Reduced Locomotor Activity Research Articles

Nicotinamide adenine dinucleotide supplementation fails to enhance anesthetic recovery in rodents

Nicotinamide Adenine Dinucleotide (NAD+) is implicated in bioenergetics, DNA repair, and senescence. Depletion of NAD+ is associated with aging and neurodegenerative disease, prompting a growing interest in NAD+ supplementation. With rising over-the-counter use of NAD, understanding their impact on anesthetic recovery becomes essential. This study investigates the effect of NADH, a common NAD+ precursor, on anesthesia in rodents. Baseline and post-anesthesia (1.5% isoflurane) open field and Y-maze activity were recorded in adult male and female C57BL/6 mice (n = 8–10/group). NADH (150 mg/kg, intraperitoneal) or vehicle (0.9% normal saline) were given at baseline or during anesthesia. The NADH-treated group exhibited a significant decrease in open-field activity relative to vehicle-treated. This diminished activity was reflected in reduced distance travelled and average velocity after emergence from anesthesia in the NADH-treated group. NADH treatment did not improve Y-maze performance after anesthesia, partly related to reduced locomotor activity in the NADH-treated group. This study demonstrates that NADH does not appear to hasten recovery from anesthesia. Instead, there was a depression in open-field activity and no change in Y-maze performance with NADH supplementation, indicators of locomotive and cognitive recovery in rodents. The broad implications of NAD+ in aging are likely to shape supplementation trends, highlighting the importance of understanding the potential influence of administering NAD+ on anesthetic sensitivity and recovery.

Individual Behavioral Syndromes and Shoal Characteristics in Farmed and Wild Acrossocheilus fasciatus

This study investigates the individual behavioral syndromes and shoal characteristics of farmed and wild populations of the cyprinid Acrossocheilus fasciatus to elucidate the factors influencing the efficacy of fish stock enhancement. We examined two wild populations from Quzhou and Lishui, in Zhejiang Province, China, and one farmed population from the same geographical location as the Quzhou wild population. Individual behavioral syndromes were thoroughly evaluated alongside shoal characteristics. Results indicated that farmed A. fasciatus exhibited greater boldness, exploratory behavior, and sociability compared to their wild counterparts. Wild populations demonstrated distinct behavioral traits, with the Quzhou population showing reduced locomotor activity and sociability, and the Lishui population displaying timidity. Shoal analysis revealed that wild fish had higher cohesion and shoal synchronization compared to farmed fish. Additionally, mixed groups exhibited intermediate locomotor behaviors but decreased cohesion, particularly in the Quzhou population. These findings underscore significant behavioral differences between farmed and wild fish, as well as among wild fish from different geographical locations, emphasizing the need for tailored training and environmental modifications in stock enhancement programs to improve survival.

Sulfamethizole Attenuates Pentylenetetrazole-Induced Seizures in Mice via mTOR Inhibition.

Epilepsy affects at least 1% of the global population of all socioeconomic backgrounds. Data obtained from previous studies suggest the role of mTOR signaling in epileptogenesis. The present study aimed to investigate the hypothesis that mTOR inhibitor sulfamethizole might produce antiepileptic effects in pentylenetetrazole (PTZ)-induced kindling seizures in mice. For induction of kindling, mice were administered 40 mg/kg PTZ on alternate days for 13 days. The severity of kindling was analyzed using a seizure intensity score. Rotarod performance, actophotometer, and chimney tests were performed to check muscle coordination and locomotor functions. mTOR and IL-6 levels were measured in the brain homogenate. Histological analyses were done using hematoxylin-eosin and cresyl violet stains. Sulfamethizole was administered daily at 10 and 50 mg/kg doses. PTZ administration resulted in kindling seizures in the PTZ-veh group. In addition, mice from the PTZ-veh group showed decreased fall time in rotarod performance, reduced locomotor activity, and failed chimney tests. mTOR and IL-6 levels were also increased in the brain, along with neuronal degeneration and a decreased layer of neuronal cells in the hippocampus. Treatment with sulfamethizole at 50 mg/kg significantly ameliorated seizure intensity score, seizure latency and duration, muscle coordination, and locomotor functions compared to the PTZ-veh group. It also downregulated brain mTOR and IL-6 expression significantly. In conclusion, sulfamethizole showed antiepileptic activity against PTZ-induced kindling seizure in mice via mTOR inhibition.

Triangulating evidence from the GALENOS living systematic review on trace amine-associated receptor 1 (TAAR1) agonists in psychosis.

Trace amine-associated receptor 1 (TAAR1) agonists offer a new approach, but there is uncertainty regarding their effects, exact mechanism of action and potential role in treating psychosis. To evaluate the available evidence on TAAR1 agonists in psychosis, using triangulation of the output of living systematic reviews (LSRs) of animal and human studies, and provide recommendations for future research prioritisation. This study is part of GALENOS (Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis). In the triangulation process, a multidisciplinary group of experts, including those with lived experience, met and appraised the first co-produced living systematic reviews from GALENOS, on TAAR1 agonists. The animal data suggested a potential antipsychotic effect, as TAAR1 agonists reduced locomotor activity induced by pro-psychotic drug treatment. Human studies showed few differences for ulotaront and ralmitaront compared with placebo in improving overall symptoms in adults with acute schizophrenia (four studies, n = 1291 participants, standardised mean difference (SMD) 0.15, 95% CI -0.05 to 0.34). Large placebo responses were seen in ulotaront phase three trials. Ralmitaront was less efficacious than risperidone (one study, n = 156 participants, SMD = -0.53, 95% CI -0.86 to -0.20). The side-effect profile of TAAR1 agonists was favourable compared with existing antipsychotics. Priorities for future studies included (a) using different animal models of psychosis with greater translational validity; (b) animal and human studies with wider outcomes including cognitive and affective symptoms and (c) mechanistic studies and investigations of other potential applications, such as adjunctive treatments and long-term outcomes. Recommendations for future iterations of the LSRs included (a) meta-analysis of individual human participant data, (b) including studies that used different methodologies and (c) assessing other disorders and symptoms. This co-produced, international triangulation examined the available evidence and developed recommendations for future research and clinical applications for TAAR1 agonists in psychosis. Broader challenges included difficulties in assessing the risk of bias, reproducibility, translation and interpretability of animal models to clinical outcomes, and a lack of individual and clinical characteristics in the human data. The research will inform a separate, independent prioritisation process, led by lived experience experts, to prioritise directions for future research.

Age is associated with altered locomotor and hypothermic response to acute nicotine.

Cigarette smoking is at an all-time low. However, nicotine consumption has diversified with the introduction of commercial tobacco products that include Electronic Nicotine Delivery Systems. Nicotine is the main psychoactive component of tobacco and contributes to the addictive properties of tobacco products. Prolonged nicotine exposure induces neural adaptations that promote addiction-related behaviors in an age-dependent manner. Here, we investigated nicotine sensitivity among young adult and middle-aged male mice by comparing initial responses to nicotine tartrate from different suppliers. We observed that all nicotine compounds tested in the present study induced a robust reduction in locomotor activity and body temperature, and nicotine exposure resulted in increased serum cotinine concentration. We observed age-related differences in the magnitude and the time course of nicotine responses for locomotor and hypothermic effects. Reduction in locomotor activity was larger among young adult mice, but the time course of this response was similar for both age groups. Nicotine-induced reduction in body temperature was of a comparable magnitude for both age groups but young adults showed a faster decrease than middle-aged mice. These results suggest that age of exposure is a key factor contributing to nicotine sensitivity and its potential addictive effects. These responses were consistently produced for nicotine tartrate from different sources. Our findings reveal distinct responses between young adults and middle-aged mice, suggesting that age-specific neurobiological mechanisms in nicotine sensitivity continue developing into adulthood. These age-related variations in nicotine response are crucial for developing targeted interventions and understanding the risk factors for nicotine dependence across the lifespan.

Agmatine Attenuates Behavioral and Biochemical Alterations in Rats Exposed to Ethanol during Adolescence

Background: Ethanol is a psychoactive substance and its use throughout adolescence may have a role in the development of alcoholism in adulthood which causes behavioral changes and structural alterations in particular brain regions that may be the source of these cognitive and motor impairments. As an endogenous amine, agmatine has drawn a lot of interest in relation to drug addiction and its aftereffects. It is an endogenous neuromodulator that has been shown to be a potential agent to manage diverse central nervous system (CNS) disorders. The current investigation aims to elucidate the role of agmatine in mediating behavioral alterations resulting from prolonged exposure to ethanol in rats during their early adolescent years. Methods: Rats received saline (1 ml/kg, p.o.) or ethanol (5 g/kg/day, 35% v/v) once a day from PND 28 to PND 49. Chronic ethanol intoxication during the CNS developing may induce sustainable neurobehavioral alterations in rats. After PND 70, the rats were subjected to behavioural and biochemical tests. Results: Chronic ethanol exposure significantly reduced locomotor activity, increased anxiety-like and depressive behaviors, and impaired cognitive function in adolescent rats. These behavioral alterations were accompanied by elevated oxidative stress, decreased hippocampal BDNF levels, increased levels of proinflammatory cytokines, and disrupted neurotransmitter balance. Agmatine administration at both 40 mg/kg and 80 mg/kg doses notably improved locomotor activity, reduced anxiety and depressive behaviors, and enhanced cognitive performance. Additionally, agmatine treatment reduced oxidative stress, restored BDNF levels, normalized TNF-α and IL6 levels, and corrected the neurotransmitter imbalance in ethanol-exposed rats. Conclusion: Prolonged exposure to ethanol during adolescence elicits persistent behavioural changes, characterized by diminished spontaneous locomotion and impaired balance. Administration of Agmatine effectively restores locomotor activity, alleviates anxiety and depression, and enhances both spatial learning and recognition memory in rats exposed to ethanol. Additionally, agmatine treatment attenuates oxidative stress indicators, including nitrite and lipid peroxidation levels, specifically in the cerebral cortex. These findings suggest that Agmatine holds potential as a viable therapeutic intervention for mitigating both the behavioural and biochemical repercussions induced by ethanol exposure in the rat model.

Potassium Release From the Habenular Astrocytes Induces Depressive-Like Behaviors in Mice.

The habenula has been implicated in psychiatric disorders such as depression, primarily because of its role in the modulation of the dopaminergic and serotonergic systems, which play a role in the pathophysiology of these disorders. Despite growing evidence supporting the role of the habenula in behavioral regulation, the process by which neural cells develop in the habenula remains elusive. Since the habenular anlage is found in the prosomere 2 domain expressing transcription factor Dbx1 in mouse embryos, we hypothesized that the Dbx1-expressing prosomere domain is a source of astrocytes that modulate neuronal activity in the habenula. To address this, we examined the cell lineage generated from Dbx1-expressing cells in male mice using tamoxifen-inducible Cre recombinase under the control of the Dbx1 promoter. Perinatal induction of Cre activity labeled cells migrating radially from the ventricular zone to the pial side of the habenular anlage, and eventually showed astrocyte-like morphology with expression of the marker protein, S100β, for mature astrocytes in the habenula of the adult mouse. Photostimulation of astrocytes expressing ChR2 released potassium ions into the extracellular space, which in turn excited the neurons with an increased firing rate in the lateral habenula. Finally, photostimulation of habenular astrocytes exacerbated depression-like phenotypes with reduced locomotor activity, exaggerated despair behavior and impaired sucrose preference in open-field, tail suspension and sucrose preference tests, respectively. These results indicated that the Dbx1-expressing perinatal domain generated astrocytes that modulated neuronal activity via the regulation of extracellular potassium levels.

Effects of piperine-haloperidol mixture on ketamine induced schizophrenia rats and metabolism-mediated inhibitory potency: in-vivo and in-vitro evaluation.

Haloperidol, a conventional antipsychotic, wasmixed with piperine in a ketamine-induced schizophrenia rat model to evaluate the interaction potential of this mixture through in-vitro and in-vivo analyses. Piperine, known for its CYP450 enzyme inhibitory effects, enhances the bioavailability of various drugs. Initial in-vitro assays using a high-throughput fluorometric method showed that the haloperidol-piperine mixture inhibited CYP3A4 and CYP2D6 enzymes, comparable to positive controls. In-vivo pharmacokinetic results revealed that piperine significantly increased haloperidol's plasma concentration and area under the curve while reducing clearance, indicating enhanced bioavailability. Pharmacodynamic assessments showed reductions in locomotor activity, immobility time, dopamine levels, and nitric oxide, with increased superoxide dismutase levels in the haloperidol-piperine group compared to haloperidol alone, reflecting enhanced therapeutic efficacy. These findings indicate that piperine can increase haloperidol exposure, potentially allowing for dose reduction and minimizing dose-related side effects. Limitations of this study include reliance on a rat model, which may not fully replicate human metabolism, and lack of long-term safety assessment. Future studies should explore the clinical applicability of this mixture in human trials, particularly focusing on safety, dosage optimization, and long-term effects. Additionally, understanding piperine's role in different metabolic pathways could guide the development of targeted bioavailability enhancers, improving efficacy for a range of CYP450-metabolized medications.

Zebrafish in-vivo study reveals deleterious activity of human TBC1D24 genetic variants linked with autosomal dominant hearing loss

Hearing loss is a common sensory impairment with a heterogeneous genetic etiology. Genetic variants in the TBC1D24 gene have recently emerged as an important cause of the non-syndromic autosomal dominant hearing loss (ADHL). However, the molecular mechanism behind the TBC1D24-associated ADHL is unknown. Using a zebrafish model, we investigated involvement of TBC1D24 in hearing and the functional effects of the associated ADHL-causing genetic variants. We show that the morpholino-mediated knock-down of Tbc1d24 resulted in defective ear kinocilia structure and reduced locomotor activity of the embryos. The observed phenotypes were rescued by a wild-type TBC1D24 mRNA but not by a mutant mRNA carrying the ADHL-causing variant c.553G>A (p.Asp185Asn), supporting its pathogenic potential. CRISPR-Cas9-mediated knock-out of tbc1d24 led to mechanosensory deficiency of lateral line neuromasts. Overexpression of TBC1D24 mRNA resulted in developmental abnormalities associated with ciliary dysfunction and mesendodermal mispatterning. We observed that the ADHL-causing TBC1D24 variants: c.553G>A (p.Asp185Asn); c.1460A>T (p.His487Leu), c.1461C>G (p.His487Gln) or a novel variant c.905T>G (p.Leu302Arg) alleviated the effect of overexpression, indicating that these variants disrupt the TBC1D24 function. Furthermore, the zebrafish phenotypes correspond to the severity of ADHL. Specific changes in ear structures upon TBC1D24 overexpression further highlighted its tissue-specific role in ciliary function and inner ear development. Our findings provide functional evidence for the pathogenic potential of the ADHL-causing TBC1D24 variants and lead to new insights into the function of TBC1D24 in cilia morphogenesis.

Abstract 4135662: Dietary Inulin Improves Glucose Metabolism and Energy Balance in Obese Mice via Adipocyte Free Fatty Acid Receptor 2 (FFAR2)

Background: Inulin is a non-digestible prebiotic dietary fiber that can promote metabolic health including reduced body weight and improved glucose metabolism via effects on gut microbiota. We hypothesize that inulin prevents obesity-associated cardiometabolic alterations by augmenting the production of short-chain fatty acids (SCFA) from gut microbiota, which activate free fatty acid receptor 2 (FFAR2), a major SCFA receptor, in murine adipose tissue. Methods: 8-week-old male C57BL/6J (wild-type, WT; n=34) and adipocyte FFAR2-knockout (Ad-FFAR2 KO; n=25) mice were fed a high-fat high-sucrose (HFHS) diet for 8 weeks, then randomized into experimental groups to receive either continued HFHS (n=8-13), or HFHS containing inulin (10% w/w chicory root inulin; n=17-21) for a further 5 weeks. Body weight was recorded weekly, food intake, body composition, and indirect calorimetry were assessed before and after the inulin intervention, and intraperitoneal glucose and insulin tolerance tests were performed. Subcutaneous and visceral white adipose tissue (WAT) samples were collected at the study termination. Results: HFHS-fed Ad-FFAR2 KO mice showed higher body weight (7.4%), fat mass, and WAT weight due to increased food intake, with worse glucose tolerance compared to WT mice. In WT mice, inulin significantly reduced body weight gain and body adiposity. These effects were associated with reduced locomotor activity and respiratory quotient (RQ) without effects on energy expenditure and were accompanied by improvements in glucose tolerance. Strikingly, inulin had no effect on body weight or body adiposity in Ad-FFAR2 KO mice but reduced RQ, locomotor activity, and improved glucose tolerance similar to WT mice. Conclusions: Our findings suggest that FFAR2 signaling in adipose tissue is crucial for improving cardiometabolic outcomes in obesity and that gut metabolites responsive to dietary interventions, such as inulin, are potential targets for obesity treatment strategies.

Chronic corticosterone exposure causes anxiety- and depression-related behaviors with altered gut microbial and brain metabolomic profiles in adult male C57BL/6J mice

Chronic exposure to glucocorticoids in response to long-term stress is thought to be a risk factor for major depression. Depression is associated with disturbances in the gut microbiota composition and peripheral and central energy metabolism. However, the relationship between chronic glucocorticoid exposure, the gut microbiota, and brain metabolism remains largely unknown. In this study, we first investigated the effects of chronic corticosterone exposure on various domains of behavior in adult male C57BL/6J mice treated with the glucocorticoid corticosterone to evaluate them as an animal model of depression. We then examined the gut microbial composition and brain and plasma metabolome in corticosterone-treated mice. Chronic corticosterone treatment resulted in reduced locomotor activity, increased anxiety-like and depression-related behaviors, decreased rotarod latency, reduced acoustic startle response, decreased social behavior, working memory deficits, impaired contextual fear memory, and enhanced cued fear memory. Chronic corticosterone treatment also altered the composition of gut microbiota, which has been reported to be associated with depression, such as increased abundance of Bifidobacterium, Turicibacter, and Corynebacterium and decreased abundance of Barnesiella. Metabolomic data revealed that long-term exposure to corticosterone led to a decrease in brain neurotransmitter metabolites, such as serotonin, 5-hydroxyindoleacetic acid, acetylcholine, and gamma-aminobutyric acid, as well as changes in betaine and methionine metabolism, as indicated by decreased levels of adenosine, dimethylglycine, choline, and methionine in the brain. These results indicate that mice treated with corticosterone have good face and construct validity as an animal model for studying anxiety and depression with altered gut microbial composition and brain metabolism, offering new insights into the neurobiological basis of depression arising from gut-brain axis dysfunction caused by prolonged exposure to excessive glucocorticoids.

Neuroprotective Roles of Lauric Acid and Resveratrol: Shared Benefits in Neuroinflammation and Anxiety, Distinct Effects on Memory Enhancement.

Neuroinflammation can be triggered by a high-fat/high-fructose diet (HFFD), and CD36 may be an underlying mechanism. Lauric acid (LA), the major fatty acid in coconut oil, and resveratrol, the plant-based polyphenolic compound, may exert anti-inflammatory effects. Therefore, this study investigated the possible effects of LA and resveratrol on diet-induced neuroinflammation and CD36. Healthy male C57BL/6 mice (8 weeks of age, n = 31) were fed a control diet (10%kcal fat) or diets containing high fat (60%kcal fat) and fructose (5% w/v fructose drinking water) for 6 weeks, ad libitum. Supplemented to the HFFD, mice daily received resveratrol (7.5 mg/kg) (HFFD-RSV) or LA (750 mg/kg) (HFFD-LA). At the end of the study, HFFD resulted in anxiety-like behavior, reduced locomotor activity, neuroinflammation (increased brain GFAP, IL-6, MCP-1, IFN-γ, TNF-α), and systemic inflammation (increased plasma GFAP, IFN-γ, TNF-α, IL-12p70, reduced plasma IL-10). HFFD-RSV and HFFD-LA alleviated HFFD-induced anxiety-like behavior, neuroinflammation, and systemic inflammation. HFFD-LA improved memory. Brain and plasma CD36 levels were increased by HFFD and reduced by HFFD-RSV or HFFD-LA. Dietary resveratrol and LA intake may alleviate HFFD-induced neuroinflammation, systemic inflammation, and anxiety-like behavior and improve memory, as CD36 may be an underlying mechanism.

Purkinje cell hyperexcitability and depressive-like behavior in mice lacking erg3 (ether-à-go-go-related gene) K+ channel subunits.

Potassium channels stabilize the resting potential and neuronal excitability. Among them, erg (ether-à-go-go-related gene) K+ channels represent a subfamily of voltage-gated channels, consisting of erg1, erg2, and erg3 subunits; however, their subunit-specific neuronal functions in vivo are barely understood. To find erg3- and erg1-mediated functions, we generated global Kcnh7 (erg3) and conditional Kcnh2 (erg1) knockout mice. We found that erg3 channels stabilize the resting potential and dampen spontaneous activity in cerebellar Purkinje cells (PCs) and hippocampal CA1 neurons, whereas erg1 channels have suprathreshold functions. Lack of erg3 subunits induced hyperexcitability with increased action potential firing in PCs, but not in CA1 neurons. Notably, erg3 depletion caused depressive-like behavior with reduced locomotor activity, strongly decreased digging behavior, and shorter latencies to fall off a rotating wheel, while learning and memory remained unchanged. Our data show that erg K+ channels containing erg3 subunits mediate a neuronal subthreshold K+ current that plays important roles in the regulation of locomotor behavior in vivo.

Evaluation of Anxiolytic Activity of Angiotensin Receptor Blockers Using Actophotometer Test in Wistar Rats.

Introduction Anxiety disorders are common mental illnesses impacting quality of life, with current treatments like benzodiazepines andselective serotonin reuptake inhibitors (SSRIs)facing limitations due to side effects. Angiotensin receptor blockers (ARBs), used primarily for hypertension, have shown potential neuropsychiatric benefits, including anxiolytic effects. This study explores the anxiolytic effects of two ARBs, telmisartan and losartan, by evaluating locomotor activity in Wistar rats, aiming to identify new treatment options for anxiety through modulation of the renin-angiotensin system. Aim To evaluate the anxiolytic activity of telmisartan and losartan in experimental Wistar rats. Materials and methods The study was carried out afterconsent was obtained from the Institutional Animal Ethics Committee (IAEC). The rats were divided into four groups: group 1 (control group) received distilled water (2 ml/kg), group 2 (diazepam 2 mg/kg group) received diazepam (2 mg/kg), group 3 (telmisartan 5 mg/kg group) received telmisartan (5 mg/kg), and group 4 (losartan 5 mg/kg group) received losartan (5 mg/kg). The actophotometer test, which measures the locomotor activity levels of rats, was utilized to evaluate their anxiolytic activity. The percent decrease in locomotor activity was calculated for statistical evaluation. Results Our investigation found that the telmisartan 5 mg/kg and losartan 5 mg/kg groups had considerable anxiolytic activity (p<0.05) compared to the control group, and it was comparableto the diazepam 2 mg/kg (p>0.05) group. Conclusion The findings of our study indicate that ARBs, specifically telmisartan 5 mg/kg and losartan 5 mg/kg, exhibit potential anxiolytic effects, evidenced by a significant reduction in locomotor activity in the actophotometer test. These results imply that ARBs could be considered as possible therapeutic agents for anxiety, providing a new perspective on their use beyond traditional cardiovascular applications.

Molecular and immunohistochemical alterations in fluoride-induced neurological impediment in adult rats

SummaryThis study highlights the potential neurotoxic and impaired behavioral effects associated with high fluoride concentrations in drinking water. PurposeFluoride is known to cause neurotoxicity, evinced by lower I.Q. levels in children from high-fluoride regions as compared to those in low-fluoride regions. Thus, the present study was designed to investigate the molecular mechanism behind the neurological and behavioural changes induced by sodium fluoride in Wistar rats. Material and methodsA total of 24 female Wistar rats, aged six weeks and weighing approximately 150–220 g, were randomly divided into three groups: Group I (control) received reverse osmosis (R.O.) water, Group II received Sodium Fluoride (NaF) at 10 ppm, and Group III received NaF at 50 ppm in their drinking water for 60 days. The animals underwent behavioural tests including the Forced Swim Test (F.S.T.), Open Field Test (OFT), and Novel Object Recognition Test (N.O.R.T.), to assess any alterations in behaviour. After 60 days, the animals were euthanized, and their blood and brain samples were analysed to evaluate biochemical changes by Western Blot/I.H.C. analysis of B.A.X., Bcl2, LC3B, TLR4, PARP1, p53, Caspase, α-Synuclein, PARKIN, NeuN, KI67, DNM-1, and M.F.N. for assessing molecular pathways for toxicity. ResultsImpaired locomotion, memory impairment, and behaviour resembling depression in the animals were evinced by reduced mobility index in the F.S.T., discrimination index in the N.O.R.T., and reduced locomotor activity in the open field test results. Additionally, alterations in antioxidant levels and oxidative stress parameters were observed in the brain. The expression levels of various apoptotic and inflammatory biomarkers (B.A.X., Bcl2, TLR4, PARP1, p53, and Caspase) showed apoptosis in neurons. The confocal studies showed increased expression of inflammatory (α-Synuclein, PARKIN), apoptotic (LC3B, B.A.X., p53, KI67), and mitochondrial dysfunction (NeuN, DNM-1, M.F.N.) markers in fluoride-treated animals. Toxicity was more prominent in 50 ppm of fluoride-treated animals. ConclusionFluoride showed potent neuronal toxicity as evidenced by alterations of various molecular markers.

Evaluation of (S)-T1 and (S)-T2 ligands targeting α3β4 nAChR as potential nicotine addiction pharmacotherapy.

Substance use disorders (SUDs) represent a significant global health concern, demanding the development of effective pharmacological treatments. To address this, an investigation was conducted to examine the anti-addictive properties of two compounds, (S)-T1 and (S)-T2, which specifically target the α3β4 nicotinic acetylcholine receptor (nAChR). The effects of (S)-T1 and (S)-T2 on nicotine-induced conditioned place preference (CPP), locomotor activity and dopamine levels in particular brain regions associated to addiction were investigated and compared in male C57BL/6N mice. The results demonstrate that neither (S)-T1 nor (S)-T2 induced place conditioning or conditioned place aversion (CPA), suggesting the absence of rewarding or aversive effects. Both compounds significantly attenuated nicotine-induced CPP, with (S)-T1 exhibiting a dose-dependent effect. Furthermore, the co-administration of (S)-T2 (10mg/kg) with nicotine markedly reduced locomotor activity compared to nicotine treatment alone. Additionally, dopamine analysis revealed that nicotine increased dopamine levels in the nucleus accumbens (NAc) and dorsal striatum, whereas the co-administration of (S)-T1 (1, 3, and 10mg/kg) and (S)-T2 (10mg/kg) significantly decreased dopamine levels in these brain regions. No significant effects were observed in the prefrontal cortex (PFC). These findings suggest that (S)-T1 and (S)-T2 hold promise for treating nicotine addiction by attenuating nicotine-induced CPP and modulating dopamine release in key reward-related brain regions. Further research is needed to gain insights into the underlying mechanisms behind their anti-addictive effects and substantiate their potential for treating nicotine addiction.

Daily rhythms in metabolic and locomotor behaviour of prematurely ageing PolgA mice.

Ageing is an inherent and intricate biological process that takes place in living organisms as time progresses. It involves the decline of multiple physiological functions, leading to body structure and overall performance modifications. The ageing process differs among individuals and is influenced by various factors, including lifestyle, environment and genetic makeup. Metabolic changes and reduced locomotor activity are common hallmarks of ageing. Our study focuses on exploring these phenomena in prematurely ageing PolgA(D257A/D257A) mice (also known as PolgA) aged 41-42 weeks, as they closely mimic human ageing. We assess parameters such as oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory exchange ratio (RER) and locomotor activity using a metabolic cage for 4 days and comparing them with age-matched wild-type littermates (WT). Our findings revealed that VO2, VCO2, RER, locomotor activities, water intake and feeding behaviour show a daily rhythm, aligning with roughly a 24-h cycle. We observed that the RER was significantly increased in PolgA mice compared to WT mice during the night-time of the light-dark cycle, suggesting a shift towards a higher reliance on carbohydrate metabolism due to more food intake during the active phase. Additionally, female PolgA mice displayed a distinct phenotype with reduced walking speed, walking distance, body weight and grip strength in comparison to male PolgA and WT mice, indicating an early sign of ageing. Taken together, our research highlights the impact of sex-specific patterns on ageing traits in PolgA mice aged 41-42 weeks, which may be attributable to human ageing phenotypes. The unique genetic composition and accelerated ageing characteristics of PolgA mice make them invaluable in ageing studies, facilitating the investigation of underlying biological mechanisms and the identification of potential therapeutic targets for age-related diseases.

Exposure to the herbicide tebuthiuron affects behavior, enzymatic activity, morphology and physiology of the midgut of the stingless bee Partamona helleri

Partamona helleri is an important pollinator in the Neotropics. However, this bee faces an increased risk of pesticide exposure, potentially affecting both individual bees and entire colonies. Thus, this study aimed to evaluate the effects of the herbicide tebuthiuron on behavior, antioxidant activity, midgut morphology, and signaling pathways related to cell death, cell proliferation and differentiation in P. helleri workers. tebuthiuron significantly reduced locomotor activity and induced morphological changes in the midgut. The activity of the detoxification enzymes superoxide dismutase and glutathione S-transferase increased after exposure, indicating a detoxification mechanism. Furthermore, the herbicide led to alterations in the number of positive cells for signaling-pathway proteins in the midgut of bees, suggesting induction of apoptotic cell death and disruption of midgut epithelial regeneration. Therefore, tebuthiuron may negatively impact the behavior, antioxidant activity, morphology, and physiology of P. helleri workers, potentially posing a threat to the survival of this non-target organism.

Exposure Effects of Environmentally Relevant Concentrations of the Tricyclic Antidepressant Amitriptyline in Early Life Stage Zebrafish.

Antidepressants are one of the most globally prescribed classes of pharmaceuticals, and drug target conservation across phyla means that nontarget organisms may be at risk from the effects of exposure. Here, we address the knowledge gap for the effects of chronic exposure (28 days) to the tricyclic antidepressant amitriptyline (AMI) on fish, including for concentrations with environmental relevance, using zebrafish (Danio rerio) as our experimental model. AMI was found to bioconcentrate in zebrafish, was readily transformed to its major active metabolite nortriptyline, and induced a pharmacological effect (downregulation of the gene encoding the serotonin transporter; slc6a4a) at environmentally relevant concentrations (0.03 μg/L and above). Exposures to AMI at higher concentrations accelerated the hatch rate and reduced locomotor activity, the latter of which was abolished after a 14 day period of depuration. The lack of any response on the features of physiology and behavior we measured at concentrations found in the environment would indicate that AMI poses a relatively low level of risk to fish populations. The pseudopersistence and likely presence of multiple drugs acting via the same mechanism of action, however, together with a global trend for increased prescription rates, mean that this risk may be underestimated using current ecotoxicological assessment paradigms.

Effect of Cinnamaldehyde Chalcone on Behavior in Adult Zebrafish (Danio rerio): In Silico Approach.

The study focuses on the anxiolytic potential of chalcone (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (CHALCNM) in adult zebrafish. Successfully synthesized in 58 % yield, CHALCNM demonstrated no toxicity after 96 h of exposure. In behavioral tests, CHALCNM (40 mg/kg) reduced locomotor activity and promoted less anxious behavior in zebrafish, confirmed by increased permanence in the light zone of the aquarium. Flumazenil reversed its anxiolytic effect, indicating interaction with GABAA receptors. Furthermore, CHALCNM (4 and 20 mg/kg) preserved zebrafish memory in inhibitory avoidance tests. Virtual screening and ADMET profile studies suggest high oral bioavailability, access to the CNS, favored by low topological polarity (TPSA≤75 Å2) and low incidence of hepatotoxicity, standing out as a promising pharmacological agent against the GABAergic system. In molecular coupling, CHALCNM demonstrated superior affinity to diazepam for the GABAA receptor. These results reinforce the therapeutic potential of CHALCNM in the treatment of anxiety, highlighting its possible future clinical application.