In most fish and tetrapods, regulation of cardiovascular system is traditionally attributed to the actions of the sympathetic and parasympathetic nervous systems on the heart and vasculature. Beyond the classic neurotransmitters (adrenaline, noradrenaline, and dopamine), the vascular endothelium can synthesize newly discovered catecholamines that modulate vascular tone and cardiac function independently of neuronal release, but their cardiorespiratory effects in fish remain unknown. Therefore, we characterized the cardiorespiratory responses of conscious rainbow trout (Oncorhynchus mykiss; n=18) to ultra-low doses (100 fmol/kg to 10nmol/kg) of 6-nitrodopamine (6-ND), 6-cyanodopamine (6-CYD), and 6-nitroadrenaline (6-NADR), comparing them to classical catecholamines (dopamine and adrenaline; 10nmol/kg). The order of injection was randomized. Then, α₁-adrenoceptor blockade with prazosin (2.38μmol/kg) was performed and a single 10nmol/kg bolus challenge of the newly discovered catecholamine, adrenaline and dopamine in a random order. Fish were instrumented with a dorsal aortic catheter to allow bolus drug administration and measurement of mean arterial pressure and heart rate, as well as a buccal cannula to monitor ventilatory rate and amplitude. All three newly discovered catecholamines induced hypertension and concomitant bradycardia, with significant effects even at the lowest doses. Prazosin abolished bradycardia to 6-NADR, as well as the effects of adrenaline. In contrast, the hypertensive and bradycardic responses to 6-ND, 6-CYD, and dopamine were unaffected. None of the catecholamines affected ventilation. We provide new in vivo evidence that ultra-low doses of 6-substituted catecholamines elevate arterial pressure and trigger bradycardia via α₁-adrenoceptor independent mechanisms, suggesting alternative vascular pathways and a potential physiological role in fish.

Timing Matters: Leveraging Positron Emission Tomography Imaging and Hormonal Cycles for Precision Psychiatry in Female Mental Health.

Multiplexed neurochemical monitoring reveals glutamate modulates dopamine neurotransmission in the nucleus accumbens.

Purinergic modulation of neurotransmission is a primary strategy employed in rapid neuroprotection during and after ischemic stroke. While the contributions of adenosine and ATP to the purinome are well-documented, guanosine-based regulatory activity has remained under-investigated. In the ischemia-vulnerable CA1 region of the hippocampus, dopamine serves as both a neurotransmitter involved in long-term potentiation during memory acquisition and as a regulator focused on modulating glutamate activity. Dopamine has been suggested as a potential protective force against glutamate-induced excitotoxicity in early ischemia. Here, we investigate changes in dopamine signaling during ischemia and demonstrate that guanosine administration during injury has an immediate protective effect. We observe rapid suppression of dopamine release following ischemic insult that is completely restored with administration of a low micromolar dose of guanosine. Changes in dopamine signaling and short-term mRNA production further suggest that guanosine's rapid regulatory role may be partially achieved through the adenosine A1 and A2a receptors and that it facilitates dopamine reuptake through the dopamine transporter DAT. We present the first evidence that guanosine plays a rapid regulatory role in dopamine neurotransmission and that it may function as a broad facilitator of neurotransmitter reuptake, diversifying our understanding of the purinome in ischemia.

In order to achieve pain relief without associated tolerance and dependence risks of general opioids like morphine, researchers have designed AT121 as potent safe alternative. In this study, we evaluated the analgesic and neurochemistry effects of AT121, a bifunctional partial agonist at Mu and nociceptin/orphanin FQ peptide (NOP) receptors, compared to morphine in hippocampal neurons for the measurement of dopamine neurotransmitters concentration and action potential of cortical neurons isolated from newborn BALB/c mice. This helps us to predict and assess its success in vivo by detecting the effect of AT121 in vitro. This activates G0/Gi protein pathways while blocking the β-arrestin pathway, significantly delayed action potential generation, prolonged spike duration, and reduced amplitude, without altering firing thresholds or inducing tolerance over a two-hour window. In contrast, morphine has produced similar analgesic effects but with a higher risk of tolerance. Co-administration of AT121 and morphine improved these changes, whereas naloxone failed to reverse AT121's effects, suggesting distinct receptor interactions. Dopamine quantification in hippocampal culture media revealed that morphine, alone or combined with AT121, markedly elevated extracellular dopamine, consistent with its reinforcing properties to morphine on analgesia. Notably, AT121 alone led to significantly lower dopamine levels compared to control, indicating a reduced risk of triggering reward-related pathways. Together, these findings highlight AT121 as a promising candidate for both acute and chronic pain management, and suggest its offering potent analgesia with a lower likelihood of tolerance and addiction following chronic opioid exposure.

Dopamine is a key neurotransmitter and neuromodulator that regulates many critical brain functions. Accurate monitoring of its level is essential for neuroscience as well as the diagnosis and treatment of many brain diseases. In this work, we developed a new electrochemical sensor, comprising phosphorus-doped graphitic carbon nitride (P-g-C3N4) and zeolitic imidazolate framework 67 (ZIF-67), for dopamine detection. In this composite electrode material, ZIF-67 provides numerous adsorption and sensing sites, while P-g-C3N4 enhances overall electrical conductivity and stability. Cyclic voltammetry tests reveal the redox behavior of dopamine at the surface of the composite electrode across various pH values and scan rates. Using differential pulse voltammetry, the sensitivity and selectivity of this dopamine sensor were assessed, identifying a limit of detection of 0.39 nM. Further successful quantification of dopamine in urine samples suggests the potential practical use of this new composite electrochemical sensor for detecting dopamine and/or other neurotransmitters.

Synaptic zinc (Zn2+) modulates dopamine and glutamate neurotransmission by binding to the dopamine transporter and glutamate receptors. Among other neurotransmitters, dopamine and glutamate critically regulate physiological processes and behaviors relevant to substance use disorders (SUDs) and addiction. In addition, Zn2+ interacts with inhibitory neurotransmitter systems, including GABA and glycine receptors, further influencing the excitatory-inhibitory balance within circuits relevant to addiction. Nevertheless, the specific involvement of synaptic Zn2+ in such processes is unknown. We propose that synaptic Zn2+ serves as an environmentally derived factor that can influence the vulnerability to and development of SUDs and addiction via its interaction with proteins that regulate dopamine and glutamate neurotransmission in addiction-relevant brain circuits.

Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy also induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal and addiction1-7. Strategies to limit adverse effects traditionally include developing MOR agonists that have low intrinsic efficacy or that preferentially activate G-protein signalling over β-arrestin signalling8. Here we identify a novel MOR agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes. DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signalling profile, and diminished efficacy at the MOR-galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance or MOR downregulation after repeated exposure. Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents.

Dual Stress Postischemia Deprivation Depression via Metabolic Disturbance in Rodents.

Organic cation transporters 1-3 (OCTs 1-3), especially OCT3, have emerged as "high-capacity" uptake transporters for the aminergic neurotransmitters serotonin, norepinephrine, and dopamine from the synapse. We previously reported the 6- and 7-chloro analogs of 2-aminodihydroquinazoline (i.e., A6CDQ and A7CDQ, respectively) as novel inhibitors of OCTs. Here, we synthesized and evaluated a focused series of analogs bearing substituents at the aryl 5-, 6-, 7-, or 8-position. All compounds inhibited action at OCT1, OCT2, and especially OCT3. The present study centered primarily on OCT3 because it has been implicated in the action of antidepressants. Through this work, seven analogs were found to be more potent, or at least equipotent, at OCT3 than A6CDQ or A7CDQ. Additionally, three analogs were found, as with A6CDQ and A7CDQ, to be active in the mouse tail suspension test - a well-established proxy for evaluating potential antidepressant-like action. Our 3D molecular modeling studies identified SER474, ASP478, and CYS477 as key residues in the binding interactions of the 2-aminodihydroquinazoline (ADQ) chemotype at OCT3. Furthermore, the binding mode of ADQ analogs and the extensive size of the binding pocket warrant further examination of the scaffold, and particularly of additional aryl substituents to exploit this region of bulk tolerance.

BackgroundExcessive alcohol consumption is a global health issue and a leading cause of disease, disability, and mortality. This study aimed to determine the effects of a 24-hour ethanol exposure, post-exposure withdrawal (cessation of alcohol intake), and post-exposure withdrawal relief on the sensorimotor performance of the nematode Caenorhabditis elegans.MethodsA modified kinetic chemotaxis assay (commonly referred as “diacetyl race”) was conducted with worm populations subjected to three different doses of ethanol pre-exposure to assess the impact of ethanol on locomotion. Additionally, we employed lifespan, mobility, gene expression analysis and imaging assays to evaluate health status and molecular alterations occurring in the worms under different levels of ethanol exposure.ResultsWild-type, dopamine receptor mutant and serotonin biosynthesis null mutant worms presented different responses to ethanol in the kinetic chemotaxis assay. Furthermore, exposure to ethanol altered vesicle exocytosis in dopaminergic and serotonergic neurons and the expression of a panel of genes associated with stress responses. Additionally, 24-hour ethanol exposure differentially influenced the lifespan of wild-type and mutant worms.ConclusionsDifferent responses, which may be relevant to the pathogenesis of human alcohol use disorder, were observed in wild-type worms, a dopamine receptor mutant, and a serotonin biosynthesis null mutant in a variety of assays performed. Furthermore, we present a 3-step experimental model for drug tolerance, based on the well-established kinetic chemotaxis behavioral paradigm (“diacetyl race”). This model provides new insights into the effects of alcohol in worms, particularly regarding the roles of dopamine and serotonin neurotransmission. Importantly, this model holds potential for investigating the effects of other addictive substances beyond alcohol.

Objective: Our research will investigate the potential of anti-depressant effect of fermented Dacus carota (Carrrot) Kanji by using of various behavioral models like Forced Swim Test (FST), Tail Suspension Test (TST), We will also investigate brain neurotransmitter levels, including serotonin, and dopamine. Materials and Methods: Preparation of Carrot Kanji - The fermented carrot kanji was prepared using Daucus carota (carrot), water, salt, and mustard seeds The mixture was transferred into a clean, airtight container to maintain the integrity of the fermentation process. Experimental Animals: In this study, a total of 30 animals (adult male mice 25-30g; 6 animals per group) were used to assess the effects of Kanji and an antidepressant. These animals were housed in standard laboratory conditions with a 12-hour light/dark cycle, and they were provided with food and water ad libitum. Results and Discussion: The results of the behavioral and biochemical analyses demonstrated that Kanji, particularly at higher doses, exhibited antidepressant-like and anxiolytic-like effects, similar to the widely used antidepressant Fluoxetine. The Forced Swim Test (FST) and Tail Suspension Test (TST) both revealed significant reductions in immobility and increases in active behaviors with the higher doses of Kanji, suggesting its potential as a natural alternative for treating depressive-like disorders. Summary and Conclusion: The results from this study suggest that Kanji, particularly at higher doses, exhibits significant antidepressant-like and anxiolytic-like effects, comparable to the widely used antidepressant Fluoxetine. The behavioral tests such as the Forced Swim Test (FST), Tail Suspension Test (TST), demonstrated that Kanji effectively reduced immobility time and promoted active coping behaviors, suggesting potential therapeutic benefits for treating depressive-like and anxiety-like symptoms.

ABSTRACTTyrosine hydroxylase deficiency (THD) is a rare genetic disorder caused by biallelic pathogenic variants in the Th gene, leading to a deficiency in the rate‐limiting enzyme for the synthesis of dopamine (DA) and other catecholamine neurotransmitters. THD is associated with dystonia and infantile parkinsonism with a broad and complex spectrum and variable response to l‐Dopa therapy. TH1‐p.R202H is a frequent THD variant that affects TH stability and activity. The Th knock‐in (Th‐ki) mice with the equivalent mutation (Th‐p.R203H) present reduced TH and DA levels, biological and molecular alterations, different phosphorylation patterns and altered distribution of dopaminergic markers relative to wild‐type mice. Th‐ki mice displayed significantly reduced TH, especially in the striatum, but also in the cortex, olfactory bulb, cerebellum, substantia nigra, globus pallidus, and spinal cord, a decrease that is not associated with dopaminergic neuronal degeneration. No changes were observed in Th‐mRNA expression, and the decreased level of TH in the concrete brain areas in Th‐ki mice appears to be due to defective TH protein axonal transport. Moreover, we characterized the development of dopaminergic neurons in the substantia nigra and neuronal plasticity in various brain regions. Our results indicated that alterations in TH expression within specific striatal GABAergic interneurons due to TH deficiency may potentially disrupt the balance of inhibitory neurotransmission in the striatum. Overall, our findings demonstrate that TH deficiency disrupts striatal inhibitory circuitry and triggers compensatory neuronal plasticity, without causing neuronal degeneration.

Increased responsivity to pharmacological manipulations of dopamine D1 receptors in binge eating prone rats.

To research the therapeutic effect and compatibility mechanism of Astragali Radix-Safflower (ARSA) main effective parts in cerebral ischemia/reperfusion injury (CI/RI), especially pharmacokinetics and pharmacodynamics study. Nine formulas of three main effective parts (total flavonoids of Astragali Radix, total saponins of Astragali Radix and safflower yellow pigment) of ARSA were formulated according to L9 (34) orthogonal design. The sample collection was performed via blood-brain dual-channel microdialysis, combined with LC-MS/MS to quantify six components (hydroxysafflor yellow A, astragaloside IV, calycosin-7-O-β-D-glucopyranoside, ononin, calycosin, and formononetin) of ARSA and five neurotransmitters (aspartic acid, 5-hydroxytryptamine, γ-aminobutyric acid, dopamine, and glutamate) associated with CI/RI. The entropy weight method and the partial least square method were applied to analyze data. The best compatibility prescription of the main effective parts of ARSA was total flavonoids of Astragali Radix 600 mg/kg, total saponins of Astragali Radix 140 mg/kg, and safflower yellow pigment 840 mg/kg, which had a better therapeutic effect and the largest total area under the curve than other formulas. Undergoing CI/RI, glutamate was primarily regulated among the five neurotransmitters, and the components with the greater impact on neurotransmitter modulation were hydroxysafflor yellow A and astragaloside IV. The different compatibility of effective parts of traditional Chinese medicine would influence the pharmacokinetics parameters of each active component in CI/RI rats. Orthogonal compatibility and total statistical moment method provided a way to find the best compatibility. This study provided a pattern for the exploration of traditional Chinese medicine compatibility.

Synaptic aging is a core manifestation of brain aging arising from the convergence of fundamental biological aging processes, including genomic instability, loss of proteostasis, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation. As highly energy-dependent and protein-rich sites of neuronal communication, synapses are particularly vulnerable to age-associated molecular stress. Accumulating evidence indicates that age-related impairments in synaptic vesicle trafficking, recycling, and neurotransmitter homeostasis precede neuronal loss and represent early drivers of cognitive decline and neurodegeneration. Disruption of vesicle dynamics compromises neurotransmitter release, synaptic plasticity, and circuit stability, thereby accelerating synaptic failure. Dysregulation of key neurotransmitter systems, including acetylcholine, dopamine, glutamate, and γ-aminobutyric acid, further exacerbates synaptic dysfunction and cognitive impairment. These changes are driven by interconnected aging mechanisms, wherein impaired proteostasis promotes the accumulation of dysfunctional synaptic proteins, mitochondrial dysfunction limits ATP availability for vesicle mobilisation, and persistent neuroinflammation heightens synaptic vulnerability. Emerging evidence also implicates age-related blood-brain barrier disruption and gut-brain axis dysregulation as additional modulators of synaptic integrity via immune, metabolic, and neurochemical pathways. This review synthesises recent advances in understanding the molecular mechanisms of synaptic aging, with a focus on vesicle dynamics and neurotransmitter imbalance, and discusses therapeutic strategies aimed at enhancing synaptic resilience to promote healthy brain aging.

Ketamine, a substance used for anesthesia and known for inducing dissociation, can lead to addiction and the development of severe withdrawal symptoms. Ketamine alters brain networks before affecting somesthetic sensation. Ketamine abuse was especially prevalent in East and Southeast Asia, and its popularity has continued to expand globally in recent decades. Ketamine is gaining popularity in the public and private sectors as a cheaper off-label depression treatment. Unfortunately, ketamine may cause side effects, such as heart and blood vessel instability, respiratory depression, liver injury, hallucinations, etc. The pain-relieving and mental effects of ketamine might induce reliance; thus, it should be used cautiously. This review highlights the neurobiological processes underpinnings of ketamine's addictive potential, withdrawal, and its effects on brain networks like the prefrontal cortex, hippocampus, and mesolimbic pathway, which play vital roles in decision-making, memory, and reward processing. In addition, the involvement of neurotransmitter systems, specifically glutamate and dopamine, in mediating the addictive properties of ketamine and the neuroadaptive changes that occurred during withdrawal are also discussed. It also explains that low-dose ketamine can alter the secretion of stress hormone cortisol and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, possibly attributed to the current repurposing study of ketamine as a fast-acting antidepressant. Understanding these pathways is essential for developing effective ketamine addiction treatments, managing withdrawal symptoms, and possibly reversing brain changes for the betterment of human health and psychological well- being.

Study of neurotransmitter dopamine interaction with DNA by electrochemical and spectroscopic methods.

For memories to remain relevant and adaptive over the lifespan, modifications under specific conditions are required. Memory reconsolidation theory suggests that when a memory is reactivated, it can become labile, a state known as destabilization. This process is regulated by complex and dynamic neurobiological changes representing biological boundary conditions, which likely protect important memories from undergoing unnecessary or potentially maladaptive modifications. External cues, such as prediction error or other forms of salient novel information, can promote destabilization of these resistant memory traces. Accordingly, various neurobiological mechanisms related to the signaling of prediction errors and salient novelty have been implicated in overcoming boundary conditions, permitting memory modification. Here, we review the existing literature regarding the mechanisms for overcoming biological boundary conditions, with specific focus on the role of the neurotransmitter dopamine and its well documented functions related to prediction error, novelty detection, and memory reconsolidation. We aim to describe the nuanced role of dopamine in these processes as it pertains to destabilizing modification-resistant memories, highlight potential interactions with alternate neurotransmitter systems for this process, and bridge findings from reward learning and novelty processing to convey a holistic view of dopamine's role in memory reconsolidation more broadly.

Therapeutic potential of SSZ in modulating Alzheimer’s disease pathology: A multi-targeted experimental approach