Changes In Locomotor Activity Research Articles

Continuous locomotor activity monitoring to assess animal welfare following intracranial surgery in mice.

Locomotor activity can serve as a readout to identify discomfort and pain. Therefore, monitoring locomotor activity following interventions that induce potential discomfort may serve as a reliable method for evaluating animal health, complementing conventional methods such as body weight measurement. In this study, we used the digital ventilated cage (DVC®) system for the assessment of circadian locomotor activity, in addition to body weight monitoring, following intracranial stereotaxic surgery in an Alzheimer's disease mouse model (C57BL/6J/APPswe/PSEN1dE9). Stereotaxic surgery did not affect the organization of circadian locomotor activity of both 7-8-week-old and 19-21-week-old mice. However, we observed that both young and old mice exhibited a significant decrease in activity during the dark phase. Also, our study shows that changes in locomotor activity exhibit higher sensitivity in detecting alterations indicative of animal health compared to measuring body weight. In contrast to 7-8-week-old mice, where we observed no genotypic differences in locomotor activity, 19-21-week-old APP/PS1 mice showed increased locomotor activity compared to wild-type mice. Furthermore, our analyses revealed that a subset of the 7-8-week-old mice showed increased locomotor activity during the initial peak of the dark phase. One mouse experienced sudden death early in life, possibly due to epileptic seizures. Altogether, our findings affirm continuous activity measurements as used in the DVC® as a highly valuable objective method for post-surgical welfare monitoring. Its discerning capacity not only facilitates circadian locomotor rhythm assessment but also enables the identification of individual aberrant activity patterns, possibly indicative of epileptic seizures.

Scopoletin and rutin attenuate ethanol reward in mouse-conditioned place preference test

IntroductionIn Traditional Chinese Medicine (TCM), Morinda citrifolia Linn. (Hai ba ji), is utilized for its various parts such as leaves, fruits, flowers, roots, and bark, serving as a tonic and addressing ailments including fever, skin, eye, throat, and gum issues, as well as nausea, vomiting, and neurological diseases. Previous research indicated that M. citrifolia Linn. fruit and its juice reduced ethanol-conditioned place preference (CPP) in mice, with scopoletin (SCOP) and rutin (RUT) proposed as the main bioactive compounds responsible for this effect. This study aimed to evaluate the impact of SCOP and RUT on ethanol reward using the CPP test in mice. MethodsThe CPP protocol consisted of a habituation phase spanning 3 days, a 1-day preconditioning phase, 10 days of conditioning, a rest day, and a post-conditioning day. The vehicle-saline control and vehicle-ethanol control groups received oral administration of a 1 % w/v solution of sodium carboxymethyl cellulose (CMC) at a dosage of 10 ml/kg. SCOP and RUT were administered orally at doses ranging from 0.05 to 1 mg/kg body weight (bw), while acamprosate (ACAM) was administered at a dosage of 300 mg/kg bw, all one hour before postconditioning. Statistical analyses utilized both repeated measures two-way and one-way ANOVA. ResultsOral administration of SCOP (0.05, 0.1, and 0.5 mg/kg bw) and RUT (0.05 mg/kg bw) one hour before postconditioning testing on day 16 markedly reduced ethanol CPP in mice. Additionally, SCOP and RUT at all tested doses (0.05–1 mg/kg bw, p.o.) did not induce any changes in normal locomotor activity in mice. DiscussionThese results suggest that SCOP and RUT diminish ethanol reward in mice, underscoring the therapeutic potential of these phytochemicals in managing alcohol use disorder.

Effects of voluntary chronic intermittent access to ethanol on the behavioral performance in adult C57BL/6 J mice

BackgroundChronic alcohol drinking increases the risk of alcohol use disorders, causing various neurological disorders. However, the impact of different ethanol levels on a spectrum of behaviors during chronic drinking remains unclear. In this study, we established an intermittent access to ethanol in a two-bottle choice (IA2BC) procedure to explore the dose-dependent effects of ethanol on the behavioral performance of C57BL/6 J mice. MethodsAdult male C57BL/6 J mice were provided voluntary access to different ethanol concentrations (0 %, 5 %, 10 %, and 20 % ethanol) under a 12-week IA2BC paradigm. A battery of behavioral tests was administered to assess alterations in pain threshold, anxiety-like behaviors, locomotor activity, motor coordination, and cognition. Ethanol consumption and preference were monitored during each session. Moreover, the liver, heart, and lung tissues were examined using pathological microscopy. ResultsThe average (standard deviation) ethanol consumption of mice under the IA2BC paradigm increased dose-dependently to 5.1 (0.2), 8.7 (0.7), and 15.9 (0.8) g/kg/24 h with 5 %, 10 %, and 20 % ethanol, respectively. However, there is no significant difference in ethanol preference among all the ethanol groups. Chronic ethanol drinking caused hyperalgesia, cognitive impairment, and motor incoordination, but caused no changes in body temperature, locomotor activity, or anxiety-like behaviors. Minor histopathological alterations in the liver were detected; however, no major abnormal pathology was observed in the heart or lungs. ConclusionThese findings clarify the link between ethanol dosage and behavioral changes in mice over a 12-week IA2BC paradigm, thereby bridging the knowledge gap regarding the effects of chronic ethanol drinking on neurological disorders.

Influence of gestational window on offspring vascular health in rodents with in utero exposure to electronic cigarettes.

Studies have shown cerebrovascular dysfunction in offspring with full-gestational electronic cigarette (Ecig) exposure, but little is known about how individual trimester exposure impacts offspring health. This study aimed to determine if there is a critical window during gestation that contributes to vascular and anxiety-like behavioural changes seen with full-term exposure. To test this, rats were time-mated, and the pregnant dams were randomly assigned to Ecig exposure during first trimester (gestational day, GD2-7), second trimester (GD8-14), third trimester (GD15-21) or full-term gestation (GD2-21). We also assessed the effect of maternal preconception exposure. Both male and female offspring from all maternal exposure conditions were compared to offspring from dams under ambient air (control) conditions. Ecig exposure consisted of 60-puffs/day (5days/week) using either 5 or 30watts for each respective exposure group. We found that maternal exposure to Ecig in the second and third trimesters resulted in a decrease (23-38%) in vascular reactivity of the middle cerebral artery (MCA) reactivity in 3- and 6-month-old offspring compared to Air offspring. Further, the severity of impairment was comparable to the full-term exposure (31-46%). Offspring also displayed changes in body composition, body mass, anxiety-like behaviour and locomotor activity, indicating that Ecigs influence neurodevelopment and metabolism. Maternal preconception exposure showed no impact on offspring body mass, anxiety-like behaviour, or vascular function. Thus, the critical exposure window where Ecig affects vascular development in offspring occurs during mid- to late-gestation in pregnancy, and both 5W and 30W exposure produce significant vascular dysfunction compared to Air. KEY POINTS: Exposure to electronic cigarettes (Ecigs) is known to increase risk factors for cardiovascular disease in both animals and humans. Maternal Ecig use during pregnancy in rodents is found to impair the vascular health of adolescent and adult offspring, but the critical gestation window for Ecig-induced vascular impairment is not known. This study demonstrates Ecig exposure during mid- and late-gestation (i.e. second or third trimester) results in impaired endothelial cell-mediated dilatation (i.e. middle cerebral artery reactivity) and alters anxiety-like behaviour in offspring. Maternal exposure prior to conception did not impact offspring's vascular or anxiety-like behavioural outcomes. Rodent models have been a reliable and useful predictor of inhalation-induced harm to humans. These data indicate maternal use of Ecigs during pregnancy should not be considered safe, and begin to inform clinicians and women about potential long-term harm to their offspring.

Antidepressant-like and antioxidant effects of Morus nigra L. in rats subjected to the unpredictable chronic mild stress model

This study aimed to evaluate the antidepressant-like and antioxidant potential of the aqueous leaf extract of Morus nigra L. in rats subjected to unpredictable chronic mild stress (UCMS). Male Wistar rats were divided into four groups, control and stressed, and treated with saline or aqueous extract of M. nigra. The dose administered was 10 mg/kg daily by gavage for 5 weeks concurrently with UCMS. M. nigra extract which showed syringic acid, quercetin, and rutin, as major phenolic compounds decreased the immobility time without changes in locomotor activity of stressed rats, in the forced swimming and open field tests, respectively. In addition, the extract diminished carbonylated proteins, lipid peroxidation, and nitrite levels in the brains of rats subjected to UCMS. These data reinforced antidepressant-like properties with the involvement of oxidative stress modulation by M. nigra extract pointing it as a possible new adjuvant treatment for depression.

Overlapping Central Clock Network Circuitry Regulates Circadian Feeding and Activity Rhythms in Drosophila.

The circadian system coordinates multiple behavioral outputs to ensure proper temporal organization. Timing information underlying circadian regulation of behavior depends on a molecular circadian clock that operates within clock neurons in the brain. In Drosophila and other organisms, clock neurons can be divided into several molecularly and functionally discrete subpopulations that form an interconnected central clock network. It is unknown how circadian signals are coherently generated by the clock network and transmitted across output circuits that connect clock cells to downstream neurons that regulate behavior. Here, we have exhaustively investigated the contribution of clock neuron subsets to the control of two prominent behavioral outputs in Drosophila: locomotor activity and feeding. We have used cell-specific manipulations to eliminate molecular clock function or induce electrical silencing either broadly throughout the clock network or in specific subpopulations. We find that clock cell manipulations produce similar changes in locomotor activity and feeding, suggesting that overlapping central clock circuitry regulates these distinct behavioral outputs. Interestingly, the magnitude and nature of the effects depend on the clock subset targeted. Lateral clock neuron manipulations profoundly degrade the rhythmicity of feeding and activity. In contrast, dorsal clock neuron manipulations only subtly affect rhythmicity but produce pronounced changes in the distribution of activity and feeding across the day. These experiments expand our knowledge of clock regulation of activity rhythms and offer the first extensive characterization of central clock control of feeding rhythms. Despite similar effects of central clock cell disruptions on activity and feeding, we find that manipulations that prevent functional signaling in an identified output circuit preferentially degrade locomotor activity rhythms, leaving feeding rhythms relatively intact. This demonstrates that activity and feeding are indeed dissociable behaviors, and furthermore suggests that differential circadian control of these behaviors diverges in output circuits downstream of the clock network.

Beneficial effect of GABA-producing Lactiplantibacillus strain LPB145 isolated from cheese starters evaluated in anxiety- and depression-like behaviours in rats.

In a previous study, we reported the in vitro potential probiotic and gamma-aminobutyric acid (GABA) production, of several strains from a collection of Lactiplantibacillus (Lpb) strains within the community of natural whey starters from the artisanal cheese industry. GABA is a non-protein amino acid widely distributed in nature and produced in animals, plants, and microorganisms. However, the best known role of GABA is its function as the major inhibitory neurotransmitter of the central nervous system. Preclinical and clinical evidence suggests that the GABAergic system has a relevant role in mental health disorders, such as anxiety and major depression. The modulation of the GABAergic system has been suggested as a potential strategy for treatment, one such mechanism of modulation is the influence of the microbiota-gut-brain axis through probiotic treatments. The present study was designed to investigate the in vivo probiotic potential of LPB145, a Lactiplantibacillus strain previously characterised as a GABA-producing potentially probiotic strain. Therefore, we evaluated the behavioural effects of chronic oral administration of LPB145 on rats' anxiety- and depression-like behaviours, using the elevated plus maze, open field, and the forced swimming test. The impact of LPB145 strain treatment on the gut microbiota structure and diversity was assessed to discern a possible mechanism of action of the LPB145 treatment through the microbiota-gut-brain axis. Our results showed that LPB145 administration induced an antidepressive-like behaviour without changes in locomotor activity. In contrast, the treatment did not modify the experimental anxiety. The structure and diversity of the intestinal microbiota remained unaffected by the treatment when compared to the control. However, specific clades that could be implicated in the behavioural changes did show differences in their relative abundance. These findings provide evidence regarding the potential of probiotic strains isolated from alimentary sources, to modulate the microbiota-gut-brain axis and positively impact mental health.

Lack of Bmal1 leads to changes in rhythmicity and impairs motivation towards natural stimuli.

Maintaining proper circadian rhythms is essential for coordinating biological functions in mammals. This study investigates the effects of daily arrhythmicity using Bmal1-knockout (KO) mice as a model, aiming to understand behavioural and motivational implications. By employing a new mathematical analysis based on entropy divergence, we identified disrupted intricate activity patterns in mice derived by the complete absence of BMAL1 and quantified the difference regarding the activity oscillation's complexity. Changes in locomotor activity coincided with disturbances in circadian gene expression patterns. Additionally, we found a dysregulated gene expression profile particularly in brain nuclei like the ventral striatum, impacting genes related to reward and motivation. Further investigation revealed that arrhythmic mice exhibited heightened motivation for food and water rewards, indicating a link between circadian disruptions and the reward system. This research sheds light on how circadian clock alterations impact the gene expression regulating the reward system and how this, in turn, can lead to altered seeking behaviour and motivation for natural rewards. In summary, the present study contributes to our understanding of how reward processing is under the regulation of circadian clock machinery.

Robust Methods for Assessing the Characteristics of Locomotor Activity Based on Markerless Video Capture Data

Introduction. Analysis of locomotor activity is essential in a number of biomedical and pharmacological research designs, as well as environmental monitoring. The movement trajectories of biological objects can be represented by time series exhibiting a complex multicomponent structure and non-stationary dynamics, thus limiting the effectiveness of conventional correlation and spectral time series analysis methods. Recordings obtained using markerless technologies are typically characterized by enhanced noise levels, including both instrumental noise and anomalous errors associated with false estimates of the location of the points of interest, as well as gaps in the trajectories, promoting an urgent need in the development of robust methods to assess the characteristics of locomotor activity.Aim. Development of robust methods for assessing the characteristics of locomotor activity capable of efficient processing of noisy recordings obtained by markerless video-based motion capture systems.Materials and methods. In order to assess the characteristics of locomotor activity, the relative movements of body parts of laboratory animals were analyzed using the stability metrics of the mutual dynamics of their trajectories, their relative delays, as well as the relative duration of the recording fragments when relatively stable mutual dynamics could be observed. The local maxima of the cross-correlation function of two body fragments, the minima of the standard deviation of the difference between their Hilbert phases, as well as their relative delays, were used as the metrics of mutual dynamics.Results. The considered phase metrics were shown to explicitly reflect changes in locomotor activity, while the assessment of time delays using phase metric was shown to be prone to periodic error. The above limitation could be largely overcome using the correlation metrics, assuming that phase and correlation metrics could be combined.Conclusion. The proposed robust methods provide stable estimates of the characteristics of locomotor activity based on markerless video capture recordings, altogether increasing the efficiency of diagnostic procedures and assessment of the therapeutic effect during rehabilitation.

Glutamatergic signaling from melanin-concentrating hormone-producing neurons: A requirement for memory regulation, but not for metabolism control.

Melanin-concentrating hormone-producing neurons (MCH neurons), found mainly in the lateral hypothalamus and surrounding areas, play essential roles in various brain functions, including sleep and wakefulness, reward, metabolism, learning, and memory. These neurons coexpress several neurotransmitters and act as glutamatergic neurons. The contribution of glutamate from MCH neurons to memory- and metabolism-related functions has not been fully investigated. In a mouse model, we conditionally knocked out Slc17a6 gene, which encodes for vesicular glutamate transporter 2 (vGlut2), in the MCH neurons exclusively by using two different methods: the Cre recombinase/loxP system and in vivo genome editing using CRISPR/Cas9. Then, we evaluated several aspects of memory and measured metabolic rates using indirect calorimetry. We found that mice with MCH neuron-exclusive vGlut2 ablation had higher discrimination ratios between novel and familiar stimuli for novel object recognition, object location, and three-chamber tests. In contrast, there was no significant change in body weight, food intake, oxygen consumption, respiratory quotient, or locomotor activity. These findings suggest that glutamatergic signaling from MCH neurons is required to regulate memory, but its role in regulating metabolic rate is negligible.

Ketamine and fluoxetine exert similar actions on prelimbic and infralimbic responsivity to lateral septal nucleus stimulation in Wistar rats

Ketamine is a dissociative anesthetic that has been proposed to be a useful alternative in cases of a poor response to other treatments in patients with depression. Remarkably, beneficial clinical actions of ketamine are detected once its psychotropic actions disappear. Therefore, clinical actions may occur independently of dose. Most current studies focus on actions of ketamine on neurotrophic factors, but few studies have investigated actions of ketamine on neural structures for which actions of antidepressants have been previously explored. Lateral septal nucleus (LSN) stimulation reduces neural activity in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Fluoxetine increases inhibitory responsivity of the LSN-IL connection. In the present study, actions of an anesthetic dose of ketamine were compared with a high dose of fluoxetine on behavior and neural responsivity 24 h after drug administration. Fluoxetine reduced immobility in the forced swim test without changing locomotor activity in the open field test. Ketamine strongly decreased locomotor activity and did not produce changes in immobility. In another set of Wistar rats that received similar drug treatment regimens, the results indicated that LSN stimulation in saline-treated animals produced a long-lasting inhibitory afterdischarge in these mPFC subregions. Actions of ketamine on the LSN-mPFC connection reproduced actions of fluoxetine, consisting of accentuated inhibition of the LSN action on the mPFC. These findings suggest that independent of different actions on neurotransmission, the common final pathway of antidepressants lies in their actions on forebrain structures that are related to emotional regulation.

Polluted water from a storage dam (Villa Victoria, méxico) induces oxidative damage, AChE activity, embryotoxicity, and behavioral changes in Cyprinus carpio larvae

The Villa Victoria dam is one of the most important storage reservoirs in Mexico since it distributes water to more than 20 million inhabitants in the Metropolitan Zone of Mexico City. In this dam, the common carp (Cyprinus carpio) is an important food resource for the inhabitants, so the aim of this work was to evaluate the oxidative damage (lipoperoxidation, oxidized proteins, antioxidant enzymes activity and gene expression), AChE, embryotoxicity and behavioral changes in C. carpio embryos and larvae exposed to water from Villa Victoria dam for 24, 48, 72 and 96 h. The embryotoxicity was evaluated trough the General Morphology Score (GMS) and the teratogenic index. Behavioral changes in basal locomotor activity and thigmotaxis were evaluated in a DanioVision, Noldus ™. An increase in lipid and protein oxidation as well as modification of CAT, SOD and GPx enzymatic activity was observed during the exposure times. The GMS indicated a low development in the embryos, the teratogenic index was less than 1, however teratogenic effects as yolk edema, fin malformation, head malformation and scoliosis were observed. In parallel, an increase in AChE activity and gene expression was observed reflecting changes in distance traveled of the basal locomotor activity and thigmotaxis at the sampling points. In conclusion, pollutants in water from Villa Victoria dam caused oxidative damage, changes in SOD, CAT, GPx and AChE activity as well as embryotoxicity and modifications in the behavior of C. carpio larvae. This study demonstrates the need to implement restoration programs for this reservoir since, contamination in the Villa Victoria dam could eventually endanger aquatic life and human health.

Pharmacokinetics, pharmacodynamics and antinociceptive effects of buprenorphine following transdermal administration to horses

ObjectiveThis study describes the pharmacokinetics and pharmacodynamics, including antinociceptive effects, of a transdermal buprenorphine solution in horses. It was hypothesized that transdermal application would lead to sustained blood concentrations and antinociceptive effects with fewer adverse effects compared with intravenous (IV) injection. Study designProspective nonrandomized four-part parallel experimental study. AnimalsA group of eight horses (three mares and five geldings) aged 6–12 years. MethodsHorses were administered incremental doses of 15, 30 and 45 μg kg–1 of buprenorphine transdermal solution and a single IV dose of 5 μg kg–1 of buprenorphine with a 2 week washout period between treatments. Concentrations of buprenorphine were determined in plasma using liquid chromatography–tandem mass spectrometry and modeled using a nonlinear mixed effects population pharmacokinetic model to determine pharmacokinetic parameters. Pharmacodynamic effects, including changes in locomotor activity, heart rate, body temperature, gastrointestinal borborygmi, thermal and mechanical nociceptive thresholds were recorded. Mixed effects analysis of variance and post hoc comparisons were performed using a Bonferroni multiple comparison adjustment to assess differences in pharmacodynamic parameters between baseline and each time point within each dose group and between dose groups at the same time point. ResultsTransdermal application of buprenorphine resulted in low systemic concentrations relative to IV injection. Bioavailability after transdermal application was 11%. Thermal nociceptive thresholds were significantly (p < 0.05) increased (4.3–10.7% relative to baseline) for up to 72 hours in the IV dose group, but only sporadically in the transdermal dose groups (2.5–9.9% relative to baseline). Changes in locomotor activity, heart rate and borborygmi varied over time and with dose. Conclusions and clinical relevanceLimited thermal antinociceptive effects were observed at the transdermal doses studied likely owing to limited absorption relative to IV dosing. Future studies may be directed toward investigating antinociceptive effects of higher transdermal doses and different application sites.

Aging in zebrafish is associated with reduced locomotor activity and strain dependent changes in bottom dwelling and thigmotaxis.

Aging is associated with a wide range of physiological and behavioral changes in many species. Zebrafish, like humans, rodents, and birds, exhibits gradual senescence, and thus may be a useful model organism for identifying evolutionarily conserved mechanisms related to aging. Here, we compared behavior in the novel tank test of young (6-month-old) and middle aged (12-month-old) zebrafish from two strains (TL and TU) and both sexes. We find that this modest age difference results in a reduction in locomotor activity in male fish. We also found that background strain modulated the effects of age on predator avoidance behaviors related to anxiety: older female TL fish increased bottom dwelling whereas older male TU fish decreased thigmotaxis. Although there were no consistent effects of age on either short-term (within session) or long-term (next day) habituation to the novel tank, strain affected the habituation response. TL fish tended to increase their distance from the bottom of the tank whereas TU fish had no changes in bottom distance but instead tended to increase thigmotaxis. Our findings support the use of zebrafish for the study of how age affects locomotion and how genetics interacts with age and sex to alter exploratory and emotional behaviors in response to novelty.

Green supported of silver nanoparticles on the surface of reduced graphene oxide: Investigation of its anti-epileptic activity on experimental models of epilepsy in mice

This research demonstrated a novel, simple and environmentally safe process for the fabrication of graphene/silver composite using Malva sylvestris flower extract as a capping and reducing agent. Initially, the Malva sylvestris flower was used to make modified reduced graphene oxide that was coated by extract. The phytochemical groups of extract that have poylphenolic function can act as the green reducing agent for capping and reducing Ag ions on the surface of rGO (Reduced Graphene Oxide) to make the desired rGO/M.S./Ag NPs nanocomposite. The FT-IR, TEM, FE-SEM-EDX and XRD results confirmed the successful fabrication of the desired nanocomposite. The efficacy of the rGO/M.S./Ag NPs was first tested using the 6-Hz-induced seizure model. Subsequently, its effectiveness was assessed against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Additionally, the impact of the potent rGO/M.S./Ag NPs nanocomposite on Gamma amino butyric acid (GABA) levels in the brain was investigated to elucidate its potential mechanism of action. Furthermore, the effective rGO/M.S./Ag NPs nanocomposite underwent an actophotometer test to evaluate its potential to induce deficits in locomotor activity. During the 6-Hz seizure test, the rGO/M.S./Ag NPs nanocomposite demonstrated a significant and dose-dependent reduction in 6-Hz-induced seizures at doses of 30 and 90 µg/kg. Subsequently, the rGO/M.S./Ag NPs nanocomposite was assessed in MES and PTZ models. Interestingly, rGO/M.S./Ag NPs provided substantial and dose-dependent protection against MES (P < 0.01) and PTZ-induced (P < 0.01) seizures in mice. The rGO/M.S./Ag NPs nanocomposite exhibited a notable increase in brain GABA levels (P < 0.01) compared to the control, while showing no significant change in locomotor activity across all tested doses. Notably, a higher dose of rGO/M.S./Ag NPs nanocomposite (90 µg/kg, p.o.) and Diazepam (5 mg/mg, p.o.) completely prevented convulsions in all anticonvulsant tests. These results indicate that the rGO/M.S./Ag NPs nanocomposite possesses significant anticonvulsant properties, with one potential mechanism being the enhancement of GABA levels in the brain.

NSC689857, an inhibitor of Skp2, produces antidepressant-like effects in mice.

We have previously reported that two inhibitors of an E3 ligase S-phase kinase-associated protein 2 (Skp2), SMIP004 and C1, have an antidepressant-like effect in non-stressed and chronically stressed mice. This prompted us to ask whether other Skp2 inhibitors could also have an antidepressant effect. Here, we used NSC689857, another Skp2 inhibitor, to investigate this hypothesis. The results showed that administration of NSC689857 (5 mg/kg) produced an antidepressant-like effect in a time-dependent manner in non-stressed male mice, which started 8 days after drug administration. Dose-dependent analysis showed that administration of 5 and 10 mg/kg, but not 1 mg/kg, of NSC689857 produced antidepressant-like effects in both non-stressed male and female mice. Administration of NSC689857 (5 mg/kg) also induced antidepressant-like effects in non-stressed male mice when administered three times within 24 h (24, 5, and 1 h before testing) but not when administered acutely (1 h before testing). In addition, NSC689857 and fluoxetine coadministration produced additive antidepressant-like effects in non-stressed male mice. These effects of NSC689857 were not associated with the changes in locomotor activity. Administration of NSC689857 (5 mg/kg) also attenuated depression-like behaviors in male mice induced by chronic social defeat stress, suggesting therapeutic potential of NSC689857 in depression. Overall, these results suggest that NSC689857 is capable of exerting antidepressant-like effects in both non-stressed and chronically stressed mice.

Further proof on the role of accumbal nNOS in cocaine-seeking behavior in rats.

Cocaine use disorder (CUD) remains a severe health problem with no effective pharmacological therapy. One of the potential pharmacological strategies for CUD pharmacotherapy includes manipulations of the brain glutamatergic (Glu) system which is particularly involved in drug withdrawal and relapse. Previous research indicated a pivotal role of ionotropic N-methyl-D-aspartate (NMDA) receptors or metabotropic receptors' type 5 (mGlu5) receptors in controlling the reinstatement of cocaine. Stimulation of the above molecules results in the activation of the downstream signaling targets such as neuronal nitric oxide synthase (nNOS) and the release of nitric oxide. In this paper, we investigated the molecular changes in nNOS in the prefrontal cortex and nucleus accumbens following 3 and 10days of cocaine abstinence as well as the effectiveness of nNOS blockade with the selective enzyme inhibitor N-ω-propyl-L-arginine hydrochloride (L-NPA) on cocaine seeking in male rats. The effect of L-NPA on locomotor activity in drug-naïve animals was investigated. Ten-day (but not 3-day) cocaine abstinence from cocaine self-administration increased nNOS gene and protein expression in the nucleus accumbens, but not in the prefrontal cortex. L-NPA (0.5-5mg/kg) administered peripherally did not change locomotor activity but attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue. Our findings support accumbal nNOS as an important molecular player for cocaine seeking while its inhibitors could be considered as anti-cocaine pharmacological tools in male rats.

The role of mGluR5 on the therapeutic effects of ketamine in Wistar rats

RationaleKetamine produces dissociative, psychomimetic, anxiolytic, antidepressant, and anesthetic effects in a dose dependent manner. It has a complex mechanism of action that involve alterations in other glutamate receptors. The metabotropic glutamate receptor 5 (mGluR5) has been investigated in relation to the psychotic and anesthetic properties of ketamine, while its role in mediating the therapeutic effects of ketamine remains unknown.ObjectivesWe investigated the role of mGluR5 on the antidepressant, anxiolytic and fear memory-related effects of ketamine in adult male Wistar rats.MethodsTwo sets of experiments were conducted. We first utilized the positive allosteric modulator CDPPB to investigate how acute mGluR5 activation regulates the therapeutic effects of ketamine (10 mg/kg). We then tested the synergistic antidepressant effect of mGluR5 antagonism and ketamine by combining MTEP with a sub-effective dose of ketamine (1 mg/kg). Behavioral despair, locomotor activity, anxiety-like behavior, and fear memory were respectively assessed in the forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and auditory fear conditioning.ResultsEnhancing mGluR5 activity via CDPPB occluded the antidepressant effect of ketamine without changing locomotor activity. Furthermore, concomitant administration of MTEP and ketamine exhibited a robust synergistic antidepressant effect. The MTEP + ketamine treatment, however, blocked the anxiolytic effect observed by sole administration of MTEP or the low dose ketamine.ConclusionsThese findings suggest that suppressed mGluR5 activity is required for the antidepressant effects of ketamine. Consequently, the antagonism of mGluR5 enhances the antidepressant effectiveness of low dose ketamine, but eliminates its anxiolytic effects.

Vulnerability of Spatial Pattern Separation in 5xFAD Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD) is the most common cause of dementia and remains incurable. This age-related neurodegenerative disease is characterized by an early decline in episodic and spatial memory associated with progressive disruption of the hippocampal functioning. Recent clinical evidence suggests that impairment of the spatial pattern separation (SPS) function, which enables the encoding and storage of episodic spatial information, may be an indicator of the early stages of AD. The aim of our study was to characterize SPS performance at a prodromal stage in 5xFAD transgenic mouse model of AD. Behavioral performance of male wild-type (WT) and 5xFAD mice (n = 14 per group) was assessed from the age of 4 months in two validated paradigms of SPS function either based on spontaneous exploration of objects or on the use of a touchscreen system. Compared with age-matched WT littermates, a mild deficit in SPS function was observed in the object recognition task in 5xFAD mice, whereas both groups showed similar performance in the touchscreen-based task. These results were observed in the absence of changes in locomotor activity or anxiety-like behavior that could have interfered with the tasks assessing SPS function. Our results indicate an early vulnerability of the SPS function in 5xFAD mice in the paradigm based on spontaneous exploration of objects. Our work opens up the possibility of examining the early neurobiological processes involved in the decline of episodic memory and may help to propose new therapeutic strategies in the context of AD.

Bupropion and varenicline administration reversed depressive behavior induced by acetamiprid exposure in mice: the role of nAChRs in depression.

Acetamiprid (ACE), is a popular neonicotinoid pesticide, that has a high affinity for mammalian nicotinic acetylcholine receptors (nAChRs). Therefore, ACE might induce depressive effects by perturbing the cholinergic system in mammalian. The aim of this study was to evaluate the effects of ACE exposure on depressive-like behaviors and grip strength (GS) in mice. Also the possible role of nAChR activation in depression was assessed by varenicline, and bupropion. Male Swiss mice (27±2g) were daily exposed to ACE by gavage (0.1, 1, 5mg/kg), behavioral tests took place after 3h, 7days and 15days, the subacute ACE (0.1mg/kg) exposure was assessed after 30days. Varenicline (0.5mg/kg) or bupropion (4mg/kg) were injected intraperitoneally 30min prior exposure to (1mg/kg) ACE. The locomotor activity, forced swimming test (FST), and sucrose preference (SP) test were assessed. After a week ACE dose dependently increased the immobility time during FST, and after 15days' depressive behavior was observed equally for ACE (0.1-5mg/kg). The subacute exposure (0.1mg/kg) significantly increased the immobility time, SP also declined that revealed anhedonia. These behavioral changes showed that ACE can initiate depressive effects. The changes in locomotor activity were not significant. GS significantly reduced following a week of exposure to ACE (1-5mg/kg) that indicated neurotoxicity. These effects were antagonized by bupropion or varenicline, thus ACE effect on nAChRs was essential in initiating the depressive behavior.