Role of serotonin in the lack of sensitization caused by prolonged food deprivation in Aplysia.

Food deprivation may cause neurological dysfunctions including memory impairment. The mollusk Aplysia is a suitable animal model to study prolonged food deprivation-induced memory deficits because it can sustain up to 14 days of food deprivation (14DFD). Sensitization of defensive withdrawal reflexes has been used to illustrate the detrimental effects of 14DFD on memory formation. Under normal feeding conditions (i.e., two days food deprivation, 2DFD), aversive stimuli lead to serotonin (5-HT) release into the hemolymph and neuropil, which mediates sensitization and its cellular correlates including increased excitability of tail sensory neurons (TSNs). Recent studies found that 14DFD prevents both short-term and long-term sensitization, as well as short-term increased excitability of TSNs induced by in vitro aversive training. This study investigated the role of 5-HT in the absence of sensitization and TSN increased excitability under 14DFD. Because 5-HT is synthesized from tryptophan obtained through diet, and its exogeneous application alone induces sensitization and increases TSN excitability, we hypothesized that 1) 5-HT level may be reduced by 14DFD and 2) 5-HT may still induce sensitization and TSN increased excitability in 14DFD animals. Results revealed that 14DFD significantly decreased hemolymph 5-HT level, which may contribute to the lack of sensitization and its cellular correlates, while ganglia 5-HT level was not changed. 5-HT exogenous application induced sensitization in 14DFD Aplysia, albeit smaller than that in 2DFD animals, suggesting that this treatment can only induce partial sensitization in food deprived animals. Under 14DFD, 5-HT increased TSN excitability indistinguishable from that observed under 2DFD. Taken together, these findings characterize 5-HT metabolic deficiency under 14DFD, which may be compensated, at least in part, by 5-HT exogenous application.

Ventral hippocampus is more sensitive to fluoxetine-induced changes in extracellular 5-HT concentration, membrane 5-HT transporter level and immobility times.

Hippocampal responses to selective 5-HT reuptake inhibitor (SSRI) have long been studied. However, its sub-regional involvements in mediating SSRI's pharmacological effects have not been fully addressed. The current study sought to investigate neurochemical, neurobiological and neurobehavioral changes in response to direct fluoxetine perfusion into the ventral and dorsal sub-regions of the hippocampus in C57BL/6 mice. Following fluoxetine perfusion, time courses of dialysate 5-HT, 5-HT transporter (5-HTT) protein (total, membrane and cytoplasmic fractions), locomotion, and immobility times in the forced swim test (FST) and tail suspension test (TST) were determined. At baseline, 5-HT uptake efficiency assessed by the no-net-flux microdialysis, and 5-HTT protein were measured as well. Results show that fluoxetine dose-dependently increased dialysate 5-HT, lowered membrane 5-HTT protein and increased cytoplasmic fraction without changing the total level, decreased immobility times in both the FST and TST, with greater responses all detected in the ventral sub-region compared to the dorsal sub-region. Fluoxetine didn't affect locomotor activity, ruling out the possibility that fluoxetine's effects on immobility maybe due to alteration in locomotion. Besides, lower 5-HT uptake efficiency and lower membrane 5-HTT protein level were found in the ventral sub-region at baseline. Together, the sub-regional differences at baseline and in responses to fluoxetine added powerful evidence to support the existence of two distinct 5-HT sub-systems in the hippocampus, with greater changes to fluoxetine detected in the ventral sub-system.

Environmentally persistent free radicals on photoaged nanopolystyrene induce neurotoxicity by affecting dopamine, glutamate, serotonin and GABA in Caenorhabditis elegans.

Microplastics are widely detected in the environment and induce toxic effects in various organisms. However, the properties and toxicity associated with environmentally persistent free radicals (EPFRs) in photoaged nanopolystyrene (NPS) remain largely unknown. We investigated the generation of EPFRs on photoaged NPS and their neurotoxicity and underlying mechanism in Caenorhabditis elegans. The results suggested that photoaging induces the generation of EPFRs and reactive oxygen species (O2•-, •OH, and 1O2), which altered the physicochemical properties (morphology, crystallinity, and functional groups) of NPS. Acute exposure to 1 µg/L of NPS-60 (NPS with light irradiation time of 60 d) significantly decreased locomotion behaviors and neurotransmitter contents (e.g., glutamate, serotonin, dopamine, and γ-aminobutyric acid). Treatment with N-acetyl-L-cysteine (NAC) by radical quenching test significantly reduced EPFRs levels on the aged NPS, and the toxicity of NAC-quenching NPS was decreased in nematodes compared to those in photoaged NPS. EPFRs also caused dysfunction of neurotransmission-related gene expression in C. elegans. Thus, EPFRs generated on photoaged NPS contributed to neurotoxicity by affecting dopamine, glutamate, serotonin, and γ-aminobutyric acid neurotransmission. The study highlights the potential risks of photoaged NPS and the contributions of EPFRs to toxicity.

The anticonvulsant effect of saiga horn on febrile seizures by regulating brain serotonin content and inhibiting neuroinflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Saiga antelope horn (SAH) is derived from the Saiga antelope (Saiga tatarica Linnaeus) of the bovidae family. SAH has been used for the treatment of febrile seizures (FS) in children for thousands of years in China. Due to the biological protection of Saiga antelope and its ethical reasons, the application of SAH has been widely restricted. Unfortunately, the field of artificial manufacturing of SAH is still blank at present. The mechanism of SAH in the treatment of FS is still unclear, which seriously hinders the further development of artificial antelope horns and the search for substitutes for SAH. At present, there is an urgent need to determine the mechanism of SAH in the treatment of FS, so as to provide a theoretical basis for artificial antelope horn and its substitutes. AIM OF THE STUDY: To explore the anti-FS effect of natural SAH on FS rat model and its possible mechanism, and to provide a theoretical basis for the subsequent manufacture of artificial antelope horns and the search for the best substitutes. MATERIALS AND METHODS: FS was induced by a warm water bath (48 ± 0.5 °C). The latency and seizure grade of FS were observed and recorded. Hematoxylin-eosin (HE) staining was used to observe the functional defect of hippocampal cells. The contents of tryptophan (TRP), serotonin (5-HT), IL-1ß and TNF-a in rat brain tissue were determined by ELISA. qRT-PCR and Western blot were used to detect the expression of 5-HT synthesis related neurotransmitter receptors, catalytic enzymes and inflammatory factors in hippocampus. Immunofluorescence was used to observe the expression of TPH2 protein in the dorsal raphe nucleus of rat brain. RESULTS: After pretreating rats with SAH, the seizure grade of FS was significantly reduced and the latency was prolonged. SAH can reduce the histological damage of hippocampal tissue induced by FS in rats. Further analysis of ELISA results showed that SAH significantly increased the levels of TRP and 5-HT in the brain of FS rats, and significantly decreased the levels of IL-1ß and TNF-a. The results of QPCR showed that SAH could up-regulate the expression of ER-ß and TPH2 mRNA and down-regulate the expression of IL-1ß and TNF-ɑ mRNA in the hippocampus of rats. In addition, WB and immunofluorescence results showed that SAH could significantly up-regulate the expression of ER-ß/TPH2/5-HT pathway in the hippocampus of FS rats and the expression of TPH2 protein in the raphe nucleus, but had no significant effect on SERT protein in the hippocampus of FS rats. In addition, ER-ß protein inhibitor PHTPP significantly inhibited the therapeutic effect of SAH on FS rats. CONCLUSIONS: The present study demonstrates that SAH has a significant anticonvulsant effect on the FS rat model. The mechanism may be related to the increase of TRP content and up-regulation the expression of ER-ß/TPH2/5-HT signaling pathway in the brain of FS rats, thereby increasing the content of 5-HT in the brain and reducing the content of IL-1ß and TNF-a in the brain.

Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT2C receptor in the mouse brain.

BACKGROUND: Serotonin (5-HT) 5-HT2C receptor mRNA editing (at five sites, A-E), implicated in neuropsychiatric disorders, including clinical depression, remains unexplored during alcohol abstinence-often accompanied by depressive symptoms. METHODS: We used deep sequencing to investigate 5-HT2C receptor editing in mice during early ethanol deprivation following prolonged alcohol exposure and mice lacking tryptophan hydroxylase (TPH)2, a key enzyme in central 5-HT production. We also examined Tph2 expression in ethanol-deprived animals using quantitative real-time PCR (qPCR). RESULTS: Cessation from chronic 10% ethanol exposure in a two-bottle choice paradigm enhanced immobility time and decreased latency in the forced swim test (FST), indicating a depression-like phenotype. In the hippocampus, ethanol-deprived "high ethanol-drinking" mice displayed reduced Tph2 expression, elevated 5-HT2C receptor editing efficiency, and decreased frequency of the D mRNA variant, encoding the less-edited INV protein isoform. Tph2-/- mice showed attenuated receptor editing in the hippocampus and elevated frequency of non-edited None and D variants. In the prefrontal cortex, Tph2 deficiency increased receptor mRNA editing at site D and reduced the frequency of AB transcript, predicting a reduction in the corresponding partially edited VNI isoform. CONCLUSIONS: Our findings reveal differential effects of 5-HT depletion and ethanol cessation on 5-HT2C receptor editing. Central 5-HT depletion attenuated editing in the prefrontal cortex and the hippocampus, whereas ethanol deprivation, coinciding with reduced Tph2 expression in the hippocampus, enhanced receptor editing efficiency specifically in this brain region. This study highlights the interplay between 5-HT synthesis, ethanol cessation, and 5-HT2C receptor editing, providing potential mechanism underlying increased ethanol consumption and deprivation.

The possible place for psychedelics in pharmacotherapy of mental disorders.

Since its emergence in the 1960s, the serotonergic theory of depression bore fruit in the discovery of a plethora of antidepressant drugs affecting the lives of millions of patients. While crucial in the history of drug development, recent studies undermine the effectiveness of currently used antidepressant drugs in comparison to placebo, emphasizing the long time it takes to initiate the therapeutic response and numerous adverse effects. Thus, the scope of contemporary pharmacological research shifts from drugs affecting the serotonin system to rapid-acting antidepressant drugs. The prototypical representative of the aforementioned class is ketamine, an NMDA receptor antagonist capable of alleviating the symptoms of depression shortly after the drug administration. This discovery led to a paradigm shift, focusing on amino-acidic neurotransmitters and growth factors. Alas, the drug is not perfect, as its therapeutic effect diminishes circa 2 weeks after administration. Furthermore, it is not devoid of some severe side effects. However, there seems to be another, more efficient, and safer way to target the glutamatergic system. Hallucinogenic agonists of the 5-HT2A receptor, commonly known as psychedelics, are nowadays being reconsidered in clinical practice, shedding their infamous 1970s stigma. More and more clinical studies prove their clinical efficacy and rapid onset after a single administration while bearing fewer side effects. This review focuses on the current state-of-the-art literature and most recent clinical studies concerning the use of psychedelic drugs in the treatment of mental disorders. Specifically, the antidepressant potential of LSD, psilocybin, DMT, and 5-MeO-DMT will be discussed, together with a brief summary of other possible applications.

Examination of the mechanism of Piezo ion channel in 5-HT synthesis in the enterochromaffin cell and its association with gut motility.

In the gastrointestinal tract, serotonin (5-hydroxytryptamine, 5-HT) is an important monoamine that regulates intestinal dynamics. QGP-1 cells are human-derived enterochromaffin cells that secrete 5-HT and functionally express Piezo ion channels associated with cellular mechanosensation. Piezo ion channels can be blocked by Grammostola spatulata mechanotoxin 4 (GsMTx4), a spider venom peptide that inhibits cationic mechanosensitive channels. The primary aim of this study was to explore the effects of GsMTx4 on 5-HT secretion in QGP-1 cells in vitro. We investigated the transcript and protein levels of the Piezo1/2 ion channel, tryptophan hydroxylase 1 (TPH1), and mitogen-activated protein kinase signaling pathways. In addition, we observed that GsMTx4 affected mouse intestinal motility in vivo. Furthermore, GsMTx4 blocked the response of QGP-1 cells to ultrasound, a mechanical stimulus.The prolonged presence of GsMTx4 increased the 5-HT levels in the QGP-1 cell culture system, whereas Piezo1/2 expression decreased, and TPH1 expression increased. This effect was accompanied by the increased phosphorylation of the p38 protein. GsMTx4 increased the entire intestinal passage time of carmine without altering intestinal inflammation. Taken together, inhibition of Piezo1/2 can mediate an increase in 5-HT, which is associated with TPH1, a key enzyme for 5-HT synthesis. It is also accompanied by the activation of the p38 signaling pathway. Inhibitors of Piezo1/2 can modulate 5-HT secretion and influence intestinal motility.

Metabolomics of early blight (Alternaria solani) susceptible tomato (Solanum lycopersicum) unfolds key biomarker metabolites and involved metabolic pathways.

Tomato (Solanum lycopersicum) is among the most important commercial horticultural crops worldwide. The crop quality and production is largely hampered due to the fungal pathogen Alternaria solani causing necrotrophic foliage early blight disease. Crop plants usually respond to the biotic challenges with altered metabolic composition and physiological perturbations. We have deciphered altered metabolite composition, modulated metabolic pathways and identified metabolite biomarkers in A. solani-challenged susceptible tomato variety Kashi Aman using Liquid Chromatography-Mass Spectrometry (LC-MS) based metabolomics. Alteration in the metabolite feature composition of pathogen-challenged (m/z 9405) and non-challenged (m/z 9667) plant leaves including 8487 infection-exclusive and 8742 non-infection exclusive features was observed. Functional annotation revealed putatively annotated metabolites and pathway mapping indicated their enrichment in metabolic pathways, biosynthesis of secondary metabolites, ubiquinone and terpenoid-quinones, brassinosteroids, steroids, terpenoids, phenylpropanoids, carotenoids, oxy/sphingolipids and metabolism of biotin and porphyrin. PCA, multivariate PLS-DA and OPLS-DA analysis showed sample discrimination. Significantly up regulated 481 and down regulated 548 metabolite features were identified based on the fold change (threshold ≥ 2.0). OPLS-DA model based on variable importance in projection (VIP scores) and FC threshold (> 2.0) revealed 41 up regulated discriminant metabolite features annotated as sphingosine, fecosterol, melatonin, serotonin, glucose 6-phosphate, zeatin, dihydrozeatin and zeatin-ß-D-glucoside. Similarly, 23 down regulated discriminant metabolites included histidinol, 4-aminobutyraldehyde, propanoate, tyramine and linalool. Melatonin and serotonin in the leaves were the two indoleamines being reported for the first time in tomato in response to the early blight pathogen. Receiver operating characteristic (ROC)-based biomarker analysis identified apigenin-7-glucoside, uridine, adenosyl-homocysteine, cGMP, tyrosine, pantothenic acid, riboflavin (as up regulated) and adenosine, homocyctine and azmaline (as down regulated) biomarkers. These results could aid in the development of metabolite-quantitative trait loci (mQTL). Furthermore, stress-induced biosynthetic pathways may be the potential targets for modifications through breeding programs or genetic engineering for improving crop performance in the fields.

Effect of Prolonged Exposure to Short Daylight and a Tryptophan Hydroxylase Inhibitor on the Behavior and Brain Serotonin System in Danio rerio.

We studied the effect of reduced tryptophan hydroxylase (TPH) activity and short daylight exposure on the behavior and the 5-HT system of the brain in D. rerio. Male and female D. rerio were exposed for 30 days to standard (12:12 h light:dark) and short (4:20 h light:dark) photoperiods in the presence or absence of TPH inhibitor (p-chlorophenylalanine, pCPA, 5 mg/liter). On day 31, the fish behavior in the "novel tank diving" test, their sex and body weight were determined, and the levels of pCPA, 5-HT, and its metabolite 5-HIAA were measured by HPLC; the levels of the key genes encoding metabolism enzymes (Tph1a, Tph1b, Tph2, and Mao) and receptors of 5-HT (Htr1aa, Htr2aa) were assessed by real-time PCR with reverse transcription. The short daylight exposure caused masculinization of females, reduced body weight, and motor activity in the "novel tank diving" test, but did not affect the 5-HT system of the brain. Long-term pCPA treatment had no effect on sex and body weight, significantly reduced the 5-HIAA level, but increased Tph1a and Tph2 gene expression in the brain. No effects of the interaction of short daylight and pCPA exposure on the sex, body weight, behavior, and 5-HT system of the brain were found. Thus, a moderate decrease in TPH activity cannot potentiate the negative effects of short daylight exposure on the sex, body weight, behavior, and 5-HT system of D. rerio.

Vitamin D modulation of brain-gut-virome disorder caused by polystyrene nanoplastics exposure in zebrafish (Danio rerio).

BACKGROUND: Many studies have investigated how nanoplastics (NPs) exposure mediates nerve and intestinal toxicity through a dysregulated brain-gut axis interaction, but there are few studies aimed at alleviating those effects. To determine whether and how vitamin D can impact that toxicity, fish were supplemented with a vitamin D-low diet and vitamin D-high diet. RESULTS: Transmission electron microscopy (TEM) showed that polystyrene nanoplastics (PS-NPs) accumulated in zebrafish brain and intestine, resulting in brain blood-brain barrier basement membrane damage and the vacuolization of intestinal goblet cells and mitochondria. A high concentration of vitamin D reduced the accumulation of PS-NPs in zebrafish brain tissues by 20% and intestinal tissues by 58.8% and 52.2%, respectively, and alleviated the pathological damage induced by PS-NPs. Adequate vitamin D significantly increased the content of serotonin (5-HT) and reduced the anxiety-like behavior of zebrafish caused by PS-NPs exposure. Virus metagenome showed that PS-NPs exposure affected the composition and abundance of zebrafish intestinal viruses. Differentially expressed viruses in the vitamin D-low and vitamin D-high group affected the secretion of brain neurotransmitters in zebrafish. Virus AF191073 was negatively correlated with neurotransmitter 5-HT, whereas KT319643 was positively correlated with malondialdehyde (MDA) content and the expression of cytochrome 1a1 (cyp1a1) and cytochrome 1b1 (cyp1b1) in the intestine. This suggests that AF191073 and KT319643 may be key viruses that mediate the vitamin D reduction in neurotoxicity and immunotoxicity induced by PS-NPs. CONCLUSION: Vitamin D can alleviate neurotoxicity and immunotoxicity induced by PS-NPs exposure by directionally altering the gut virome. These findings highlight the potential of vitamin D to alleviate the brain-gut-virome disorder caused by PS-NPs exposure and suggest potential therapeutic strategies to reduce the risk of NPs toxicity in aquaculture, that is, adding adequate vitamin D to diet. Video Abstract.

Serotonin receptor 4 agonism prevents high fat diet induced reduction in GLP-1 in mice.

Hormone-producing enteroendocrine cells (EECs) are present throughout the gastrointestinal tract and respond to various nutrient and gut microbiota produced metabolites stimuli. Two important EEC subtypes, Glucagon like peptide-1 (GLP-1) producing L-cells and serotonin (5-HT) producing enterochromaffin (EC) cells interact via paracrine signaling and exhibit bidirectional regulation of expression and secretion of produced hormones. Accordingly, in vitro studies suggest potential to modulate 5-HT secretion by GLP-1 receptor agonism, and L-cell differentiation via serotonin receptor 4 agonism. However, the importance of this cellular signaling on host metabolism is poorly understood. In this study, we found that two weeks of high fat diet (HFD) feeding reduced RNA expression of gut hormones, including proglucagon (Gcg) gene encoding GLP-1 and Tryptophan hydroxylase1 (Tph1) gene encoding rate limiting enzyme in 5-HT synthesis, specifically in the colon and reduced plasma GLP-1 levels. Levels of propionate and butyrate were also reduced following HFD. However, supplementation of sodium propionate did not improve HFD induced reduction in GLP-1. In contrast, chemical induction of serotonin receptor 4 promoted GLP-1 levels, colonic Gcg RNA expression accompanied by improvement in glucose tolerance in HFD-fed mouse. Thus, this study suggests a novel mechanism to improve glucose tolerance via serotonin receptor 4 stimulation in the HFD induced obese mouse model.

The Effects of Unilateral Labyrinthectomy on Monoamine Neurotransmitters in the Medial Vestibular Nucleus of Rats.

BACKGROUND: This study aimed to investigate the effects of unilateral labyrinthectomy (UL) on monoamine neurotransmitters in the medial vestibular nucleus (MVN) of rats. METHODS: Adult Sprague-Dawley rats were utilized for the vestibular impaired animal model through UL. The success of the model establishment and the recovery process were evaluated using vestibular behavioral tests, including spontaneous nystagmus, postural asymmetry, and balance beam test. Additionally, the expression levels of c-Fos protein in the MVN were assessed by immunofluorescence. Furthermore, changes in the expression levels of monoamine neurotransmitters, including 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), and histamine in the MVN, were analyzed using high-performance liquid chromatography (HPLC) at different time points after UL (4 h, 8 h, 1 day, 2 days, 4 days, and 7 days). RESULTS: Compared to the sham control group, the UL group exhibited the most pronounced vestibular impairment symptoms at 4 h post-UL, which significantly decreased at 4 days and almost fully recovered by 7 days. Immunofluorescence results showed a notable upregulation of c-Fos expression in the MVN subsequent to the UL-4 h, serving as a reliable indicator of heightened neuronal activity. In comparison with the sham group, HPLC analysis showed that the levels of 5-HT and NE in the ipsilesional MVN of the UL group were significantly elevated within 4 days after UL, and peaked on 1 day and 2 days, respectively. DA showed an increasing trend at different time points up to 7 days post-UL, while histamine levels significantly increased only at 1 day post-UL. CONCLUSIONS: UL-induced dynamic changes in monoamine neurotransmitters during the early compensation period in the rat MVN may be associated with the regulation of the central vestibular compensation mechanism by the MVN.

D-mannose is a rapid inducer of ACSS2 to trigger rapid and long-lasting antidepressant responses through augmenting BDNF and TPH2 levels.

The potentiation of synaptic plasticity and serotonin generation by brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (TPH2) is well characterized to facilitate rapid and long-lasting antidepressant actions. Therefore, the identification of the key protein that simultaneously controls both BDNF and TPH2 is important for the treatment of depression. We show here that a lack of acetyl-CoA synthetase short-chain family member 2 (ACSS2) causes impairments in BDNF-dependent synaptic plasticity and tryptophan hydroxylase 2 (TPH2)-mediated serotonin generation, thereby contributing to spontaneous and chronic restraint stress (CRS)-induced depressive-like behavior in mice. Conversely, D-mannose is identified as a rapid ACSS2 inducer and thus mediates rapid and long-lasting antidepressant-like effects. Mechanistically, acute and chronic D-mannose administration inhibits the phosphorylation of EF2 to increase BDNF levels and reverse the reduction of TPH2 histone acetylation and transcription. We reveal that ACSS2 promotes TPH2 histone acetylation and transcription with the requirement of AMPK activation. To elevate nuclear ACSS2 levels, D-mannose can rapidly and persistently activate AMPK via Ca2+-CAMKK2 and the lysosomal AXIN-LKB1 pathway to facilitate its fast-acting and persistent antidepressant responses. Taken together, the results presented here reveal that ACSS2 functions as a novel target to link rapid and persistent antidepressant actions and further suggest that D-mannose is a potential therapeutic agent to resist depression through its augmentation of the ACSS2 dependent BDNF and TPH2 pathways.

Reduction of p11 in dorsal raphe nucleus serotonergic neurons mediates depression-like behaviors.

The pathology of depression is related to the imbalance of various neurotransmitters. The dorsal raphe nucleus (DRN), the main brain region producing 5-HT, is crucially involved in the pathophysiology of depression. It contains several neuron types, in which GABAergic neurons are activated by stimuli associated with negative experiences and 5-HT neurons are activated by reward signals. However, little is known about its underlying molecular mechanisms. Here, we found that p11, a multifunctional protein associated with depression, was down-regulated by chronic social defeat stress in 5-HTDRN neurons. Knockdown of p11 in DRN induced depression-like behaviors, while its overexpression in 5-HTDRN neurons alleviated depression-like behavior caused by chronic social defeat stress. Further, p11 regulates membrane trafficking of glutamate receptors in 5-HTDRN neurons, suggesting a possible molecular mechanism underlying the participation of p11 in the pathological process of depression. This may facilitate the understanding of the molecular and cellular basis of depression.

Molecular Photoswitches Regulating the Activity of the Human Serotonin Transporter.

Serotonin is an essential mediator regulating diverse neural processes, and its deregulation is related to the development of debilitating neurological diseases. In particular, the human serotonin transporter (hSERT) is fundamental in completing the synaptic neural cycle by allowing reuptake of serotonin. Its inhibition is particularly attractive, especially as a pharmacological target against depressive syndrome. Here, we analyze, by using long-range molecular dynamic simulations, the behavior of a molecular photoswitch whose cis- and trans-isomers inhibit the hSERT differently. In particular, we evidence the structural and molecular basis behind the higher inhibiting capacity of the cis-isomer, which blocks more efficiently the hSERT conformational cycle, leading to serotonin uptake.

Co-exposure to lead, mercury, and cadmium induces neurobehavioral impairments in mice by interfering with dopaminergic and serotonergic neurotransmission in the striatum.

Humans are exposed to lead (Pb), mercury (Hg), and cadmium (Cd) through various routes, including drinking water, and such exposure can lead to a range of toxicological effects. However, few studies have investigated the toxic effects of exposure to mixtures of metals, particularly in relation to neurotoxicity. In this study, 7-week-old male mice were exposed to Pb, Hg, and Cd individually or in combination through their drinking water for 28 days. The mice exposed to the metal mixture exhibited significantly reduced motor coordination and impaired learning and memory abilities compared to the control group and each of the single metal exposure groups, indicating a higher level of neurotoxicity of the metal mixture. The dopamine content in the striatum was significantly lower in the metal mixture exposure group than in the single metal exposure groups and the control group. Furthermore, compared to the control group, the metal mixture exposure group showed a significantly lower expression level of tyrosine hydroxylase (TH) and significantly higher expression levels of dopamine transporter (DAT), tryptophan hydroxylase 1 (TPH1), and serotonin reuptake transporter (SERT). Notably, there were no significant differences in SERT expression between the single metal exposure groups and the control group, but SERT expression was significantly higher in the metal mixture exposure group than in the single metal and control groups. These findings suggest that the key proteins involved in the synthesis and reuptake of dopamine (TH and DAT, respectively), as well as in the synthesis and reuptake of serotonin (TPH1 and SERT, respectively), play crucial roles in the neurotoxic effects associated with exposure to metal mixtures. In conclusion, this study demonstrates that simultaneous exposure to different metals can impact key enzymes involved in dopaminergic and serotonergic neurotransmission processes, leading to disruptions in dopamine and serotonin homeostasis and consequently a range of detrimental neurobehavioral effects.

Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2.

Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood1. Dysfunction of monoaminergic circuits has been implicated in various neurodegenerative and neuropsychiatric disorders2. Vesicular monoamine transporters (VMATs) pack monoamines into vesicles for synaptic release and are essential to neurotransmission3-5. VMATs are also therapeutic drug targets for a number of different conditions6-9. Despite the importance of these transporters, the mechanisms of substrate transport and drug inhibition of VMATs have remained elusive. Here we report cryo-electron microscopy structures of the human vesicular monoamine transporter VMAT2 in complex with the antichorea drug tetrabenazine, the antihypertensive drug reserpine or the substrate serotonin. Remarkably, the two drugs use completely distinct inhibition mechanisms. Tetrabenazine binds VMAT2 in a lumen-facing conformation, locking the luminal gating lid in an occluded state to arrest the transport cycle. By contrast, reserpine binds in a cytoplasm-facing conformation, expanding the vestibule and blocking substrate access. Structural analyses of VMAT2 also reveal the conformational changes following transporter isomerization that drive substrate transport into the vesicle. These findings provide a structural framework for understanding the physiology and pharmacology of neurotransmitter packaging by synaptic vesicular transporters.

[Central Administration of p-Hydroxyamphetamine Produces a Behavioral Stimulant Effect in Rodents: Contribution of Dopamine and Serotonin Neurotransmission].

p-Hydroxyamphetamine (p-OHA) is an active metabolite of amphetamine (AMPH) and methamphetamine (METH), and can be detected in the brain for a relatively long period after high-dose administration of AMPH in rodents. p-OHA may be involved in the abnormal behavior observed during the withdrawal period after a chronic administration of AMPH or METH. Therefore, the author investigated the effect of an intracerebroventricular (i.c.v.) administration of p-OHA on the changes of locomotor activity and prepulse inhibition (PPI) in the acoustic startle response in rodents. The i.c.v. administration of p-OHA significantly increased locomotor activity in mice. This effect was prevented by a pretreatment with a dopamine (DA) uptake inhibitor. Furthermore, local infusion of p-OHA into the nucleus accumbens (NAc) significantly increased locomotor activity in rats. Together these results suggest that dopaminergic systems in the rodent NAc may play important roles in p-OHA-induced locomotor activity. Next, the author tested the effects of the i.c.v. administration of p-OHA on PPI in mice. p-OHA induced PPI disruptions that were significantly improved by the pretreatment with a typical or an atypical antipsychotic, D2 or D4 receptor antagonists, respectively. p-OHA-induced PPI disruptions were also improved by a serotonin (5-HT)2A receptor antagonist, a 5-HT synthesis inhibitor or a 5-HT neurotoxin. These results suggest that p-OHA-induced PPI disruptions were mediated by DA and 5-HT release and subsequent stimulation of D2, D4 and 5-HT2A receptors. Our recent series of reports indicate that the study of p-OHA may provide new insights into drug abuse as well as psychiatric disorders such as schizophrenia.

[Possible involvement of FFAR1 signaling in mouse emotional behaviors through the regulation of brain monoamine releases].

The free fatty acid receptor 1 (FFAR1) is suggested to function as a G protein-coupled receptor for medium- to long-chain free fatty acids. We have previously shown that FFAR1 signaling pathway plays an important suppressive role in spinal nociceptive processing after peripheral inflammation and nerve injury, and that FFAR1 agonists might serve as a new class of analgesics for treating inflammatory and neuropathic pain. To further pursue the functional significance of central FFAR1 signaling, we investigated the possible involvement of FFAR1 in endogenous pain modulation, depressive-like behavior, and aberrant behavior induced by addictive drugs using FFAR1 agonist (GW9508), FFAR1 antagonist (GW1100), and FFAR1 gene-deficient mice. As a result, FFAR1-deficient mice were found to exhibit stronger inflammatory and peripheral neuropathic pain-like behavior as well as depressive-like behavior. In particular, we noticed that peripheral nerve injury-induced depressive-like behavior was insensitive to imipramine. Next, we employed in vivo microdialysis to investigate whether FFAR1 is actually involved in the regulation of brain monoamines (dopamine and serotonin) releases. Our findings suggest that FFAR1 indirectly regulates dopamine release by promoting serotonin release. Thus, we are currently investigating how FFAR1 is involved in behavioral changes induced by addictive drugs such as cocaine and morphine. In this review, we briefly discuss about the possible involvement of FFAR1 in cocaine-induced locomotor hyperactivity.

Metabolomics-mediated elucidation of rice responses to salt stress.

MAIN CONCLUSION: Role of salinity responsive metabolites of rice and its wild species has been discussed. Salinity stress is one of the important environmental stresses that severely affects rice productivity. Although, several vital physio-biochemical and molecular responses have been activated in rice under salinity stress which were well described in literatures, the mechanistic role of salt stress and microbes-induced metabolites to overcome salt stress in rice are less studied. Nevertheless, over the years, metabolomic studies have allowed a comprehensive analyses of rice salt stress responses. Hence, we review the salt stress-triggered alterations of various metabolites in rice and discuss their significant roles toward salinity tolerance. Some of the metabolites such as serotonin, salicylic acid, ferulic acid and gentisic acid may act as signaling molecules to activate different downstream salt-tolerance mechanisms; whereas, the other compounds such as amino acids, sugars and organic acids directly act as protective agents to maintain osmotic balance and scavenger of reactive oxygen species during the salinity stress. The quantity, type, tissues specificity and time of accumulation of metabolites induced by salinity stress vary between salt-sensitive and tolerant rice genotypes and thus, contribute to their different degrees of salt tolerance. Moreover, few tolerance metabolites such as allantoin, serotonin and melatonin induce unique pathways for activation of defence mechanisms in salt-tolerant varieties of rice, suggesting their potential roles as the universal biomarkers for salt tolerance. Therefore, these metabolites can be applied exogenously to the sensitive genotypes of rice to enhance their performance under salt stress. Furthermore, the microbes of rhizosphere also participated in rice salt tolerance either directly or indirectly by regulating their metabolic pathways. Thus, this review for the first time offers valuable and comprehensive insights into salt-induced spatio-temporal and genotype-specific metabolites in different genotypes of rice which provide a reference point to analyze stress-gene-metabolite relationships for the biomarker designing in rice. Further, it can also help to decipher several metabolic systems associated with salt tolerance in rice which will be useful in developing salt-tolerance cultivars by conventional breeding/genetic engineering/exogenous application of metabolites.