Affect Locomotor Activity Research Articles

The synthetic cannabinoid agonist WIN 55,212-2 reduces experimental pruritus via CB2 receptor activation

Pruritus (i.e., the experience that evokes a desire to scratch) is an adaptive process that can become maladaptive, leading to a persistent scratch-itch cycle that potentiates pruritus and increases the risk of infection. Cannabinoid drugs have been reported to decrease pruritus, but often at doses that also decrease locomotor activity, which confounds assessments of utility. To determine the utility of cannabinoids in treating pruritus without undesirable adverse effects, the current preclinical study investigated a range of doses of the synthetic cannabinoid agonist, WIN 55,212-2, and two minor Cannabis phytoconstituents, Δ8-tetrahydrocannabinol and β-caryophyllene, in experimentally induced pruritus in male and female C57BL/6J adult mice. WIN 55,212-2 reduced compound 48/80-induced scratching, and this antipruritic effect was prevented by either chemically blocking (via SR144528 antagonism) or genetically deleting the CB2 cannabinoid receptor. The CB2 receptor selective agonist, JWH-133, also attenuated compound 48/80-induced scratching, while the CB1 positive allosteric modulator, ZCZ011, had no effect. Similarly, the minor phytocannabinoid Δ8-tetrahydrocannabinol reduced scratching at doses that did not affect locomotor activity. In contrast, the sesquiterpene cannabis constituent β-caryophyllene induced scratching, acting as a pruritogen. These preclinical data support the continuing investigation of cannabinoid receptor modulation as a potential therapeutic strategy for pruritus.

Discovery of novel thiosemicarbazone-acridine targeting butyrylcholinesterase with antioxidant, metal complexing and neuroprotector abilities as potential treatment of Alzheimer's disease: In vitro, in vivo, and in silico studies

Inhibition of cholinesterases, combined with antioxidant activity, metal-chelating capacity, and neuroprotection, is recognized as an effective multitarget therapy for the treatment of Alzheimer's disease (AD). Based on our in-house thiosemicarbazone-acridine compounds, this study recognized these derivatives as possible multi-target-directed ligand (MTDL). Initial screening against cholinesterases identified CL-01, which exhibited a promising IC50 value of 0.71 μM against butyrylcholinesterase (BChE). Twelve new derivatives were designed based on CL-01 aiming to retain the BChE inhibitory activity while incorporating a MTDL profile, including antioxidant properties and metal-complexing abilities. Among the new derivatives, CL-13 maintained a good BChE inhibition (IC50 = 1.15 μM) with improved selective index against acetylcholinesterase (SI = 9.2). The acridine nucleus was important for the activity, as its saturated tetrahydroacridine analogue (TA-01) showed a decrease in cholinesterases inhibition potencies and altered the mode of inhibition, revealing for the first time distinct functional roles for the two nuclei. Moreover, CL-13 emerged as a promising lead compound, demonstrating interesting antioxidant activity (DPPH EC50 = 47.01 μM), chelating capacity of biometals involved in Aβ aggregation and/or oxidative stress, and a lack of neurotoxicity at 50 μM in SH-SY5Y cells. It also exhibited neuroprotective effects in an in vitro oxidative stress model induced by H2O2. Finally, in vivo experiments confirmed that CL-13 effectively reversed scopolamine-induced cognitive impairment, without affecting locomotor activity in the mice.

Acute Administration of Edaravone Improves Cognitive Impairment in a Mouse Model of mPFC Ischemia: Crosstalk Between Necroptosis, Neuroinflammation, and Antioxidant Defense.

Edaravone (Eda), a well-known free radical scavenger, has been reported as a possible therapeutic agent for ischemic stroke patients' recovery. This study aimed to investigate the effects of time-dependent treatment with Eda on medial prefrontal cortex (mPFC) ischemia. Mice were randomly allocated into six groups: control, sham, normal saline, Eda-I, Eda-II, and Eda-III. After induction of a photothrombotic ischemia in the mPFC region, Eda-I, Eda-II, and Eda-III groups received 3mg/kg Eda intraperitoneally at the times of 0, 2, and 6h post-surgery. After 1day of recovery, the mice underwent behavioral tests (open field, novel object recognition, and T-maze). Next, necroptosis, NOD-like receptor protein 3 (NLRP3), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related protein levels were measured in the lesioned area using western blot analysis. For double confirmation, IL-1β and IL-18 were also assessed by immunofluorescence in the area. Further, histological evaluations were performed to measure tissue damage. The results showed that mPFC ischemia impaired recognition and spatial working memory without affecting locomotor activity, while immediate Eda administration improved cognitive impairments. Furthermore, acute Eda treatment reduced RIP1, RIP3, and MLKL levels, inhibited NLRP3 inflammasome proteins (NLRP3, ASC, and Cas1), decreased IL-1β and IL-18, upregulated Nrf2 and its targets (NQO-1 and HO-1), and diminished tissue damage. Our results highlighted the effects of acute administration of Eda post-stroke on improving cognitive impairments by suppressing necroptosis and NLRP3 inflammasome pathways and activating the Nrf2 antioxidant defense mechanism.

Activation of ventral pallidum-projecting neurons in the nucleus accumbens via 5-HT2C receptor stimulation regulates motivation for wheel running in male mice

Rodents have a strong motivation for wheel running; however, the neural mechanisms that regulate their motivation remain unknown. We investigated the possible involvement of serotonin (5-HT) systems in regulating motivation for wheel running in male mice. Systemic administration of a 5-HT1A receptor antagonist (WAY100635) increased the number of wheel rotations, whereas administration of a 5-HT2A or 5-HT2C receptor antagonist (volinanserin or SB242084, respectively) decreased it. In the open field test, neither WAY100635 nor volinanserin affected locomotor activity, whereas SB242084 increased locomotor activity. To identify the brain regions on which these antagonists act, we locally injected these into the motivational circuitry, including the nucleus accumbens (NAc), dorsomedial striatum (DM-Str), and medial prefrontal cortex (mPFC). Injection of SB242084 into the NAc, but not the DM-Str or mPFC, reduced the number of wheel rotations without altering locomotor activity. The local administration of WAY100635 or volinanserin to these brain regions did not affect the number of wheel rotations. Immunohistochemical analyses revealed that wheel running increased the number of c-Fos-positive cells in the NAc medial shell (NAc-MS), which was reduced by systemic SB242084 administration. In vitro slice whole-cell recordings showed that bath application of the 5-HT2C receptor agonist lorcaserin increased the frequency of spontaneous excitatory and inhibitory postsynaptic currents in the ventral tegmental area (VTA)-projecting neurons, whereas it only increased the frequency of spontaneous excitatory postsynaptic currents in ventral pallidum (VP)-projecting neurons in the NAc-MS. These findings suggest that the activation of VP-projecting NAc-MS neurons via 5-HT2C receptor stimulation regulates motivation for wheel running.

The ethanolic extract of Osmanthus fragrans var. thunbergii flowers ameliorates depressive-like behaviors of mice by modulating the serotonin system and suppressing neuroinflammation.

It is crucial to explore the impact of dietary interventions on depression and develop functional antidepressant foods, due to the significant side effects and poor treatment compliance of antidepressant drugs. Osmanthus fragrans flowers are edible and medicinal materials owing to their delightful floral aroma and significant health benefits. Here, we evaluated the antidepressant effects of the ethanolic extract of O. fragrans var. thunbergii flowers (OFE) and investigated the mechanisms of action on the serotonin system and neuroinflammation, and analyzed the main chemical components of OFE. A single administration of OFE significantly reduced the immobility duration in the forced swimming and tail suspension tests in mice without affecting locomotor activity. OFE exhibited selective enhancing effects on 5-HTergic function invivo, as demonstrated by its potentiating effects on 5-hydroxytryptophan (5-HTP)-induced head-twitch behavior and alleviation effects on reserpine-induced ptosis deficits. In addition, OFE increased 5-hydroxytryptamine (5-HT) concentration and upregulated 5-HT1A expression in reserpine-treated mice, further validating its effects on 5-HT transmission. Interestingly, OFE significantly alleviated microglia activation and the production of inflammatory mediators, both in reserpine-treated mice invivo and lipopolysaccharide (LPS)-stimulated BV-2 cells invitro. Additionally, 62 components in OFE were identified using ultra-performance liquid chromatography quadrupole time-of-flight high-resolution mass spectrometry, and glycoside derivatives were shown to be the major constituents of OFE. The present study showed that OFE can alleviate depressive-like behaviors by modulating the serotonin system and reducing neuroinflammation. These results suggest that OFE can be valuable dietary supplements with therapeutic effects on depression.

Subchronic administration of scopolamine reverses UCMS-induced behavior in mice via eEF2 protein dephosphorylation

BackgroundThe cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment. This study aimed to examine the suitability of the unpredictable chronic mild stress (UCMS) model of depression to reproduce the above scopolamine antidepressant activity patterns.MethodsRapid and sustained antidepressant-like effects were assessed by using the splash test, sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) in animals undergoing the UCMS procedure and stress-naïve C57BL/6J mice. Western Blotting was used to measure tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2) and postsynaptic density protein 95 (PSD95) levels.ResultsScopolamine induced antidepressant-like effects in a dose-dependent manner only after subchronic, but not single, administration in the UCMS model of depression in C57BL/6J mice without affecting locomotor activity. Specifically, scopolamine administered at a dose of 0.3 mg/kg for four consecutive days significantly reversed the UCMS-induced depressive-like behavior, such as apathy, anhedonia, and behavioral despair, while scopolamine, given at the same dose but only once, did not relieve the above symptoms. Scopolamine treatment was accompanied by eEF2 protein dephosphorylation and its subsequent reactivation in the prefrontal cortex (PFC).ConclusionSubchronic administration of scopolamine is needed to ameliorate UCMS-induced depressive-like behavior. The suggested mechanism of scopolamine action covers eEF2 protein activity in the PFC.

Combinatorial therapy with sub-effective Ro25-6981 and ZL006 ameliorates depressive-like behavior in single or combined stressed male mice

Major depression is a severe neuropsychiatric disorder that poses a significant challenge to health. However, development of an effective therapy for the disease has long been difficult. Here, we investigate the efficacy of a novel combinatorial treatment employing sub-effective doses of Ro25-6981, an antagonist targeting GluN2B-containing NMDA receptors, in conjunction with ZL006, an inhibitor of the PSD95/nNOS, on mouse models of depression. We employed social isolation, chronic restraint stress, or a combination of both to establish a depressed mouse model. Treatment with the drug combination reduced depressive-like behaviors without affecting locomotor activity in mice subjected to social isolation or chronic restraint stress. Furthermore, the combination therapy ameliorated depressive-like behaviors induced by combined stress of chronic restraint followed by social isolation. Mechanistic studies revealed that the combined treatment downregulated the hippocampal nitric oxide level. However, the therapeutic benefits of this combination were negated by the activation of NMDA receptors with a low dose of NMDA or by increasing nitric oxide levels with l-arginine. Moreover, the combinatorial treatment had negligible effects on object memory and contextual fear memory. Our data establish a combined therapy paradigm, providing a potential strategy targeting major depression.

Generation and Characterization of a Novel Prkcd-Cre Rat Model.

Activity of central amygdala (CeA) PKCδ expressing neurons has been linked to appetite regulation, anxiety-like behaviors, pain sensitivity, and addiction-related behaviors. Studies of the role that CeA PKCδ+ neurons play in these behaviors have largely been carried out in mice, and genetic tools that would allow selective manipulation of PKCδ+ cells in rats have been lacking. Here, we used a CRISPR/Cas9 strategy to generate a transgenic Prkcd-cre knock-in rat and characterized this model using anatomical, electrophysiological, and behavioral approaches in both sexes. In the CeA, Cre was selectively expressed in PKCδ+ cells. Anterograde projections of PKCδ+ neurons to cortical regions, subcortical regions, several hypothalamic nuclei, the amygdala complex, and midbrain dopaminergic regions were largely consistent with published mouse data. In a behavioral screen, we found no differences between Cre+ rats and Cre- wild-type littermates. Optogenetic stimulation of CeA PKCδ+ neurons in a palatable food intake assay resulted in an increased latency to first feeding and decreased total food intake, once again replicating published mouse findings. Lastly, using a real-time place preference task, we found that stimulation of PKCδ+ neurons promoted aversion, without affecting locomotor activity. Collectively, these findings establish the novel Prkcd-Cre rat line as a valuable tool that complements available mouse lines for investigating the functional role of PKCδ+ neurons.

Antidepressant-like effects of Cimicifuga dahurica (Turcz.) Maxim. via modulation of monoamine regulatory pathways

Sheng-ma is recorded in the Compendium of Materia Medica and mainly originates from the rhizomes of Cimicifuga dahurica (Turcz.) Maxim. (CD), Cimicifuga heracleifolia Kom. and Cimicifuga foetida L. The alcoholic extract of Cimicifuga foetida L. (Brand name: Ximingting®) has been approved for the treatment of perimenopausal symptoms accompanying hot flash, depression and anxiety in China. However, there's no further study about the antidepressant-like effects of C. dahurica (CD). The aim of this study is to investigate the antidepressant-like effect of CD extracted by 75% ethanol and its possible mechanisms.The neuro-protective effects of CD on injured PC12 cells induced by corticosterone was measured firstly. Then, forced swim test (FST), tail suspension test (TST), reserpine-induced hypothermia, 5-hydroxytryptophan (5-HTP) induced head twitch response in mice and chronic unpredictable mild stress (CUMS) on sucrose preference tests were executed. Moreover, the potential mechanisms were explored by measuring levels of monoamine neurotransmitter in mice frontal cortex and hippocampus, testing monoamine oxidase enzyme A (MAO-A) activities in the brains of CUMS-exposed mice. Results showed that CD (60, 120 mg/kg) can significantly decreased the immobility period in FST and TST in mice without affecting locomotor activity. CD (30 mg/kg, 60 mg/kg, 120 mg/kg) could significantly counteracted reserpine-induced hypothermia and increased the number of head-twitches in 5-HTP induced head twitch response. It was also found that the monoamine neurotransmitter levels in the hippocampus and frontal cortex were significantly increased in 60 mg/kg and 120 mg/kg CD treated mice. In addition, CD (60 and 120 mg/kg) significantly inhibited MAO-A after 6-week CUMS exposure. CD can effectively produce an antidepressant-like effect, which involved with modulation of monoamine regulatory pathways.

Socially activated neurons in the anterior cingulate cortex are essential for social behavior in mice

Social behavior, defined as any mode of communication between conspecifics is regulated by a widespread network comprising multiple brain structures. The anterior cingulate cortex (ACC) serves as a hub region interconnected with several brain regions involved in social behavior. Because the ACC coordinates various behaviors, it is important to focus on a subpopulation of neurons that are potentially involved in social behavior to clarify the precise role of the ACC in social behavior. In this study, we aimed to analyze the roles of a social stimulus-responsive subpopulation of neurons in the ACC in social behavior in mice. We demonstrated that a subpopulation of neurons in the ACC was activated by social stimuli and that silencing the social stimulus-responsive subpopulation of neurons in the ACC significantly impaired social interaction without affecting locomotor activity or anxiety-like behavior. Our current findings highlight the importance of the social stimulus-responsive subpopulation of neurons in the ACC for social behavior and the association between ACC dysfunction and impaired social behavior, which sheds light on therapeutic interventions for psychiatric conditions.

Selective knockdown of GABAA-α2 subunit in the dorsal dentate gyrus in adulthood induces anxiety, learning and memory deficits and impairs synaptic plasticity.

Animal studies and clinical trials suggest that maintenance of gamma-aminobutyric acid (GABA)-ergic activity may be crucial in coping with stressful conditions, anxiety and mood disorders. Drugs highly efficient in promoting anxiolysis were shown to activate this system, particularly via the α2-subunit of type A receptors (GABAA α2). Given the high expression of GABAA α2 in the dentate gyrus (DG) sub-field of the hippocampus, we sought to examine whether manipulation of the α2 subunit in this area will evoke changes in emotional behaviour, memory and learning as well as in synaptic plasticity. We found that knockdown of GABAAα2 receptor specifically in the dorsal DG of rats caused increased anxiety without affecting locomotor activity. Spatial memory and learning in the Morris water maze were also impaired in GABAAα2 receptor knocked down rats, an effect accompanied by alterations in synaptic plasticity, as assessed by long-term potentiation in the DG. Our findings provide further support to the notion that emotional information processing in the hippocampus may be controlled, at least in part, via the inhibitory GABAA α2 receptor subunit, opening a potential avenue for early interventions from pre- puberty into adulthood, as a strategy for controlling anxiety-related psychopathology.

Glyphosate and its formulated product Roundup Transorb R® affect locomotor activity and reproductive and developmental parameters in Jenynsia lineata fish: An intergenerational study

Glyphosate is the most widely utilized herbicide worldwide due to its effectiveness in controlling agricultural weeds. However, its persistence in aquatic ecosystems has raised concerns about the well-being of non-target organisms such as fish. This study aimed to evaluate the effects of chronic exposure (21 days) to glyphosate or its formulated product Roundup Transorb R®, at an environmentally relevant concentration permitted by regulations in certain countries (65 μg/L of glyphosate), on the locomotor activity and reproductive success of the fish Jenynsia lineata, as well as on the morphology/development and locomotor activity of its offspring, as intergenerational effects. Neither the pure nor formulated herbicide altered the distance traveled and velocity of adult fish exposed to the herbicide (F0), but they negatively affected reproductive success, decreasing the percentage of positive response to the presence of the female, reducing the number of gravid females, causing abortions, and lowering offspring survival (F1). In the F1 generation, a decrease in weight and length was noted along with developmental abnormalities in both treatment groups (pure or formulated glyphosate), with the formulation causing more harm. Observed developmental abnormalities included muscle atrophy, ascites, pigmentary disorders, vertebral agenesis, spinal deviation, and exophthalmia. Furthermore, parental exposure to pure glyphosate led to an increase in the distance traveled and velocity of F1 (hyperlocomotion), whereas exposure to the formulated product resulted in a decrease in these behaviors (hypolocomotion) of F1. These findings highlight the toxic effects of glyphosate at very low concentrations, although varying between pure and formulated, and demonstrate the intergenerational consequences of herbicide exposure, underscoring the risk to the survival of fish offspring in glyphosate-contaminated environments.

Naloxone increases conditioned fear responses during social buffering in male rats.

Social buffering is the phenomenon in which the presence of an affiliative conspecific mitigates stress responses. We previously demonstrated that social buffering completely ameliorates conditioned fear responses in rats. However, the neuromodulators involved in social buffering are poorly understood. Given that opioids, dopamine, oxytocin and vasopressin play an important role in affiliative behaviour, here, we assessed the effects of the most well-known antagonists, naloxone (opioid receptor antagonist), haloperidol (dopamine D2 receptor antagonist), atosiban (oxytocin receptor antagonist) and SR49059 (vasopressin V1a receptor antagonist), on social buffering. In Experiment 1, fear-conditioned male subjects were intraperitoneally administered one of the four antagonists 25 min prior to exposure to a conditioned stimulus with an unfamiliar non-conditioned rat. Naloxone, but not the other three antagonists, increased freezing and decreased walking and investigation as compared with saline administration. In Experiment 2, identical naloxone administration did not affect locomotor activity, anxiety-like behaviour or freezing in an open-field test. In Experiment 3, after confirming that the same naloxone administration again increased conditioned fear responses, as done in Experiment 1, we measured Fos expression in 16 brain regions. Compared with saline, naloxone increased Fos expression in the paraventricular nucleus of the hypothalamus and decreased Fos expression in the nucleus accumbens shell, anterior cingulate cortex and insular cortex and tended to decrease Fos expression in the nucleus accumbens core. Based on these results, we suggest that naloxone blocks social buffering of conditioned fear responses in male rats.

Waterborne exposure to the antineoplastic 5-fluorouracil alters lipid composition in larval zebrafish (Danio rerio)

Antineoplastic medications are present in aquatic environments and are measured at relatively high concentrations in hospital sewage effluent. Thus, it is important to characterize risk associated with waterborne exposures to anticancer drugs. The drug 5-fluorouracil (5-FU) is used to treat several types of cancers, acting to inhibit cell division and cellular metabolism. The objectives of this study were to determine the effects of 5-FU on developmental endpoints and lipid composition in zebrafish. 5-FU did not negatively affect development nor survival in developing zebrafish at concentrations up to 1000 μg/L. However, 5-FU increased neutral lipid content in zebrafish larvae, indicating potential for lipid dysregulation. To further discern effects on lipids, lipidomics was conducted and a total of 164 lipids belonging to 14 lipid classes were identified. Significant changes (false discovery rate < 0.05) in abundance were detected for 19 lipids including some ceramides, ether-linked phosphatidylethanolamines, and sphingomyelins among others. We also measured the expression levels of 14 lipid-related enzymes and transporters (e.g., acox3, dgat1, fads2, fasn, elovl2) using real-time PCR; however, mRNA abundance levels were not affected, suggesting transcriptional changes may not be a primary mechanism underlying lipid dysregulation. Locomotor activity was measured in zebrafish as lipids are needed for swimming activity in larvae. Exposure to 5-FU did not affect locomotor activity up to 1000 μg/L. We conclude that lipids accumulate in larval zebrafish with exposure to 5-FU, which can subsequently affect lipid composition. These data reveal potential lipid signatures of 5-FU exposure and contribute to risk assessments for antineoplastic exposure in aquatic environments.

TAAR1 as a new target for the treatment of bipolar disorder: Anti-manic and anti-depressant activity of the novel agonist PCC0105004

Background: Bipolar disorder (BD) is a deleterious psychiatric disorder, and the available pharmacotherapies have limited efficacy with significant side effects. Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for neuropsychiatric disorders such as schizophrenia and substance user disorders. However, it is unknown whether TAAR1 is involved in the pathogenesis of BD. This study examined the effects and underlying mechanisms of a novel TAAR1 agonist, PCC0105004, in a rat model of ouabain (OUA)-induced BD.Methods: Intracerebroventricular (ICV) administration of OUA-induced BD model was established. The in vitro cell-based cAMP assay was used to examine TAAR1 agonism of PCC0105004. The receptor specificity of PCC0105004 was determined by an off-target panel assay that included radioligand binding and enzymatic assays. The effects of PCC0105004 on manic-like and depressive-like behaviors were evaluated in the rat BD model. TAAR1-mediated signaling and oxidative stress parameters were biochemically determined in the prefrontal cortex and the hippocampus of rats.Results: Western blotting revealed reduced TAAR1 expression level in the prefrontal cortex but unchanged in the hippocampus in model rats. PCC0105004, a TAAR1 agonist with the agonism EC50 value of 0.06182 μM, attenuated the manic-like behaviors on the 7th day and the depressive-like behaviors on the 14th day at doses that did not affect locomotor activity in the BD rats. Mechanistically, PCC0105004 exerted its behavioral effects via the reduction of ROS damage through the phosphorylation activation of the TAAR1/Akt/GSK3β/BDNF signaling pathway.Conclusion: These results demonstrated the potential antimanic-like and antidepressant-like efficacy of a novel TAAR1 agonist PCC0105004 in rats and revealed its underlying molecular basis, which supports the possibility of TAAR1 agonists as candidate pharmacotherapeutics for BD.

Exposure to flutolanil at environmentally relevant concentrations can induce image and non-image-forming failure of zebrafish larvae through neuro and visual disruptions

Numerous pesticides pose a threat to aquatic ecosystems, jeopardizing aquatic animal species and impacting human health. While the contamination of aquatic environment by flutolanil and its adverse effects on animal in the treatment of rich sheath blight have been reported, the neuro-visual effects of flutolanil at environmentally relevant concentrations remain unknown. In this study, we administered flutolanil to zebrafish embryos (0, 0.125, 0.50 and 2.0 mg/L) for 4 days to investigate its impact on the neuro and visual system. The results revealed that flutolanil induced abnormal behavior in larvae, affecting locomotor activity, stimuli response and phototactic response. Additionally, it led to defective brain and ocular development and differentiation. The disruption extended to the neurological system and visual phototransduction of larvae, evidenced by significant disturbances in genes and proteins related to neurodevelopment, neurotransmission, eye development, and visual function. Untargeted metabolomics analysis revealed that the GABAergic signaling pathway and increased levels of glutamine, glutamate, andγ-aminobutyric acid were implicated in the response to neuro and visual system injury induced by flutolanil, contributing to aberrant development, behavioral issues, and endocrine disruption. This study highlights the neuro-visual injury caused by flutolanil in aquatic environment, offering fresh insights into the mechanisms underlying image and non-image effects.

Decreased hippocampal microglial cell activation by methanolic extract from the leaves of Mallotus oppositifolius (Geiseler) Müll. Arg contributes to its antidepressant-like effect

Background Natural remedies with neuroprotective effect are useful in neuroinflammation-associated depression. Although Mallotus oppositifolius extract (MOE) has previously demonstrated antidepressant and anti-inflammatory properties, its neuroprotective effect remains unknown. Thus, the study evaluated the effect of MOE on lipopolysaccharide (LPS)-induced neuroinflammation-associated depression in mice. Methods Antidepressant-like effect of MOE (10 – 100 mg/kg), fluoxetine (20 mg/kg) and minocycline (50 mg/kg) was established in naïve Institute of Cancer Research (ICR) mice using the forced swim (FST), tail suspension (TST) and open-space swim (OSST) tests. In a separate experiment, FST and TST were used to assess the effect of an 11-day pre-treatment with MOE (10 – 100 mg/kg) or minocycline (50 mg/kg) on LPS (1 mg/kg) neuroinflammation at 6 and 24 hours post LPS. Following these tests, mice were sacrificed and their hippocampi isolated to evaluate their resting and activated microglial cells using Golgi-Cox staining technique. Open-field test was used to assess locomotor activity. Results MOE, fluoxetine and minocycline significantly reduced immobility in FST, TST and OSST compared to vehicle (p &lt; 0.05), confirming their antidepressant-like effect. Interestingly, MOE’s antidepressant-like effect was faster than fluoxetine and minocycline. Conversely, LPS treatment increased immobility behavior at 6 and 24 hours, suggestive of neuroinflammation-induced depression. Compared to vehicle group, pre-treatment with MOE and minocycline ameliorated LPS-induced hippocampal microglial activation and reversed increased immobility behavior without affecting locomotor activity (p &lt; 0.05). Resting microglial cell count was significantly increased by MOE pre-treatment in the OSST-challenged mice compared to vehicle group (p &lt; 0.01). Similarly, MOE pre-treatment reversed LPS-induced reduction in resting microglial count, and restored resting microglial count to normal levels compared to LPS naive vehicle group. Conclusions Collectively, the results suggest that MOE exerts neuroprotective effect against LPS-induced neuroinflammation by decreasing the activation of microglia and increasing resting microglial count. This contributes to its antidepressant-like effect.

Additive anxiolytic-like effect of citicoline and ACPA in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice

The cannabinoid system plays a key role in stress-related emotional symptoms such as anxiety. Citicoline is a supplemental substance with neuroprotective properties that alleviates anxiety-related behaviors. There is a relation between the actions of cannabinoids and cholinergic systems. So, we decided to evaluate the effects of intracerebroventricular (i.c.v.) infusion of cannabinoid CB1 receptor agents on citicoline-produced response to anxiety-like behaviors in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice. For i.c.v. microinjection of drugs, a guide cannula was inserted in the left lateral ventricle. ARS was induced by movement restraint for 4 h. Anxiety-related behaviors were assessed using an elevated plus maze (EPM). The results showed that induction of ARS for 4 h decreased the percentage of time spent in the open arms (%OAT) and the percentage of entries to the open arms (%OAE) without affecting locomotor activity, showing anxiogenic-like behaviors. i.c.v. infusion of ACPA (1 µg/mouse) induced an anxiolytic-like effect due to the enhancement of %OAT in the NARS and ARS mice. Nonetheless, i.c.v. microinjection of AM251 (1 µg/mouse) decreased %OAT in the NARS and ARS mice which suggested an anxiogenic-like response. Intraperitoneal (i.p.) administration of citicoline (80 mg/kg) induced an anxiolytic-like effect by the augmentation of %OAT in the ARS mice. Furthermore, when ACPA and citicoline were co-administrated, ACPA potentiated the anxiolytic-like effect induced by citicoline in the NARS and ARS mice. On the other hand, when AM251 and the citicoline were co-injected, AM251 reversed the anxiolytic-like response induced by the citicoline in the NARS and ARS mice. The results of this research exhibited an additive effect between citicoline and ACPA on the induction of anxiolytic-like response in the NARS and ARS mice. Our results indicated an interaction between citicoline and cannabinoid CB1 receptor drugs on the control of anxiety-like behaviors in the NARS and ARS mice.

Pigment matters: Behavior and lateralization of albino and pigmented fish (Bronze Corydoras) in aquaculture

Animal welfare science recognizes fish as sentient beings capable of experiencing pain, stress, and various emotions. As social interactions and mutual relationships are essential for fish welfare, the social environment in aquacultures is important for fish welfare. Pigmentation influences fish social behavior, e.g., communication and/or shoaling behavior. We investigated how pigmentation and shoal phenotypic composition affect locomotor activity in relation to feeding, exploratory behavior, sheltering and lateralization in holding tanks and Y-mazes in pigmented and albino Bronze Corydoras (Corydoras aeneus). The fish were divided into three treatment groups: pigm only, alb only, and mix groups. Each group comprised 12 shoals, with a total of 288 fish distributed across 36 shoals, each containing eight individuals. The study revealed behavioral differences between fish with pigmented and albino phenotypes, both within and among shoals. For both phenotypes, an increase in locomotor activity before feeding was followed by a decrease in activity after food consumption, indicating an anticipatory response and a shift from foraging to postfeeding behavior. In the mixed shoals, pigmented fish exhibited greater activity and sheltering behavior than albino fish. Both albino and pigmented fish showed lateralization toward the right arm of the Y-maze; however, in the mixed shoals, the preference for the right arm was not significant. Albino fish reached the shelter at the end of the Y-maze more often; however, in the mixed shoals, albino fish maintained their success rate in exploring the maze, while pigmented fish showed an increased success rate. We emphasize the significance of considering phenotypic variation and shoal composition when evaluating fish behavior and welfare. Such insights can inform the management of practices in aquaculture and ornamental breeding to ensure optimal fish welfare and enhance their overall quality of life.

HIV-1 Tat and morphine interactions dynamically shift striatal monoamine levels and exploratory behaviors over time.

Despite the advent of combination anti-retroviral therapy (cART), nearly half of people infected with HIV treated with cART still exhibit HIV-associated neurocognitive disorders (HAND). HAND can be worsened by co-morbid opioid use disorder. The basal ganglia are particularly vulnerable to HIV-1 and exhibit higher viral loads and more severe pathology, which can be exacerbated by co-exposure to opioids. Evidence suggests that dopaminergic neurotransmission is disrupted by HIV exposure, however, little is known about whether co-exposure to opioids may alter neurotransmitter levels in the striatum and if this in turn influences behavior. Therefore, we assayed motor, anxiety-like, novelty-seeking, exploratory, and social behaviors, and levels of monoamines and their metabolites following 2 weeks and 2 months of Tat and/or morphine exposure in transgenic mice. Morphine decreased dopamine levels, but significantly elevated norepinephrine, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid, which typically correlated with increased locomotor behavior. The combination of Tat and morphine altered dopamine, DOPAC, and HVA concentrations differently depending on the neurotransmitter/metabolite and duration of exposure but did not affect the numbers of tyrosine hydroxylase-positive neurons in the mesencephalon. Tat exposure increased the latency to interact with novel conspecifics, but not other novel objects, suggesting the viral protein inhibits exploratory behavior initiation in a context-dependent manner. By contrast, and consistent with prior findings that opioid misuse can increase novelty-seeking behavior, morphine exposure increased the time spent exploring a novel environment. Finally, Tat and morphine interacted to affect locomotor activity in a time-dependent manner, while grip strength and rotarod performance were unaffected. Together, our results provide novel insight into the unique effects of HIV-1 Tat and morphine on monoamine neurochemistry that may underlie their divergent effects on motor and exploratory behavior.