Search

Introduction: Colistin (CMS) is used for the curation of infections caused by multidrug-resistant bacteria. CMS is constrained by toxicity, particularly in kidney and neuronal cells. The recommended human doses are 2.5–5 mg/kg/day, and the toxicity is linked to higher doses. So far, the in vivo toxicity studies have used doses even 10-fold higher than human doses. It is essential to investigate the impact of metabolic response of doses, that are comparable to human doses, to identify biomarkers of latent toxicity. The innovation of the current study is the in vivo stimulation of CMS's impact using a range of CMS doses that have never been investigated before, i.e., 1 and 1.5 mg/kg. The 1 and 1.5 mg/kg, administered in mice, correspond to the therapeutic and toxic human doses, based on previous expertise of our team, regarding the human exposure. The study mainly focused on the biochemical impact of CMS on the metabolome, and on the alterations provoked by 50%-fold of dose increase. The main objectives were i) the comprehension of the biochemical changes resulting after CMS administration and ii) from its dose increase; and iii) the determination of dose-related metabolites that could be considered as toxicity monitoring biomarkers.Methods: The in vivo experiment employed two doses of CMS versus a control group treated with normal saline, and samples of plasma, kidney, and liver were analysed with a UPLC-MS-based metabolomics protocol. Both univariate and multivariate statistical approaches (PCA, OPLS-DA, PLS regression, ROC) and pathway analysis were combined for the data interpretation.Results: The results pointed out six dose-responding metabolites (PAA, DA4S, 2,8-DHA, etc.), dysregulation of renal dopamine, and extended perturbations in renal purine metabolism. Also, the study determined altered levels of liver suberylglycine, a metabolite linked to hepatic steatosis. One of the most intriguing findings was the detection of elevated levels of renal xanthine and uric acid, that act as AChE activators, leading to the rapid degradation of acetylcholine. This evidence provides a naïve hypothesis, for the potential association between the CMS induced nephrotoxicity and CMS induced 39 neurotoxicity, that should be further investigated.

Dopamine has effects on the mammalian heart. These effects can include an increase in the force of contraction, and an elevation of the beating rate and the constriction of coronary arteries. Depending on the species studied, positive inotropic effects were strong, very modest, or absent, or even negative inotropic effects occurred. We can discern five dopamine receptors. In addition, the signal transduction by dopamine receptors and the regulation of the expression of cardiac dopamine receptors will be of interest to us, because this might be a tempting area of drug development. Dopamine acts in a species-dependent fashion on these cardiac dopamine receptors, but also on cardiac adrenergic receptors. We will discuss the utility of drugs that are currently available as tools to understand cardiac dopamine receptors. The molecule dopamine itself is present in the mammalian heart. Therefore, cardiac dopamine might act as an autocrine or paracrine compound in the mammalian heart. Dopamine itself might cause cardiac diseases. Moreover, the cardiac function of dopamine and the expression of dopamine receptors in the heart can be altered in diseases such as sepsis. Various drugs for cardiac and non-cardiac diseases are currently in the clinic that are, at least in part, agonists or antagonists at dopamine receptors. We define the research needs in order to understand dopamine receptors in the heart better. All in all, an update on the role of dopamine receptors in the human heart appears to be clinically relevant, and is thus presented here. [ABSTRACT FROM AUTHOR]

The use of clinical psychoactive drugs often poses unpredictable threats to fetal development. Catechol-O-methyltransferase (COMT) is a key enzyme that regulates dopamine metabolism and a promising target for modulation of cognitive functions. Opicapone, a newly effective third-generation peripheral COMT inhibitor, is used for the treatment of Parkinson's disease (PD) and possibly to improve other dopamine-related disorders such as alcohol use disorder (AUD) and obsessive-compulsive disorder (OCD). The widespread use of opicapone will inevitably lead to biological exposure and damage to the human body, such as affecting fetal development. However, the effect of opicapone on embryonic development remains unknown. Here, zebrafish larvae were used as an animal model and demonstrated that a high concentration (30 μM) of opicapone exposure was teratogenic and lethal, while a low concentration also caused developmental delay such as a shortened body size, a smaller head, and reduced locomotor behaviors in zebrafish larvae. Meanwhile, opicapone treatment specifically increased the level of dopamine (DA) in zebrafish larvae. The depletion response of the total glutathione level (including oxidized and reduced forms of glutathione) and changed antioxidant enzymes activities in zebrafish larvae suggest oxidative damage caused by opicapone. In addition, enhanced glutathione metabolism and cytokine-cytokine receptor interaction were found in zebrafish larvae treated with opicapone, indicating that opicapone treatment caused an oxidation process and immune responses. Our results provide a new insight into the significant developmental toxicity of opicapone in zebrafish larvae.

Sex differences have been reported in methamphetamine (METH) use disorder in humans and in animal models of METH exposure. Specifically, animals that self-administer METH show sex-related dissimilarities in dopamine (DA) metabolism. To better understand the molecular bases for the differences in DA metabolism, we measured the levels of mRNAs of enzymes that catalyze DA synthesis and breakdown in the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and hippocampus (HIP) of rats that had self-administered METH. There were significant sex differences in control rats, with males having higher basal levels of Th in the PFC and dSTR, Ddc in the NAc, and MaoB in the HIP. In contrast, female controls showed higher basal levels of Comt in the HIP. Male and female METH SA rats also showed some distinct responses to the drug. Specifically, female METH rats exhibited increased expression of Ddc and MaoB, whereas male METH animals showed higher levels of Comt mRNA in the PFC compared to their respective controls. In the NAc, male METH rats displayed decreased Th and Ddc mRNA levels. Together, our results identified sex-dependent and region-specific changes in the mRNA expression of several enzymes involved in DA synthesis and breakdown in response to METH SA, with the majority of differences being observed in the mesocorticolimbic dopaminergic system. These findings are of significant translational importance providing further support for the inclusion of sex as an important variable when planning and evaluating therapeutic interventions against METH use disorder in human clinical studies. [ABSTRACT FROM AUTHOR]

Lately, studies have shown that patients with Parkinson's disease (PD) report a strong craving for sweets and consume significantly more fast-acting carbohydrates than healthy controls. Consuming food with a high-sugar content is assumed to lead to an increase in insulin concentration, which could positively influence dopamine concentration in the brain and unconsciously be used by patients as kind of "self-medication" to compensate for a lack of dopamine in PD. On the other hand, high-sugar intake could also lead to insulin resistance and diabetes, which is discussed as a causative factor for progressive neurodegeneration in PD. In this critical appraisal, we discuss the role of sugar intake and insulin on dopamine metabolism in patients with PD and how this could influence the potential neurodegeneration mediated by insulin resistance. [ABSTRACT FROM AUTHOR]

Adolescent stress (AS) has been associated with higher vulnerability to psychiatric disorders such as schizophrenia, depression, or drug dependence. Moreover, the alteration of brain catecholamine (CAT) transmission in the medial prefrontal cortex (mPFC) has been found to play a major role in the etiology of psychiatric disturbances. We investigated the effect of adolescent stress on CAT transmission in the mPFC of freely moving adult rats because of the importance of this area in the etiology of psychiatric disorders, and because CAT transmission is the target of a relevant group of drugs used in the therapy of depression and psychosis. We assessed basal dopamine (DA) and norepinephrine (NE) extracellular concentrations (output) by brain microdialysis in in the mPFC of adult rats that were exposed to chronic mild stress in adolescence. To ascertain the role of an altered release or reuptake, we stimulated DA and NE output by administering either different doses of amphetamine (0.5 and 1.0 mg / kg s.c.), which by a complex mechanism determines a dose dependent increase in the CAT output, or reboxetine (10 mg/kg i.p.), a selective NE reuptake inhibitor. The results showed the following: (i) basal DA output in AS rats was lower than in controls, while no difference in basal NE output was observed; (ii) amphetamine, dose dependently, stimulated DA and NE output to a greater extent in AS rats than in controls; (iii) reboxetine stimulated NE output to a greater extent in AS rats than in controls, while no difference in stimulated DA output was observed between the two groups. These results show that AS determines enduring effects on DA and NE transmission in the mPFC and might lead to the occurrence of psychiatric disorders or increase the vulnerability to drug addiction., Competing Interests: Declaration of competing interest On the behave of all authors I declare that all authors have no conflict of interest or any financial and personal relationships with other people or organizations that could inappropriately influence (bias) our work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

DARPP-32 (dopamine and cAMP-regulated phosphoprotein Mr. 32 kDa) is a phosphoprotein that is modulated by multiple receptors integrating intracellular pathways and playing roles in various physiological functions. It is regulated by dopaminergic receptors through the cAMP/protein kinase A (PKA) pathway, which modulates the phosphorylation of threonine 34 (Thr34). When phosphorylated at Thr34, DARPP-32 becomes a potent protein phosphatase-1 (PP1) inhibitor. Since dopamine is involved in the development of GABAergic neurons and DARPP-32 is expressed in the developing brain, it is possible that DARPP-32 has a role in GABAergic neuronal development. We cloned the zebrafish darpp-32 gene (ppp1r1b) gene and observed that it is evolutionarily conserved in its inhibitory domain (Thr34 and surrounding residues) and the docking motif (residues 7-11 (KKIQF)). We also characterized darpp-32 protein expression throughout the 5 days post-fertilization (dpf) zebrafish larval brain by immunofluorescence and demonstrated that darpp-32 is mainly expressed in regions that receive dopaminergic projections (pallium, subpallium, preoptic region, and hypothalamus). We demonstrated that dopamine acutely suppressed darpp-32 activity by reducing the levels of p-darpp-32 in the 5dpf zebrafish larval brain. In addition, the knockdown of darpp-32 resulted in a decrease in the number of GABAergic neurons in the subpallium of the 5dpf larval brain, with a concomitant increase in the number of DAergic neurons. Finally, we demonstrated that darpp-32 downregulation during development reduced the motor behavior of 5dpf zebrafish larvae. Thus, our observations suggest that darpp-32 is an evolutionarily conserved regulator of dopamine receptor signaling and is required for the formation of GABAergic neurons in the developing telencephalon., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Microglial activation contributes to the neuropathology of Parkinson's disease (PD). Inhibiting M1 while simultaneously boosting M2 microglia activation may therefore be a potential treatment for PD. Apilarnil (API) is a bee product produced from drone larvae. Recent research has demonstrated the protective effects of API on multiple body systems. Nevertheless, its impact on PD or the microglial M1/M2 pathway has not yet been investigated. Thus, we intended to evaluate the dose-dependent effects of API in rotenone (ROT)-induced PD rat model and explore the role of M1/M2 in mediating its effect. Seventy-two Wistar rats were equally grouped as; control, API, ROT, and groups in which API (200, 400, and 800 mg/kg, p.o.) was given simultaneously with ROT (2 mg/kg, s.c.) for 28 days. The high dose of API (800 mg/kg) showed enhanced motor function, higher expression of tyrosine hydroxylase and dopamine levels, less dopamine turnover and α-synuclein expression, and a better histopathological picture when compared to the ROT group and the lower two doses. API's high dose exerted its neuroprotective effects through abridging the M1 microglial activity, illustrated in the reduced expression of miR-155, Iba-1, CD36, CXCL10, and other pro-inflammatory markers' levels. Inversely, API high dose enhanced M2 microglial activity, witnessed in the elevated expression of miR-124, CD206, Ym1, Fizz1, arginase-1, and other anti-inflammatory indices, in comparison to the diseased group. To conclude, our study revealed a novel neuroprotective impact for API against experimentally induced PD, where the high dose showed the highest protection via rebalancing M1/M2 polarization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with autoimmune mechanism of development. The investigation of neuroimmune interaction is one of the most developing directions in MS pathogenesis study. Catecholamines are direct mediators of this interaction and can be involved in the pathogenesis of MS by modulating cells of both innate and adaptive immune systems. The aim of this study was to investigate the influence of dopamine and norepinephrine on the ability of monocytes of patients with relapsing-remitting MS, to induce Th17- and Th1-immune response, which play a crucial role in the autoimmunity of the CNS. We found, that both dopamine and norepinephrine modulate the production of Th17- (IL-23, IL-1β, and IL-6) and Th1-promoting (IL-12p70) cytokines by activated peripheral blood mononuclear cells or CD14 + monocytes in patients with MS and in healthy subjects. We also found the inhibitory effect of dopamine and norepinephrine on monocyte-induced production of IL-17 and IFN-γ by autologous CD4 + T-cells in both groups. Finally, the multidirectional role of D 1 - and D 2 -like dopaminergic receptors in the modulatory effect of dopamine on the ability of CD14 + monocytes to activate CD4 + T-cells was established, expanding the potential role of dopamine in the neuroimmune interaction., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glioblastoma is the most aggressive brain cancer with an unfavorable prognosis for patient survival. Glioma stem cells, a subpopulation of cancer cells, drive tumor initiation, self-renewal, and resistance to therapy and, together with the microenvironment, play a crucial role in glioblastoma maintenance and progression. Neurotransmitters such as noradrenaline, dopamine, and serotonin have contrasting effects on glioblastoma development, stimulating or inhibiting its progression depending on the cellular context and through their action on glioma stem cells, perhaps changing the epigenetic landscape. Recent studies have revealed that serotonin and dopamine induce chromatin modifications related to transcriptional plasticity in the mammalian brain and possibly in glioblastoma; however, this topic still needs to be explored because of its potential implications for glioblastoma treatment. Also, it is essential to consider that neurotransmitters' effects depend on the tumor's microenvironment since it can significantly influence the response and behavior of cancer cells. This review examines the possible role of neurotransmitters as regulators of glioblastoma development, focusing on their impact on the chromatin of glioma stem cells., (© 2024. The Author(s).)

Perceptual decisions should depend on sensory evidence. However, such decisions are also influenced by past choices and outcomes. These choice history biases may reflect advantageous strategies to exploit temporal regularities of natural environments. However, it is unclear whether and how observers can adapt their choice history biases to different temporal regularities, to exploit the multitude of temporal correlations that exist in nature. Here, we show that male mice adapt their perceptual choice history biases to different temporal regularities of visual stimuli. This adaptation was slow, evolving over hundreds of trials across several days. It occurred alongside a fast non-adaptive choice history bias, limited to a few trials. Both fast and slow trial history effects are well captured by a normative reinforcement learning algorithm with multi-trial belief states, comprising both current trial sensory and previous trial memory states. We demonstrate that dorsal striatal dopamine tracks predictions of the model and behavior, suggesting that striatal dopamine reports reward predictions associated with adaptive choice history biases. Our results reveal the adaptive nature of perceptual choice history biases and shed light on their underlying computational principles and neural correlates., (© 2024. The Author(s).)

Dopamine is a neurotransmitter in the central nervous system that is essential for many bodily and mental processes, and a lack of it can cause Parkinson's disease. DNA tetrahedral (TD) nanocages are promising in bio-nanotechnology, especially as a nanocarrier. TD is highly programmable, biocompatible, and capable of cell differentiation and proliferation. It also has tissue and blood-brain barrier permeability, making it a powerful tool that could overcome potential barriers in treating neurological disorders. In this study, we used DNA TD as a carrier for dopamine to cells and zebrafish embryos. We investigated the mechanism of complexation between TD and dopamine hydrochloride using gel electrophoresis, fluorescence and circular dichroism (CD) spectroscopy, atomic force microscopy (AFM), and molecular dynamic (MD) simulation tools. Further, we demonstrate that these dopamine-loaded DNA TD nanostructures enhanced cellular uptake and differentiation ability in SH-SY5Y neuroblastoma cells. Furthermore, we extended the study to zebrafish embryos as a model organism to examine survival and uptake. The research provides valuable insights into the complexation mechanism and cellular uptake of dopamine-loaded DNA tetrahedral nanostructures, paving the way for further advancements in nanomedicine for Parkinson's disease and other neurological disorders.

Background: We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer's disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown., Methods: To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted., Results: In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling., Conclusions: Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice., (© 2024. The Author(s).)

Whilst reward pathologies are major and common in stress-related neuropsychiatric disorders, their neurobiology and treatment are poorly understood. Imaging studies in human reward pathology indicate attenuated BOLD activity in nucleus accumbens (NAc) coincident with reward anticipation but not reinforcement; potentially, this is dopamine (DA) related. In mice, chronic social stress (CSS) leads to reduced reward learning and motivation. Here, DA-sensor fibre photometry is used to investigate whether these behavioural deficits co-occur with altered NAc DA activity during reward anticipation and/or reinforcement. In CSS mice relative to controls: (1) Reduced discriminative learning of the sequence, tone-on + appetitive behaviour = tone-on + sucrose reinforcement, co-occurs with attenuated NAc DA activity throughout tone-on and sucrose reinforcement. (2) Reduced motivation during the sequence, operant behaviour = tone-on + sucrose delivery + sucrose reinforcement, co-occurs with attenuated NAc DA activity at tone-on and typical activity at sucrose reinforcement. (3) Reduced motivation during the sequence, operant behaviour = appetitive behaviour + sociosexual reinforcement, co-occurs with typical NAc DA activity at female reinforcement. Therefore, in CSS mice, low NAc DA activity co-occurs with low reward anticipation and could account for deficits in learning and motivation, with important implications for understanding human reward pathology., (© 2024. The Author(s).)

The escalating prevalence of Parkinson's disease (PD) underscores the need for innovative therapeutic interventions since current palliative measures, including the standard l-Dopa formulations, face challenges of tolerance and side effects while failing to address the underlying neurodegenerative processes. Here, we introduce DAD9 , a novel conjugate molecule that aims to combine symptomatic relief with disease-modifying strategies for PD. Crafted through knowledge-guided chemistry, the molecule combines a nonantibiotic doxycycline derivative with dopamine, preserving neuroprotective attributes while maintaining dopaminergic agonism. This compound exhibited no off-target effects on PD-relevant cell functions and sustained antioxidant and anti-inflammatory properties of the tetracycline precursor. Furthermore, it effectively interfered with the formation and seeding of toxic α-synuclein aggregates without producing detrimental oxidative species. In addition, DAD9 was able to activate dopamine receptors, and docking simulations shed light onto the molecular details of this interaction. These findings position DAD9 as a potential neuroprotective dopaminergic agonist, promising advancements in PD therapeutics.

Overexpression of the agouti-signaling protein ( asip1 ), an endogenous melanocortin antagonist, under the control of a constitutive promoter in zebrafish [Tg(Xla.Eef1a1:Cau.Asip1]iim4] ( asip1 -Tg) increases food intake by reducing sensitivity of the central satiety systems and abolish circadian activity rhythms. The phenotype also shows increased linear growth and body weight, yet no enhanced aggressiveness in dyadic fights is observed. In fact, asip1 -Tg animals choose to flee to safer areas rather than face a potential threat, thus suggesting a potential anxiety-like behavior (ALB). Standard behavioral tests, i.e., the open field test (OFT), the novel object test (NOT), and the novel tank dive test (NTDT), were used to investigate thigmotaxis and ALB in male and female zebrafish. Results showed that the asip1 -Tg strain exhibited severe ALB in every test, mainly characterized by pronounced freezing behavior and increased linear and angular swimming velocities. asip1 -Tg animals exhibited low central serotonin (5-HT) and dopamine (DA) levels and high turnover rates, thus suggesting that central monoaminergic pathways might mediate melanocortin antagonist-induced ALB. Accordingly, the treatment of asip1 -Tg animals with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), reversed the ALB phenotype in NTDT as well as 5-HT turnover. Genomic and anatomical data further supported neuronal interaction between melanocortinergic and serotonergic systems. These results suggest that inhibition of the melanocortin system by ubiquitous overexpression of endogenous antagonist has an anxiogenic effect mediated by serotonergic transmission., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Deposition of amyloid-β (Aβ) in the brain can impair neuronal function and contribute to cognitive decline in Alzheimer's disease (AD). Here, we found that dopamine and the dopamine precursor levodopa (also called l-DOPA) induced Aβ degradation in the brain. Chemogenetic approaches in mice revealed that the activation of dopamine release from ventral tegmental area (VTA) neurons increased the abundance and activity of the Aβ-degrading enzyme neprilysin and reduced the amount of Aβ deposits in the prefrontal cortex in a neprilysin-dependent manner. Aged mice had less dopamine and neprilysin in the anterior cortex, a decrease that was accentuated in AD model mice. Treating AD model mice with levodopa reduced Aβ deposition and improved cognitive function. These observations demonstrate that dopamine promotes brain region-specific, neprilysin-dependent degradation of Aβ, suggesting that dopamine-associated strategies have the potential to treat this aspect of AD pathology.

Negative urgency (NU), or the tendency to act rashly when stress of negative affect is high, could be the result of an insufficient control of the ventromedial prefrontal cortex (vmPFC) over the striatum, through an impaired dopamine (DA) transmission. Therefore, we investigated in vivo human stress-induced DA release in the vmPFC, its relation with fronto-striatal functional connectivity (FC), and NU in daily life. In total, 12 female healthy participants performed a simultaneous [18 F]fallypride PET and fMRI scan during which stress was induced. Regions displaying stress-induced DA release were identified and used to investigate stress-induced changes in fronto-striatal FC. Additionally, participants enrolled in an experience sampling study, reporting on daily life stress and rash actions over a 12-month-long period. Mixed models explored whether stress-induced DA release and FC moderated NU in daily life. Stress led to a lower FC between the vmPFC and dorsal striatum, but a higher FC between the vmPFC and contralateral ventral striatum. Participants with a higher FC between the vmPFC and dorsal striatum displayed more NU in daily life. A higher stress-induced DA release in the vmPFC was related to a higher stress-induced change in FC between the vmPFC and striatum. Participants with a higher DA release in the vmPFC displayed more NU in daily life. In conclusion, stress could differentially impact fronto-striatal FC whereby the connectivity with the dorsal striatum is especially important for NU in daily life. This could be mediated by a higher, but not a lower, stress-induced DA release in the vmPFC., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Controlled nigrostriatal dopamine release supports effective limb use during locomotion coordination that becomes compromised after this pathway deteriorates in Parkinson's Disease (PD). How dopamine release relates to active ongoing behavior control remains unknown. Restoring proper release strategy appears important to successful PD treatment with transplanted dopamine-producing stem cells. This is suggested by apparently distinct behavioral support from tonic or phasic release and corresponding requirements of requisite afferent control exhibited by intact nigrostriatal neurons. Our laboratory previously demonstrated that transplanted dopaminergic cells can elicit skilled movement recovery known to depend on phasic dopamine release. However, efforts to measure this movement-related dopamine release yielded seemingly paradoxical, incongruent results. In response, here we explored whether those previous observations derived from rapid reuptake transport into either transplanted cells or residual, lesion-surviving terminals. We confirmed this using minimal reuptake blockade during intrastriatal microdialysis. After unilateral dopamine depletion, rats received transplants and were subjected to our swimming protocol. Among dopamine-depleted and transplanted rats, treatment supported restoration of limb movement symmetry. Interestingly, subsequent reuptake-restricted microdialysis confirmed distinct swimming-induced dopamine increases clearly occurred among these lesioned/transplanted subjects. Thus, phasic firing control appears to contribute to transplant-derived recovery in Parkinsonian animals., Competing Interests: Declaration of Competing Interest None. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As part of the central nervous system, the optic nerve, composed of axons from retinal ganglion cells (RGCs), generally fails to regenerate on its own when injured in adult mammals. An innovative approach to promoting optic nerve regeneration involves manipulating the interactions between amacrine cells (ACs) and RGCs. Here, we identified a unique AC subtype, dopaminergic ACs (DACs), that responded early after optic nerve crush by down-regulating neuronal activity and reducing retinal dopamine (DA) release. Activating DACs or augmenting DA release with levodopa demonstrated neuroprotective effects and modestly enhanced axon regeneration. Within this context, we pinpointed the DA receptor D1 (DRD1) as a critical mediator of DAC-derived DA and showed that RGC-specific Drd1 overexpression effectively overcame subtype-specific barriers to regeneration. This strategy markedly boosted RGC survival and axon regeneration after crush and preserved vision in a glaucoma model. This study unveils the crucial role of DAC-derived DA signaling in optic nerve regeneration, holding promise for therapeutic insights into neural repair.

Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABA A receptors (α5-GABA A Rs) SH-053-2'F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2'F-R-CH3 could attenuate these changes. SH-053-2'F-R-CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2'F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2'F-R-CH3. Despite sex differences, our findings indicate that α5-GABA A Rs positive allosteric modulators may effectively attenuate some core ASD symptoms., (© 2024 International Society for Autism Research and Wiley Periodicals LLC.)

Background: Depression is known as the "mental cold" and is also considered a major cause of disability worldwide. It is estimated that over 300 million people worldwide suffer from severe depression, equivalent to 4.4% of the world's population. The monoamine hypothesis of depression predicts the underlying pathophysiological mechanisms of depression, but in-depth research has failed to find convincing evidence., Method: In this study, we will dynamically and strictly quantitatively monitor the concentration changes of monoamine transmitters in the cerebrospinal fluid (CSF) of macaques, based on our previous work. In the experiment, timed and quantitative collection of CSF samples from macaques was performed and the concentration of monoamine transmitters was determined., Result: The results showed that after 2 months of chronic stress, the concentrations of high vanillin acid (HVA) and 3,4-dihydroxy-phenylacetic acid were significantly higher in the maternal separation (MS) group, whereas there was no significant difference in dopamine and 5-hydroxyindoleacetic acid., Conclusion: This study is the first to observe the long-term dynamic relationship between early adversity, chronic stress, adolescent depression, and CSF monoamine concentrations. The research suggests that MS and chronic stress play an undeniable role in the pathogenesis of depression and that concentrations of HVA and dihydroxyphenylacetic acid are likely to serve as early markers of depressive-like symptoms in macaques., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

The dopamine transporter (DAT) is crucial for regulating dopamine signalling and is the prime mediator for the rewarding and addictive effects of cocaine 1 . As part of the neurotransmitter sodium symporter family, DAT uses the Na + gradient across cell membranes to transport dopamine against its chemical gradient 2 . The transport mechanism involves both intra- and extracellular gates that control substrate access to a central site. However, the molecular intricacies of this process and the inhibitory mechanism of cocaine have remained unclear. Here, we present the molecular structure of human DAT in complex with cocaine at a resolution of 2.66 Å. Our findings reveal that DAT adopts the expected LeuT-fold, posing in an outward-open conformation with cocaine bound at the central (S1) site. Notably, while an Na + occupies the second Na + site (Na2), the Na1 site seems to be vacant, with the side chain of Asn82 occupying the presumed Na + space. This structural insight elucidates the mechanism for the cocaine inhibition of human DAT and deepens our understanding of neurotransmitter transport. By shedding light on the molecular underpinnings of how cocaine acts, our study lays a foundation for the development of targeted medications to combat addiction., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants 1-3 . Despite decades of study, the structure, substrate binding, conformational transitions and drug-binding poses of human dopamine transporter remain unknown. Here we report structures of the human dopamine transporter in its apo state, and in complex with the substrate dopamine, the attention deficit hyperactivity disorder drug methylphenidate, and the dopamine-uptake inhibitors GBR12909 and benztropine. The dopamine-bound structure in the occluded state precisely illustrates the binding position of dopamine and associated ions. The structures bound to drugs are captured in outward-facing or inward-facing states, illuminating distinct binding modes and conformational transitions during substrate transport. Unlike the outward-facing state, which is stabilized by cocaine, GBR12909 and benztropine stabilize the dopamine transporter in the inward-facing state, revealing previously unseen drug-binding poses and providing insights into how they counteract the effects of cocaine. This study establishes a framework for understanding the functioning of the human dopamine transporter and developing therapeutic interventions for dopamine transporter-related disorders and cocaine addiction., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement 1 . Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn 2+ are without a high-resolution structural context. Here we determine the structure of hDAT in a tripartite complex with the competitive inhibitor and cocaine analogue, (-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane 2 (β-CFT), the non-competitive inhibitor MRS7292 3 and Zn 2 + (ref. 4 ). We show how β-CFT occupies the central site, approximately halfway across the membrane, stabilizing the transporter in an outward-open conformation. MRS7292 binds to a structurally uncharacterized allosteric site, adjacent to the extracellular vestibule, sequestered underneath the extracellular loop 4 (EL4) and adjacent to transmembrane helix 1b (TM1b), acting as a wedge, precluding movement of TM1b and closure of the extracellular gate. A Zn 2+ ion further stabilizes the outward-facing conformation by coupling EL4 to EL2, TM7 and TM8, thus providing specific insights into how Zn 2+ restrains the movement of EL4 relative to EL2 and inhibits transport activity., (© 2024. The Author(s).)

The core of clinic treatment of Parkinson's disease (PD) is to enhance dopamine (DA) signaling within the brain. The regulation of dopamine transporter (DAT) is integral to this process. This study aims to explore the regulatory mechanism of glial cell line-derived neurotrophic factor (GDNF) on DAT, thereby gaining a profound understanding its potential value in treating PD. In this study, we investigated the effects of GDNF on both cellular and mouse models of PD, including the glycosylation and membrane transport of DAT detected by immunofluorescence and immunoblotting, DA signal measured by neurotransmitter fiber imaging technology, Golgi morphology observed by electron microscopic, as well as cognitive ability assessed by behavior tests. This study revealed that in animal trials, MPTP-induced Parkinson's Disease (PD) mice exhibited a marked decline in cognitive function. Utilizing ELISA and neurotransmitter fiber imaging techniques, we observed a decrease in dopamine levels and a significant reduction in the intensity of dopamine signal release in the Prefrontal Cortex (PFC) of PD mice induced by MPTP. Intriguingly, these alterations were reversed by Glial Cell Line-Derived Neurotrophic Factor (GDNF). In cellular experiments, following MPP + intervention, there was a decrease in Gly-DAT modification in both the cell membrane and cytoplasm, coupled with an increase in Nongly-DAT expression and aggregation of DAT within the cytoplasm. Conversely, GDNF augmented DAT glycosylation and facilitated its membrane transport in damaged dopaminergic neurons, concurrently reversing the effects of GRASP65 depletion and Golgi fragmentation, thereby reducing the accumulation of DAT in the Golgi apparatus. Furthermore, overexpression of GRASP65 enhanced DAT transport in PD cells and mice, while suppression of GRASP65 attenuated the efficacy of GDNF on DAT. Additionally, GDNF potentiated the reutilization of neurotransmitters by the PFC presynaptic membrane, boosting the effective release of dopamine following a single electrical stimulation, ultimately ameliorating the cognitive impairments in PD mice.Therefore, we propose that GDNF enhances the glycosylation and membrane trafficking of DAT by facilitating the re-aggregation of the Golgi apparatus, thereby amplifying the utilization of DA signals. This ultimately leads to the improvement of cognitive abilities in PD mouse models. Our study illuminates, from a novel angle, the beneficial role of GDNF in augmenting DA utilization and cognitive function in PD, providing fresh insights into its therapeutic potential., (© 2024. The Author(s).)

Motivations bias our responses to stimuli, producing behavioural outcomes that match our needs and goals. Here we describe a mechanism behind this phenomenon: adjusting the time over which stimulus-derived information is permitted to accumulate towards a decision. As a Drosophila copulation progresses, the male becomes less likely to continue mating through challenges 1-3 . We show that a set of copulation decision neurons (CDNs) flexibly integrates information about competing drives to mediate this decision. Early in mating, dopamine signalling restricts CDN integration time by potentiating Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activation in response to stimulatory inputs, imposing a high threshold for changing behaviours. Later into mating, the timescale over which the CDNs integrate termination-promoting information expands, increasing the likelihood of switching behaviours. We suggest scalable windows of temporal integration at dedicated circuit nodes as a key but underappreciated variable in state-based decision-making., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Noradrenaline, also known as norepinephrine, has a wide range of activities and effects on most brain cell types 1 . Its reuptake from the synaptic cleft heavily relies on the noradrenaline transporter (NET) located in the presynaptic membrane 2 . Here we report the cryo-electron microscopy (cryo-EM) structures of the human NET in both its apo state and when bound to substrates or antidepressant drugs, with resolutions ranging from 2.5 Å to 3.5 Å. The two substrates, noradrenaline and dopamine, display a similar binding mode within the central substrate binding site (S1) and within a newly identified extracellular allosteric site (S2). Four distinct antidepressants, namely, atomoxetine, desipramine, bupropion and escitalopram, occupy the S1 site to obstruct substrate transport in distinct conformations. Moreover, a potassium ion was observed within sodium-binding site 1 in the structure of the NET bound to desipramine under the KCl condition. Complemented by structural-guided biochemical analyses, our studies reveal the mechanism of substrate recognition, the alternating access of NET, and elucidate the mode of action of the four antidepressants., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: This study aimed to determine a dopaminergic circuit required for diet-induced obesity in mice., Methods: We created conditional deletion mutants for tyrosine hydroxylase (TH) using neurotensin receptor 1 (Ntsr1) Cre and other Cre drivers and measured feeding and body weight on standard and high-fat diets. We then used an adeno-associated virus to selectively restore TH to the ventral tegmental area (VTA) Ntsr1 neurons in conditional knockout (cKO) mice., Results: Mice with cKO of Th using Vglut2-Cre, Cck-Cre, Calb1-Cre, and Bdnf-Cre were susceptible to obesity on a high-fat diet; however, Ntsr1-Cre Th cKO mice resisted weight gain on a high-fat diet and did not experience an increase in day eating unlike their wild-type littermate controls. Restoration of TH to the VTA Ntsr1 neurons of the Ntsr1-Cre Th cKO mice using an adeno-associated virus resulted in an increase in weight gain and day eating on a high-fat diet., Conclusions: Ntsr1-Cre Th cKO mice failed to increase day eating on a high-fat diet, offering a possible explanation for their resistance to diet-induced obesity. These results implicate VTA Ntsr1 dopamine neurons as promoting out-of-phase feeding behavior on a high-fat diet that could be an important contributor to diet-induced obesity in humans., (© 2024 The Obesity Society.)

The hypothesis that midbrain dopamine (DA) neurons broadcast a reward prediction error (RPE) is among the great successes of computational neuroscience. However, recent results contradict a core aspect of this theory: specifically that the neurons convey a scalar, homogeneous signal. While the predominant family of extensions to the RPE model replicates the classic model in multiple parallel circuits, we argue that these models are ill suited to explain reports of heterogeneity in task variable encoding across DA neurons. Instead, we introduce a complementary 'feature-specific RPE' model, positing that individual ventral tegmental area DA neurons report RPEs for different aspects of an animal's moment-to-moment situation. Further, we show how our framework can be extended to explain patterns of heterogeneity in action responses reported among substantia nigra pars compacta DA neurons. This theory reconciles new observations of DA heterogeneity with classic ideas about RPE coding while also providing a new perspective of how the brain performs reinforcement learning in high-dimensional environments., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

6-Cyanodopamine is a novel catecholamine released from rabbit isolated heart. However, it is not known whether this catecholamine presents any biological activity. Here, it was evaluated whether 6-cyanodopamine (6-CYD) is released from rat vas deferens and its effect on this tissue contractility. Basal release of 6-CYD, 6-nitrodopamine (6-ND), 6-bromodopamine, 6-nitrodopa, and 6-nitroadrenaline from vas deferens were quantified by LC-MS/MS. Electric-field stimulation (EFS) and concentration-response curves to noradrenaline, adrenaline, and dopamine of the rat isolated epididymal vas deferens (RIEVD) were performed in the absence and presence of 6-CYD and /or 6-ND. Expression of tyrosine hydroxylase was assessed by immunohistochemistry. The rat isolated vas deferens released significant amounts of both 6-CYD and 6-ND. The voltage-gated sodium channel blocker tetrodotoxin had no effect on the release of 6-CYD, but it virtually abolished 6-ND release. 6-CYD alone exhibited a negligible RIEVD contractile activity; however, at 10 nM, 6-CYD significantly potentiated the noradrenaline- and EFS-induced RIEVD contractions, whereas at 10 and 100 nM, it also significantly potentiated the adrenaline- and dopamine-induced contractions. The potentiation of noradrenaline- and adrenaline-induced contractions by 6-CYD was unaffected by tetrodotoxin. Co-incubation of 6-CYD (100 pM) with 6-ND (10 pM) caused a significant leftward shift and increased the maximal contractile responses to noradrenaline, even in the presence of tetrodotoxin. Immunohistochemistry revealed the presence of tyrosine hydroxylase in both epithelial cell cytoplasm of the mucosae and nerve fibers of RIEVD. The identification of epithelium-derived 6-CYD and its remarkable synergism with catecholamines indicate that epithelial cells may regulate vas deferens smooth muscle contractility., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Neuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion cells (ipRGCs), the neurons that drive nonimage-forming visual functions, express a variety of neuromodulatory receptors that tune intrinsic excitability as well as synaptic inputs. Past research has examined actions of neuromodulators on light responsiveness of ipRGCs, but less is known about how neuromodulation affects synaptic currents in ipRGCs. To better understand how neuromodulators affect synaptic processing in ipRGC, we examine actions of opioid and dopamine agonists have on inhibitory synaptic currents in ipRGCs. Although µ-opioid receptor (MOR) activation had no effect on γ-aminobutyric acid (GABA) currents, dopamine [via the D1-type dopamine receptor (D1R)]) amplified GABAergic currents in a subset of ipRGCs. Furthermore, this D1R-mediated facilitation of the GABA conductance in ipRGCs was mediated by a cAMP/PKA-dependent mechanism. Taken together, these findings reinforce the idea that dopamine's modulatory role in retinal adaptation affects both nonimage-forming and image-forming visual functions. NEW & NOTEWORTHY Neuromodulators such as dopamine are important regulators of retinal function. Here, we demonstrate that dopamine increases inhibitory inputs to intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to its previously established effect on intrinsic light responsiveness. This indicates that dopamine, in addition to its ability to intrinsically modulate ipRGC activity, can also affect synaptic inputs to ipRGCs, thereby tuning retina circuits involved in nonimage-forming visual functions.

Introduction: Parkinson's disease (PD) presents with a progressive decline in manual dexterity, attributed to dysfunction in the basal ganglia-thalamus-cortex loop, influenced by dopaminergic deficits in the striatum. Recent research suggests that the motor cortex may play a pivotal role in mediating the relationship between striatal dopamine depletion and motor function in PD. Understanding this connection is crucial for comprehending the origins of manual dexterity impairments in PD. Therefore, our study aimed to explore how motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD., Materials and Methods: We enrolled 26 mildly affected PD patients in their off-medication phase to undergo [ 18 F]FDOPA PET/CT scans for evaluating striatal dopaminergic function. EEG recordings were conducted during bimanual anti-phase finger tapping tasks to evaluate motor cortex activity, specifically focusing on Event-Related Desynchronization in the beta band. Manual dexterity was assessed using the Purdue Pegboard Test. Regression-based mediation analysis was conducted to examine whether motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD., Results: Mediation analysis revealed a significant direct effect of putamen dopamine depletion on manual dexterity for the affected hand and assembly tasks (performed with two hands), with motor cortex activity mediating this association. In contrast, while caudate nucleus dopamine depletion showed a significant direct effect on manual dexterity, motor cortex mediation on this association was not observed., Conclusion: Our study confirms the association between striatum dopamine depletion and impaired manual dexterity in PD, with motor cortex activity mediating this relationship., Competing Interests: Declaration of competing interest The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While the dopaminergic system is important for cognitive processes, it is also sensitive to the influence of physical activity (PA). We summarize current evidence on whether PA-related changes in the human dopaminergic system are associated with alterations in cognitive performance, discuss recent advances, and highlight challenges and opportunities for future research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Dopamine critically influences reward processing, sensory perception, and motor control. Yet, the modulation of dopaminergic signaling by sensory experiences is not fully delineated. Here, by manipulating sensory experience using bilateral single-row whisker deprivation, we demonstrated that gene transcription in the dopaminergic signaling pathway (DSP) undergoes experience-dependent plasticity in both granular and supragranular layers of the primary somatosensory (barrel) cortex (S1). Sensory experience and deprivation compete for the regulation of DSP transcription across neighboring cortical columns, and sensory deprivation-induced changes in DSP are topographically constrained. These changes in DSP extend beyond cortical map plasticity and influence neuronal information processing. Pharmacological regulation of D2 receptors, a key component of DSP, revealed that D2 receptor activation suppresses excitatory neuronal excitability, hyperpolarizes the action potential threshold, and reduces the instantaneous firing rate. These findings suggest that the dopaminergic drive originating from midbrain dopaminergic neurons, targeting the sensory cortex, is subject to experience-dependent regulation and might create a regulatory feedback loop for modulating sensory processing. Finally, using topological gene network analysis and mutual information, we identify the molecular hubs of experience-dependent plasticity of DSP. These findings provide new insights into the mechanisms by which sensory experience shapes dopaminergic signaling in the brain and might help unravel the sensory deficits observed after dopamine depletion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Although iron (Fe) is the most biologically abundant transition metal, it is highly toxic when it accumulates as Fe2+, forming a labile Fe pool and favoring the Fenton reaction. This oxidative scenario leads to a type of caspase-independent programmed cell death, referred to as ferroptosis, where following processes take place: (i) Fe2+ overload, (ii) glutathione peroxidase 4 inactivation, (iii) lipid peroxidation, and (iv) glutathione depletion. The present study sought to evaluate the consequences of Fe2+ administration on ferroptosis induction in Caenorhabditis elegans. We demonstrated higher mortality, increased lipid peroxidation, reduced glutathione peroxidase activity, and morphological damage in dopaminergic neurons upon Fe2+ overload. Pharmacological intervention at the level of lipid peroxidation with ferrostatin-1 (250 μM) mitigated the damage and returned the biochemical parameters to basal levels, revealing the potential of this therapeutical approach. Finally, to assess the relationship between ferroptosis and dopamine in a Parkinsonian background, we evaluated the UA44 worm strain which overexpresses the alpha-synuclein protein in cherry-labeled dopaminergic neurons. We demonstrated that Fe2+ administration reduced lethality associated with similar alterations in biochemical and dopaminergic morphological parameters in wild-type animals. These experiments provide mechanistic-based evidence on the efficacy of a pharmacological approach to mitigate the physiological, biochemical, and morphological consequences of Fe2+ overload. At the same time, they encourage further research on the impact of the combined effects resulting from the genetic background and dopamine signaling in a Parkinsonian phenotype., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Oleic acid (OA) is a monounsaturated compound with many health-benefitting properties such as obesity prevention, increased insulin sensitivity, antihypertensive and immune-boosting properties, etc. The aim of this study was to analyze the effect of oleic acid (OA) and some anticancer drugs against oxidative damage induced by nitropropionic acid (NPA) in rat brain. Six groups of Wistar rats were treated as follows: Group 1, (control); group 2, OA; group 3, NPA + OA; group 4, cyclophosphamide (CPP) + OA; group 5, daunorubicin (DRB) + OA; and group 6, dexrazoxane (DXZ) + OA. All compounds were administered intraperitoneally route, every 24 h for 5 days. Their brains were extracted to measure lipoperoxidation (TBARS), H 2 O 2 , Ca +2 , Mg +2 ATPase activity, glutathione (GSH) and dopamine. Glucose, hemoglobin and triglycerides were measured in blood. In cortex GSH increased in all groups, except in group 2, the group 4 showed the highest increase of this biomarker. TBARS decrease, and dopamine increase in all regions of groups 4, 5 and 6. H 2 O 2 increased only in cerebellum/medulla oblongata of group 5 and 6. ATPase expression decreased in striatum of group 4. Glucose increased in group 6, and hemoglobin increased in groups 4 and 5. These results suggest that the increase of dopamine and the antioxidant effect of oleic acid administration during treatment with oncologic agents could result in less brain injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Purpose: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function., Experimental Approach: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility., Key Results: IP2015 inhibited the uptake of 5-HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose-dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D 2 -like receptor antagonists, clozapine and (-)-sulpiride, or cutting the cavernosal nerve inhibited IP2015-induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015-mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration-dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, N G -nitro-l-arginine and a D 1 -like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum., Conclusion and Implications: Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO-mediated relaxation of the erectile tissue. This novel multi-modal mechanism of action could offer a new treatment approach to erectile dysfunction., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Spermidine is a natural biologically active substance that has widespread influences on the body., Objective: This study aims to enhance our understanding of the potential effect of spermidine on long non-coding RNA MALAT1 and explore the underlying mechanism in the rotenone-induced rat model of Parkinson's disease., Methods: Rats were sacrificed after locomotor behavioral testing. Striatal tissues were used to assess the expression of MALAT1, oxidative stress markers, and autophagy markers., Results: Our study found that treatment with spermidine for 2 weeks during the induction of the model significantly improved behavioral assessment, dopamine levels, and attenuated the histopathological changes that occurred in PD in comparison to the non-treated group., Conclusion: Our preliminary study supports the protective effect of spermidine on the activation of autophagy and its antioxidant properties. Part of the antioxidant activity is due to the inhibition of MALAT1. However, MALAT1 does not correlate with the spermidine-induced autophagy pathway., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Formosan wood mice (Apodemus semotus) are endemic rodents in Taiwan. Recently Formosan wood mice exhibit similar locomotor behaviors in the laboratory environment as in the field environment has shown. Contemporaneously, Formosan wood mice have higher moving distances of and central dopaminergic (DAergic) activities than C57BL/6 mice in behavioral test. This study tried to compare the behavioral responses between male Formosan wood mice and male C57BL/6 mice in the light-dark exploration tests. We also measured the levels of DA and 3,4-dihydroxyphenylacetic acid (DOPAC), the primary metabolite of DA, to assess the dopaminergic activity of the medial prefrontal cortex, striatum, and nucleus accumbens. Our data show that Formosan wood mice revealed higher exploration and central DAergic activities than did C57BL/6 mice in the light-dark exploration tests, and diazepam (an anxiolytics) treatment reduced the exploratory activity and central dopaminergic activities in Formosan wood mice, but not in C57BL/6 mice. After repeated exposure to light-dark exploration tests, the latency to dark zone was increased, and the duration in light zone as well as the central DAergic activity were decreased in C57BL/6 mice. This study provides comparative findings; Formosan wood mice showed the higher exploratory activities than C57BL/6 mice did, and their central DAergic activities were related to the behavioral responses in these two mice. This could potentially shed light on the reasons behind the prevalence of higher exploration and central dopaminergic activities. Using Formosan wood mice as a model to study human diseases related to hyperactivity adds significant value to the potential research., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2024 Elsevier Inc. All rights reserved.)

It is widely believed that the activation of the central dopamine (DA) system is crucial to the rewarding effects of methamphetamine (METH) and to the behavioral outcomes of METH use disorder. It was reported that METH exposure induced gasdermin D (GSDMD)-dependent pyroptosis in rats. The membrane pore formation caused by METH-induced pyroptosis may also contribute to the overflow of DA into the extracellular space and subsequently increase the DA levels in the brain. The present study firstly investigated whether the membrane pore information induced by GSDMD-dependent pyroptosis was associated with the increased DA levels in the ventral tegmental area (VAT) and nucleus accumbens (NAc) of rats self-administering METH and SY-SH5Y cells treated by METH. Subsequently, the effect of pore formation blockade or genetic inhibition of GSDMD on the reinforcing and motivational effect of METH was determined in rats, using the animal model of METH self-administration (SA). METH exposure significantly increased the activity of NLRP1/Cas-1/GSDMD pathway and the presence of pyroptosis, accompanied by the significantly increased DA levels in VTA and NAc. Moreover, intraperitoneal injections of disulfiram (DSF) or microinjection of rAAV-shGSDMD into VTA/NAc significantly reduced the reinforcing and motivational effect of METH, accompanied by the decreased level of DA in VTA and NAc. The results provided novel evidence that METH-induced pyroptosis could increase DA release in VTA and NAc via the NLRP1/Cas-1/GSDMD pathway. Additionally, membrane pores or GSDMD blockade could significantly reduce the reinforcing and motivational effect of METH. In conclusion, blocking GSDMD and membrane pore formation could be a promising potential target for the development of agents to treat METH use disorder., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests regarding the publication of this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Purpose: Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by motor dysfunction. Environmental factors, especially manganese (Mn), contribute significantly to PD. Existing therapies are focused on motor coordination, whereas nonmotor features such as neuropsychiatric symptoms are often neglected. Daidzein (DZ), a phytoestrogen, has piqued interest due to its antioxidant, anti-inflammatory, and anxiolytic properties. Therefore, we anticipate that DZ might be an effective drug to alleviate the nonmotor symptoms of Mn-induced Parkinsonism., Experimental Approach: Naïve zebrafish were exposed to 2 mM of Mn for 21 days and intervened with DZ. Nonmotor symptoms such as anxiety, social behaviour, and olfactory function were assessed. Acetylcholinesterase (AChE) activity and antioxidant enzyme status were measured from brain tissue through biochemical assays. Dopamine levels and histology were performed to elucidate neuroprotective mechanism of DZ., Key Results: DZ exhibited anxiolytic effects in a novel environment and also improved intra and inter fish social behaviour. DZ improved the olfactory function and response to amino acid stimuli in Mn-induced Parkinsonism. DZ reduced brain oxidative stress and AChE activity and prevented neuronal damage. DZ increased DA level in the brain, collectively contributing to neuroprotection., Conclusion and Implications: DZ demonstrated a promising effect on alleviating nonmotor symptoms such as anxiety and olfactory dysfunction, through the mitigation of cellular damage. These findings underscore the therapeutic potential of DZ in addressing nonmotor neurotoxicity induced by heavy metals, particularly in the context of Mn-induced Parkinsonism., (© 2024 British Pharmacological Society.)

Following reports of low striatal dopamine content in Parkinson's disease, levodopa was shown to rapidly reverse hypokinesis, establishing the model of disease as one of dopamine deficiency. Dopaminergic therapy became standard of care, yet it failed to reverse the disease, suggesting the understanding of disease was incomplete. The literature suggests the potential for toxicity of dopamine and its metabolites, perhaps more relevant given the recent evidence for elevated cytosolic dopamine levels in the dopaminergic neurons of people with Parkinson's. To understand the relevance of these data, multiple investigations are reviewed that tested dopamine reduction therapy as an alternative to dopaminergic agents. The data from use of an inhibitor of dopamine synthesis in experimental models suggest that such an approach could reverse disease pathology, which suggests that cytosolic dopamine excess is a primary driver of disease. These data support clinical investigation of dopamine reduction therapy for Parkinson's disease. Doing so will determine whether these experimental models are predictive and this treatment strategy is worth pursuing further. If clinical data are positive, it could warrant reconsideration of our disease model and treatment strategies, including a shift from dopaminergic to dopamine reduction treatment of the disease., (© 2024. The Author(s).)

This review examines the pivotal role of photoreceptor cells in ocular refraction development, focusing on dopamine (DA) as a key neurotransmitter. Contrary to the earlier view favoring cone cells, recent studies have highlighted the substantial contributions of both rod and cone cells to the visual signaling pathways that influence ocular refractive development. Notably, rod cells appeared to play a central role. Photoreceptor cells interact intricately with circadian rhythms, color vision pathways, and other neurotransmitters, all of which are crucial for the complex mechanisms driving the development of myopia. This review emphasizes that ocular refractive development results from a coordinated interplay between diverse cell types, signaling pathways, and neurotransmitters. This perspective has significant implications for unraveling the complex mechanisms underlying myopia and aiding in the development of more effective prevention and treatment strategies., Competing Interests: Declaration of competing interest The authors declare they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: This study was undertaken to investigate the effects of dietary caffeine intake on striatal dopamine function and clinical symptoms in Parkinson disease in a cross-sectional and longitudinal setting., Methods: One hundred sixty-three early Parkinson disease patients and 40 healthy controls were investigated with [ 123 I]FP-CIT single photon emission computed tomography, and striatal dopamine transporter binding was evaluated in association with the level of daily coffee consumption and clinical measures. After a median interval of 6.1 years, 44 patients with various caffeine consumption levels underwent clinical and imaging reexamination including blood caffeine metabolite profiling., Results: Unmedicated early Parkinson disease patients with high coffee consumption had 8.3 to 15.4% lower dopamine transporter binding in all studied striatal regions than low consumers, after accounting for age, sex, and motor symptom severity. Higher caffeine consumption was further associated with a progressive decline in striatal binding over time. No significant effects of caffeine on motor function were observed. Blood analyses demonstrated a positive correlation between caffeine metabolites after recent caffeine intake and dopamine transporter binding in the ipsilateral putamen., Interpretation: Chronic caffeine intake prompts compensatory and cumulative dopamine transporter downregulation, consistent with caffeine's reported risk reduction in Parkinson disease. However, this decline does not manifest in symptom changes. Transiently increased dopamine transporter binding after recent caffeine intake has implications for dopaminergic imaging guidelines. ANN NEUROL 2024;96:262-275., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The impact of environmental enrichment (EE) on natural rewards, including social and appetitive rewards, was investigated in male Swiss mice. EE, known for providing animals with various stimuli, was assessed for its effects on conditioned place preference (CPP) associated with ethanol and social stimuli. We previously demonstrated that EE increased the levels of the prosocial neuropeptide oxytocin (OT) in the hypothalamus and enhanced ethanol rewarding effects via an oxytocinergic mechanism. This study also investigated the impact of EE on social dominance and motivation for rewards, measured OT-mediated phospholipase C (PLC) activity in striatal membranes, and assessed OT expression in the hypothalamus. The role of dopamine in motivating rewards was considered, along with the interaction between OT and D 1 receptors (DR) in the nucleus accumbens (NAc). Results showed that EE mice exhibited a preference for ethanol reward over social reward, a pattern replicated by the OT analogue Carbetocin. EE mice demonstrated increased social dominance and reduced motivation for appetitive taste stimuli. Higher OT mRNA levels in the hypothalamus were followed by diminished OT receptor (OTR) signaling activity in the striatum of EE mice. Additionally, EE mice displayed elevated D 1 R expression, which was attenuated by the OTR antagonist (L-368-889). The findings underscore the reinforcing effect of EE on ethanol and social rewards through an oxytocinergic mechanism. Nonetheless, they suggest that mechanisms other than the prosocial effect of EE may contribute to the ethanol pro-rewarding effect of EE and Carbetocin. They also point towards an OT-dopamine interaction potentially underlying some of these effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Many studies show either the absence, or very low levels of, SARS-CoV-2 viral RNA and/or antigen in the brain of COVID-19 patients. Reports consistently indicate an abortive infection phenomenon in nervous cells despite the fact that they contain the SARS-CoV-2 receptor, ACE2. Dopamine levels in different brain regions are in the range of micromolar to millimolar concentrations. We have shown that sub-micromolar to low micromolar concentrations of dopamine or its precursor (levodopa) time- and dose-dependently inhibit the activity of SARS-CoV-2 main protease (Mpro), which is vital for the viral life cycle, by forming a quinoprotein. Thiol detection coupled with the assessment of Mpro activity suggests that among the 12 cysteinyl thiols, the active site, Cys145-SH, is preferentially conjugated to the quinone derived from the oxidation of dopamine or levodopa. LC-MS/MS analyses show that the Cys145-SH is covalently conjugated by dopamine- or levodopa-o-quinone. These findings help explain why SARS-CoV-2 causes inefficient replication in many nerve cell lines. It is well recognized that inhaled pulmonary drug delivery is the most robust therapy pathway for lung diseases. CVT-301 (orally inhaled levodopa) was approved by the FDA as a drug for Parkinson's patients prior to the outbreak of COVID-19 in 2018. Based on the fact that SARS-CoV-2 causes inefficient replication in the CNS with abundant endogenous Mpro inhibitor in addition to the current finding that levodopa has an Mpro-inhibitory effect somewhat stronger than dopamine, we should urgently investigate the use of CVT-301 as a lung-targeting, COVID-19, Mpro inhibitor., Competing Interests: Declaration of competing interest The authors declare that they have no current financial arrangement or affiliation with any organization that may have a direct influence on their work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)