithelium. Finally, supplementation with exogenous LPS partially restored olfactory function, suggesting that the complement alternative pathway and dopamine synthesis/metabolism are potential mechanisms underlying tralopyril-induced olfactory toxicity.

Dopamine (DA) homeostasis is crucial for several relevant body functions, including cognition. Diabetes mellitus (DM) is characterized by both cognitive decline and dopaminergic dysfunction. Methylglyoxal (MGO), a reactive neurotoxic dicarbonyl, which accumulates in DM, induces dopaminergic dysfunction, contributing to DA depletion, and is associated with cognitive deficit. However, the molecular mechanisms underlying MGO impact on dopaminergic function are still unknown. This study aims to clarify how MGO damages the dopaminergic system, analyzing the contribution of miRNAs in its deleterious effect in SH-SY5Y cells. We found that treatment with MGO significantly reduces the intracellular DA content, increasing the expression of proteins known to negatively affect DA amount, such as COMT (Catechol-O-methyltransferase), MAO (Monoamine oxidase), and α-Syn (α-synuclein), encoded by the SNCA gene. This was paralleled by a significant reduction in the expression of miR-190a and miR-214, known to be regulated by MGO in other cellular models. We found, by TARGETSCAN analysis, that these two miRNAs are predicted regulators of COMT and SNCA. Gain- and loss-of-function experiments highlighted that these miRNAs are able to modulate the expression of these proteins. We also showed that COMT is a direct target of both miR-190a and miR-214, while SNCA is a direct target of miR-190a and an indirect target for miR-214. Importantly, the transfection of miR-190a and miR-214 specific mimics reverted MGO effects on COMT and α-Syn expression and restored DA intracellular content. Thus, these miRNAs could represent innovative pharmacological targets for the treatment of DM-associated dopaminergic dysfunction and cognitive decline.

Transcriptomics provides mechanistic insights into chemical toxicity and serves as a hypothesis-generating tool for prioritizing potential adverse outcomes. Here, we introduced a transcriptomics-guided outcome prediction (T-GOP) framework, a hypothesis-informed approach that uses transcriptomic enrichment to prioritize end points for targeted experimental validation. As a case study, the ecotoxicological effects of the PFOS alternative, sodium p-perfluorous nonenoxybenzenesulfonate (OBS), were evaluated. After 28 days of exposure to environmentally relevant OBS concentrations (0.1, 1.0, and 10 μg/L), adult zebrafish accumulated OBS in the brain (363-2364 μg/kg), triggering extensive transcriptional reprogramming with 61, 134, and 1026 differentially expressed genes at the respective exposure levels. Transcriptomic analysis implicated disruption of neurotransmitter pathways, which was confirmed by targeted metabolomics, revealing profound alterations in dopaminergic and serotonergic systems. These neurochemical perturbations coincided with concentration-dependent downregulation of essential neuronal genes (e.g., bdnf, syn2a, and elavl3), increased acetylcholinesterase (AChE) activity, and brain histopathological changes. At the highest concentration, T-maze assays revealed increased memory latency, consistent with cognitive impairment as an apical outcome of the observed upstream perturbations. Benchmark concentration modeling indicated neurotoxic responses with BMC10 values ranging from 0.03 to 8.97 μg/L, with corresponding 95% credible intervals (BMCL10-BMCU10) of 0.01-20.04 μg/L. Overall, this proof-of-concept framework provides evidence for the neurotoxicity of OBS and highlights its potential environmental risk.