Search Results (50)

Strobilurins are a prominent class of fungicides capable of entering aquatic environments via runoff and leaching from the soil. Findings from previous studies suggest that strobilurins are highly toxic in aquatic environments, and evidence of acute developmental toxicity and altered behavioral responses have been emphasized. The objective here was to determine the effects of a new strobilurin, metyltetraprole (MTP), on zebrafish using developmental endpoints, gene expression, and behavioral locomotor assays. We hypothesized that MTP would cause developmental toxicity and induce hyperactivity in zebrafish (Danio rerio). To test this, developing zebrafish embryos/larvae were exposed to environmentally relevant levels of MTP (0.1, 1, 10, and 100 µg/L) until 7 days post-fertilization. Survival percentages did not differ among the treatment groups. No change in reactive oxygen species production was detected, but two genes involved in the mitochondrial electron transport chain (mt-nd3 and uqcrc2) were altered in abundance following MTP exposure. Moreover, the highest concentration (100 µg/L) of MTP caused notable hyperactivity in the zebrafish in the visual motor response test. Overall, results from this study increase our knowledge regarding sub-lethal effects of MTP, helping inform risk assessment for aquatic environments. Full article

The amygdala, especially its central nucleus (CeA), is one of the key brain structures regulating fear, anxiety and stress responses and is also involved in gut microbiota signal processing. Amygdala hyperactivity, as well as microbiota alterations, plays an important role in the pathophysiology of anxiety disorders, depression or post-traumatic stress disorder (PTSD). The present study determines whether 3 weeks of galactooligosaccharide (GOS) supplementation alleviates behavioural, haematological, immunological and gut microbiota disturbances induced by long-term electrical stimulation of the CeA in rats (Stim). The unsupplemented Stim group showed locomotor hyperactivity and higher anxiety (measured with an actometer and the elevated plus maze, respectively), as well as a decrease in white blood cells (WBCs), lymphocytes (LYMs), red blood cells (RBCs) and platelets (PLTs); an elevation of TNFα; a reduction in IL-10 concentration in plasma; and microbiota alterations as compared to the control (Sham) group. GOS supplementation alleviated all these Stim-induced adverse effects or even normalised them to the sham group level. The effect of GOS was comparable to citalopram and even more effective in WBC and PLT normalisation and IL-10 induction. The obtained results indicate the high therapeutic potential of GOS in anxiety and stress-related disorders. GOS supplementation may support conventional therapy or the prevention of PTSD, depression and anxiety disorders. Full article

Poria cocos extract attenuates MK-801-induced hyperactivity via RhoA/ROCK1 pathway modulation in mice. Background/Objectives: Poria cocos (P. cocos), a traditional East Asian medicinal mushroom, serves as a medicine and nutritional supplement, has been used to improve sleep and mood. Its bioactive compounds may regulate calcium signaling and Rho family proteins, which are linked to cytoskeletal remodeling and psychiatric symptoms. This study investigated the effects of P. cocos ethanol extract (PCEE) on Rho signaling, cytoskeleton dynamics, and behavior in MK-801-treated cells and mice. Methods: PCEE components were analyzed using HPLC. IMR-32 and Neuro2A cells were treated with MK-801 and PCEE to assess changes in F-actin (via fluorescence staining), cell migration (wound healing and Transwell assays), and Rho signaling proteins (by immunoblotting). In vivo, C57BL/6 mice received MK-801 to induce hyperactivity, followed by PCEE treatment. RhoA/ROCK1 pathway protein levels in the prefrontal cortex were analyzed. Results: PCEE reversed MK-801-induced inhibition of cell migration, F-actin disruption, and dysregulation of Rho-related proteins (RhoGDI1, RhoA, CDC42, Rac1, ROCK1, MLC2, PFN1). In mice, PCEE significantly reduced MK-801-induced hyperactivity and normalized RhoA/ROCK1 signaling in the brain. Conclusion: PCEE modulates cytoskeletal dynamics by regulating RhoA/ROCK1 signaling and attenuates MK-801-induced behavioral and molecular changes, suggesting its therapeutic potential for psychosis with fewer adverse effects. Full article

A high-fat, high-sugar diet (HFHS) is known to exacerbate oxidative stress and behavioral dysfunctions, increasing susceptibility to cognitive decline. This study aimed to evaluate the effects of Stevia rebaudiana and Stachys sieboldii on lipid peroxidation and behavioral alterations in rats fed an HFHS diet. Forty Wistar rats were divided into four groups: a control group on a standard diet, an HFHS group, and two experimental groups receiving HFHS supplemented with either Stevia or Stachys for 30 days. Behavioral responses were assessed using the Open Field Test, and oxidative stress markers (malondialdehyde, conjugated dienes, ketodienes, and Schiff bases) were measured in brain homogenates. Stevia significantly reduced oxidative stress markers by 30–51%, whereas Stachys decreased hyperactive locomotor behavior by 63–68%. Correlation analysis revealed strong associations between lipid peroxidation and behavioral parameters. These findings suggest that Stevia is more effective in reducing oxidative stress, while Stachys better regulates excessive locomotion. Both plant-based supplements exhibit neuroprotective potential, with distinct mechanisms of action, supporting their use as dietary interventions to mitigate the effects of an HFHS diet on brain function. Full article

Background/Objectives Studies in rodents indicate that disruptions in both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling pathways are involved in the development of hyperactive behavior. We examined whether vinpocetine, a phosphodiesterase type 1 inhibitor that enhances brain cAMP and cGMP levels, could mitigate locomotor hyperactivity in mice exposed to lead during early development. Methods Swiss mice were exposed to 90 ppm of lead in their drinking water throughout gestation and the first ten postnatal days. At postnatal day 10 (PN10), blood lead levels (BLLs) were about 30 µg/dL. At PN30, animals either received vinpocetine (20 mg/kg, i.p.) or a vehicle 4 h before the evaluation of locomotor activity in the open field. Results Lead-exposed males did not display differences in locomotor activity compared to controls, while lead-exposed females showed a significant increase in locomotion. Vinpocetine treatment significantly reversed the lead-induced hyperactivity in females. Conclusions These findings suggest that the cAMP and cGMP signaling pathways play a role in the hyperactivity induced by lead exposure. Full article

Lead (Pb) is a well-known neurotoxin with established adverse effects on the neurological functions of children and younger adults, including motor, learning, and memory abilities. However, its potential impact on older adults has received less attention. Using the zebrafish model, our study aims to characterize the dose–response relationship between environmentally relevant Pb exposure levels and their effects on changes in behavior and transcriptomics during the geriatric periods. We exposed two-year-old zebrafish to waterborne lead acetate (1, 10, 100, 1000, or 10,000 µg/L) or a vehicle (DMSO) for 5 days. While lower concentrations (1–100 µg/L) reflect environmentally relevant Pb levels, higher concentrations (1000–10,000 µg/L) were included to assess acute toxicity under extreme exposure scenarios. We conducted adult behavior assessment to evaluate the locomotor activity following exposure. The same individual fish were subsequently sacrificed for brain dissection after a day of recovery in the aquatic system. RNA extraction and sequencing were then performed to evaluate the Pb-induced transcriptomic changes. Higher (1000–10,000 ug/L) Pb levels induced hyperactive locomotor patterns in aged zebrafish, while lower (10–100 ug/L) Pb levels resulted in the lowest locomotor activity compared to the control group. Exposure to 100 µg/L led to the highest number of differentially expressed genes (DEGs), while 10,000 µg/L induced larger fold changes in both directions. The neurological pathways impacted by Pb exposure include functions related to neurotransmission, such as cytoskeletal regulation and synaptogenesis, and oxidative stress response, such as mitochondrial dysfunction and downregulation of heat shock protein genes. These findings emphasize a U-shape dose–response relationship with Pb concentrations in locomotor activity and transcriptomic changes in the aging brain. Full article

Opioid-related deaths are attributed to overdoses, and fentanyl overdose has been on the rise in many parts of the world, including the USA. Glutamate transporter 1 (GLT-1) has been identified as a therapeutic target in several preclinical models of substance use disorders, and β-lactams effectively enhance its expression and function. In the current study, we characterized the metabolomic profile of the nucleus accumbens (NAc) in fentanyl-overdose mouse models, and we evaluated the protective effects of the functional enhancement of GLT-1 using β-lactams, ceftriaxone, and MC-100093. BALB/c mice were divided into four groups: control, fentanyl, fentanyl/ceftriaxone, and fentanyl/MC-100093. While the control group was intraperitoneally (i.p.) injected with normal saline simultaneously with other groups, all fentanyl groups were i.p. injected with 1 mg/kg of fentanyl as an overdose after habituation with four repetitive non-consecutive moderate doses (0.05 mg/kg) of fentanyl for a period of seven days. MC-100093 (50 mg/kg) and ceftriaxone (200 mg/kg) were i.p. injected from days 5 to 9. Gas chromatography–mass spectrometry (GC-MS) was used for metabolomics, and Western blotting was performed to determine the expression of target proteins. Y-maze spontaneous alternation performance and the open field activity monitoring system were used to measure behavioral manifestations. Fentanyl overdose altered the abundance of about 30 metabolites, reduced the expression of GLT-1, and induced the expression of inflammatory mediators IL-6 and TLR-4 in the NAc. MC-100093 and ceftriaxone attenuated the effects of fentanyl-induced downregulation of GLT-1 and upregulation of IL-6; however, only ceftriaxone attenuated fentanyl-induced upregulation of TRL4 expression. Both of the β-lactams attenuated the effects of fentanyl overdose on locomotor activities but did not induce significant changes in the overall metabolomic profile. Our findings revealed that the exposure to a high dose of fentanyl causes alterations in key metabolic pathways in the NAc. Pretreatment with ceftriaxone and MC-100093 normalized fentanyl-induced downregulation of GLT-1 expression with subsequent attenuation of neuroinflammation as well as the hyperactivity, indicating that β-lactams may be promising drugs for treating fentanyl use disorder. Full article

Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and do not alter agonist binding affinity and thus lack the neurotoxicity and epileptogenic effects associated with other AMPAR modulators. In these studies, we describe the pre-clinical pharmacology of ampakine 1-(benzofurazan-5-ylcarbonyl)morpholine (CX717). CX717 modestly offsets desensitization in hippocampal patches and augments synaptic transmission in vivo. CX717 also enhances long-term potentiation in rats, which is crucial for learning and memory. CX717 enhances performance in the eight-arm radial maze and abrogates amphetamine-induced locomotor activity while being devoid of cataleptic activity in rats. CX717 also ameliorates alfentanil-induced respiratory depression in rats and is not toxic to cultured rat neurons. CX717 is active at doses of 0.3–10 mg/kg and lacked serious adverse events in safety studies in mice up to 2000 mg/kg. CX717 was also previously shown to be safe in humans and effective in reversing opiate-induced respiratory depression and hyperactivity and inattentiveness in adults with ADHD. These findings support the continued clinical investigation of CX717 in the treatment of ADHD, dementia, and opiate-induced respiratory depression. Full article

One aspect of reproducibility in preclinical research that is frequently overlooked is the physical condition in which physiological, pharmacological, or behavioural recordings are conducted. In this study, the physical conditions of mice were altered through the attachments of wireless electrophysiological recording devices (Neural Activity Tracker-1, NAT-1). NAT-1 devices are miniaturised multichannel devices with onboard memory for direct high-resolution recording of brain activity for >48 h. Such devices may limit the mobility of animals and affect their behavioural performance due to the added weight (total weight of approximately 3.4 g). The mice were additionally treated with saline (control), N-methyl-D-aspartate (NMDA) receptor antagonist MK801 (0.85 mg/kg), or the muscarinic acetylcholine receptor blocker scopolamine (0.65 mg/kg) to allow exploration of the effect of NAT-1 attachments in pharmacologically treated mice. We found only minimal differences in behavioural outcomes with NAT-1 attachments in standard parameters of locomotor activity widely reported for the open field test between the drug treatments. Hypoactivity was globally observed as a consistent outcome in the MK801-treated mice and hyperactivity in scopolamine groups regardless of NAT-1 attachments. These data collectively confirm the reproducibility for combined behavioural, pharmacological, and physiological endpoints even in the presence of lightweight wireless data loggers. The NAT-1 therefore constitutes a pertinent tool for investigating brain activity in, e.g., drug discovery and models of neuropsychiatric and/or neurodegenerative diseases with minimal effects on pharmacological and behavioural outcomes. Full article

Growing evidence suggests that activators of nuclear factor erythroid-derived 2-like 2 (Nrf2), such as sulforaphane, may represent promising novel pharmacological targets for conditions related to oxidative stress, including depressive disorder. Therefore, we conducted a study to explore the behavioral and biochemical effects of repeated (14 days) sulforaphane (SFN) treatment in the olfactory bulbectomy (OB) animal model of depression. An open field test (OFT), splash test (ST), and spontaneous locomotor activity test (LA) were used to assess changes in depressive-like behavior and the potential antidepressant-like activity of SFN. The OB model induced hyperactivity in mice during the OFT and LA as well as a temporary loss of self-care and motivation in the ST. The repeated administration of SFN (10 mg/kg) effectively reversed these behavioral changes in OB mice across all tests. Additionally, a biochemical analysis revealed that SFN (10 mg/kg) increased the total antioxidant capacity in the frontal cortex and serum of the OB model. Furthermore, SFN (10 mg/kg) significantly enhanced superoxide dismutase activity in the serum of OB mice. Overall, the present study is the first to demonstrate the antidepressant-like effects of repeated SFN (10 mg/kg) treatment in the OB model and indicates that these benefits may be linked to improved oxidative status. Full article

Porphyran, a sulfated polysaccharide found in various species of marine red algae, has been demonstrated to exhibit diverse bioactivities, including anti-inflammatory effects. However, the protective effects of porphyran against cerebral ischemia and reperfusion (IR) injury have not been investigated. The aim of this study was to examine the neuroprotective effects of porphyran against brain IR injury and its underlying mechanisms using a gerbil model of transient forebrain ischemia (IR in the forebrain), which results in pyramidal cell (principal neuron) loss in the cornu ammonis 1 (CA1) subregion of the hippocampus on day 4 after IR. Porphyran (25 and 50 mg/kg) was orally administered daily for one week prior to IR. Pretreatment with 50 mg/kg of porphyran, but not 25 mg/kg, significantly attenuated locomotor hyperactivity and protected pyramidal cells located in the CA1 area from IR injury. The pretreatment with 50 mg/kg of porphyran significantly suppressed the IR-induced activation and proliferation of microglia in the CA1 subregion. Additionally, the pretreatment significantly inhibited the overexpressions of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing protein-3 (NLRP3) inflammasome complex, and pro-inflammatory cytokines (interleukin 1 beta and interleukin 18) induced by IR in the CA1 subregion. Overall, our findings suggest that porphyran exerts neuroprotective effects against brain IR injury, potentially by reducing the reaction (activation) and proliferation of microglia and reducing NLRP3 inflammasome-mediated neuroinflammation. Full article

Benzodiazepines, psychotropic drugs, are ubiquitous in the aquatic environment due to over-consumption and inefficient removal by sewage treatment plants. Bioaccumulation with consequent behavioral and physiological effects has been reported in many aquatic species. However, the responses are species-specific and still poorly understood. To improve the knowledge, we exposed the freshwater snail Planorbarius corneus to 1, 5, or 10 µg/L of delorazepam, the most widely consumed benzodiazepine in Italy. Conventional behavioral tests were used to assess the effects on locomotor and feeding behavior. Histological and biochemical analyses were also performed to detect possible changes in the structure and composition of the foot mucus and glands. The results show a paradoxical response with reduced feeding activity and locomotor hyperactivity. Pedal mucus was altered in texture but not in composition, becoming particularly rich in fibrous collagen-like material, and a significant change in the protein composition was highlighted in the foot. In conclusion, exposure to delorazepam induces disinhibited behavior in Planorbarius corneus, potentially increasing the risk of predation, and an increase in mucus protein production, which, together with reduced feeding activity, would severely compromise energy resources. Full article

The aim of the present study was to gain a better understanding of the role of brain-derived neurotrophic factor (BDNF) and dopamine D3 receptors in the effects of chronic methamphetamine (METH) on prepulse inhibition (PPI), an endophenotype of psychosis. We compared the effect of a three-week adolescent METH treatment protocol on the regulation of PPI in wildtype mice, BDNF heterozygous mice (HET), D3 receptor knockout mice (D3KO), and double-mutant mice (DM) with both BDNF heterozygosity and D3 receptor knockout. Chronic METH induced disruption of PPI regulation in male mice with BDNF haploinsufficiency (HET and DM), independent of D3 receptor knockout. Specifically, these mice showed reduced baseline PPI, as well as attenuated disruption of PPI induced by acute treatment with the dopamine receptor agonist, apomorphine (APO), or the glutamate NMDA receptor antagonist, MK-801. In contrast, there were no effects of BDNF heterozygosity or D3 knockout on PPI regulation in female mice. Chronic METH pretreatment induced the expected locomotor hyperactivity sensitisation, where female HET and DM mice also showed endogenous sensitisation. Differential sex-specific effects of genotype and METH pretreatment were observed on dopamine receptor and dopamine transporter gene expression in the striatum and frontal cortex. Taken together, these results show a significant involvement of BDNF in the long-term effects of METH on PPI, particularly in male mice, but these effects appear independent of D3 receptors. The role of this receptor in psychosis endophenotypes therefore remains unclear. Full article

The vacuolar H⁺-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely ATP6V0C, ATP6V1A, ATP6V0A1, and ATP6V1B2, have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant ATP6V1B2 p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated Atp6v1b2^emR506* mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of Atp6v1b2^emR506* mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that Atp6v1b2^emR506* mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in ATP6V1B2 can cause seizures and that the Atp6v1b2^emR506* heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders. Full article

Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using ³⁵S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl, and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity, which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay. Full article