Aggressive Behavior In Mice Research Articles

Disruption of Cdk5-GluN2B complex by a small interfering peptide attenuates social isolation-induced escalated intermale attack behavior and hippocampal oxidative stress in mice

Social isolation has emerged as a significant issue during the COVID-19 pandemic that can adversely impact human mental health and potentially lead to pathological aggression. Given the lack of effective therapeutic interventions for aggressive behavior, alternative approaches are necessary. In this study, we utilized a genetic method combined with a pharmacological approach to identify and demonstrate the crucial role of Cdk5 in escalated intermale attack behavior induced by 2-week social isolation. Moreover, we developed a small peptide that effectively disrupts the interaction between Cdk5 and GluN2B, given the known involvement of this complex in various neuropsychiatric disorders. Administration of the peptide, either systemically or via intrahippocampal injection, significantly reduced oxidative stress in the hippocampus and attenuated intermale attack behavior induced by 2-week social isolation. These findings highlight the previously unknown role of the hippocampal Cdk5-GluN2B complex in social isolation-induced aggressive behavior in mice and propose the peptide as a promising therapeutic strategy for regulating attack behavior and oxidative stress.

Screening of Neuropharmacological Activities of Naringi crenulata (Roxb.) Nicolson Leaves

Purpose: Although the global prevalence of psychological disorders is increasing continually, the efficacies of therapeutic strategies are still very limited. Oxidative stress has been implicated in the pathogenesis of psychiatric disorders and substances possessing antioxidant activity can alleviate the mentioned conditions. Therefore, we hypothesized that Naringi crenulata (Roxb.) Nicolson leaves, a medicinal plant claimed for nerve tonic, also possess neuropharmacological activities which provide an advantage for psychiatric disorders.
 Methods: The present study was carried out to perform neuropharmacological screenings methods on sedatives and hypnotics (Phenobarbitone sodium-induced sleep latency and sleep time and Motor coordination activity), anxiolytics (elevated plus maze and open field test), anti-depressants (forced swim test and L-dopa induced hyperactive aggressive behaviour in mice) and anticonvulsants activities (PTZ and MES induced convulsions) in Swiss Albino mice and Sprague Dawley rats.
 Results: The methanolic extract of a higher dose of Phenobarbitone sodium in Naringi crenulata induced sleep latency and sleep time significant results. The extracts of Naringi crenulate showed a significant dose-dependent increase in muscle relaxation in motor coordination activity. In the experiment of PTZ-induced convulsions, the latency of seizures was prolonged by the extracts in a dose-dependent manner. Even in MES-induced convulsion, the results were extremely significant for the 400mg/kg of MENC. The depressant effect was observed to be significant to the extracts of the herb in the Open Field test and also for the Elevated Plus Maze apparatus. In the Forced Swim Test, MENC (400 mg/kg) significantly lengthened the time spent immobile (p <0.01), indicating a CNS depressive impact. Lastly in L-dopa-induced hyperactive aggressive behaviour in mice, results suggest that NC has antidepressant efficacy due to its influence on the serotonergic, noradrenergic, and dopaminergic systems.
 Conclusion: The methanolic extract of Naringi crenulata (Roxb.) Nicolson leaves showed significant neuroprotective activity. So, the extracts of Naringi crenulata can be used for the treatment of a wide variety of neurological ailments in humans.

Reduction of aggressive behaviour following hypothalamic deep brain stimulation: Involvement of 5-HT1A and testosterone

BackgroundAggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated. The hypothalamus is a key structure in the neurocircuitry of AB. An imbalance between serotonin (5-HT) and steroid hormones seems to exacerbate AB. ObjectivesTo test whether pHyp-DBS reduces aggressive behaviour in mice through mechanisms involving testosterone and 5-HT. MethodsMale mice were housed with females for two weeks. These resident animals become territorial and aggressive towards intruder mice placed in their cages. Residents had electrodes implanted in the pHyp. DBS was administered for 5 h/day for 8 consecutive encounters prior to the interaction with the intruder. After testing, blood and brains were recovered for measuring testosterone and 5-HT receptor density, respectively. In a second experiment, residents received WAY-100635 (5-HT1A antagonist) or saline injections prior to pHyp-DBS. After the first 4 encounters, the injection allocation was crossed, and animals received the alternative treatment during the next 4 encounters. ResultsDBS-treated mice showed reduced AB that was correlated with testosterone levels and an increase in 5-HT1A receptor density in the orbitofrontal cortex and amygdala. Pre-treatment with WAY-100635 blocked the anti-aggressive effect of pHyp-DBS. ConclusionsThis study shows that pHyp-DBS reduces AB in mice via changes in testosterone and 5-HT1A mechanisms.

The NLRP3 inflammasome is involved in resident intruder paradigm-induced aggressive behaviors in mice.

Background: Aggressive behaviors are one of the most important negative behaviors that seriously endangers human health. Also, the central para-inflammation of microglia triggered by stress can affect neurological function, plasticity, and behavior. NLRP3 integrates stress-related signals and is a key driver of this neural para-inflammation. However, it is unclear whether the NLRP3 inflammasome is implicated in the development of aggressive behaviors. Methods: First, aggressive behavior model mice were established using the resident intruder paradigm. Then, aggressive behaviors were determined with open-field tests (OFT), elevated plus-maze (EPM), and aggressive behavior tests (AT). Moreover, the expression of P2X7R and NLRP3 inflammasome complexes were assessed by immunofluorescence and Western blot. The levels of NLRP3 and inflammatory cytokines were evaluated using enzyme-linked immunosorbent assay (ELISA) kits. Finally, nerve plasticity damage was observed by immunofluorescence, transmission electron microscope, and BrdU staining. Results: Overall, the resident intruder paradigm induced aggressive behaviors, activated the hippocampal P2X7R and NLRP3 inflammasome, and promoted the release of proinflammatory cytokines IL-1β in mice. Moreover, NLRP3 knockdown, administration of P2X7R antagonist (A804598), and IL-1β blocker (IL-1Ra) prevented NLRP3 inflammasome-driven inflammatory responses and ameliorated resident intruder paradigm-induced aggressive behaviors. Also, the resident intruder paradigm promoted the activation of mouse microglia, damaging synapses in the hippocampus, and suppressing hippocampal regeneration in mice. Besides, NLRP3 knockdown, administration of A804598, and IL-1Ra inhibited the activation of microglia, improved synaptic damage, and restored hippocampal regeneration. Conclusion: The NLRP3 inflammasome-driven inflammatory response contributed to resident intruder paradigm-induced aggressive behavior, which might be related to neuroplasticity. Therefore, the NLRP3 inflammasome can be a potential target to treat aggressive behavior-related mental illnesses.

Chronic Inhibition of Aggressive Behavior Induces Behavioral Change in Mice.

Suppression of anger is more common than its expression among Asian individuals. Emotional suppression is considered an unhealthy emotional regulation. Most studies on emotional suppression have concluded that suppression adversely affects social outcomes, with approximately 5% of the world's population suffering from emotional disorders. However, anger suppression has not received academic attention, and details of the effects of chronic anger suppression on the central nervous system remain unclear. In this study, we performed the resident-intruder test to investigate the effect of chronic suppression of aggressive behavior in mice using a behavioral test battery and to clarify whether suppression of this aggressive behavior is stressful for mice. Mice chronically inhibited aggressive behavior and lost weight. Mice with inhibited aggressive behavior showed a reduced percentage of immobility time during the tail suspension test as well as no changes in activity, anxiety-like behavior, muscle strength, or temperature sensitivity. This study provides scientific evidence for the effects of chronic aggressive behavior inhibition on the body and central nervous system.

High-Frequency Local Field Potential Oscillations May Modulate Aggressive Behaviors in Mice.

Aggressive behavior is one of congenital social behaviors in many species, which could be promoted by social neglect or isolation in the early stages of life. Many brain regions including the medial prefrontal cortex (mPFC), medial amygdala (MeA) and ventromedial hypothalamus (VMH) are demonstrated to relate to aggressive behavior; however, the dynamic patterns of neural activities during the occurrence of this behavior remain unclear. In this study, 21-day-old male CD-1 mice were reared in social isolation conditions and cohousing conditions for two weeks. Aggressive behaviors of each subject were estimated by the resident-intruder test. Simultaneously, the local field potentials of mPFC, MeA and VMH were recorded for exploring differences in the relative power spectra of different oscillations when aggressive behaviors occurred. The results showed that the following: (1) Compared with the cohousing mice, the socially isolated mice exhibited more aggression. (2) Regardless of "time condition" (pre-, during- and post- attack), the relative power spectra of beta band in the cohousing mice were significantly greater than those in the socially isolated mice, and inversely, the relative power spectra of gamma band in the cohousing mice were significantly smaller than those in the socially isolated mice. (3) The bilateral mPFC exhibited significantly smaller beta power spectra but greater gamma power spectra compared with other brain areas regardless of rearing patterns. (4) For the right VMH of the socially isolated mice, the relative power spectra of the gamma band during attacks were significantly greater than those before attack. These results suggest that aggressive behaviors in mice could be shaped by rearing patterns and that high-frequency oscillations (beta and gamma bands) may engage in mediating aggressive behaviors in mice.

Extract of Mallotus oppositifolius (Geiseler) Müll. Arg. increased prefrontal cortex dendritic spine density and serotonin and attenuated para-chlorophenylalanine-aggravated aggressive and depressive behaviors in mice.

Background/Aim: Depression-related aggression is linked to serotonin (5-HT) and dendritic spine alterations. Although Mallotus oppositifolius extract (MOE) has potential for reducing this effect, its specific role remains uncertain. Herein, we evaluated this potential and associated alterations in the brain. Methods: A standard resident-intruder model of para-chlorophenylalanine (pCPA)-induced depression-associated aggression in male ICR mice was used. The resident mice received pCPA (300mg/kg, i. p.) for 3 consecutive days while saline-treated mice served as negative control. The pCPA aggressive mice were subsequently treated orally with either MOE (30, 100, 300mg/kg), fluoxetine (20mg/kg), tryptophan (20mg/kg) or saline (untreated pCPA group) for 28days. Locomotor activity was assessed using open field test. Serotonin (5-HT) levels in mice brain and phytochemical fingerprint of MOE were determined by high performance liquid chromatography (HPLC) while gas chromatography-mass spectrometry (GC-MS) was used to identify constituents of MOE. Dendritic spine density and morphology were evaluated using Golgi-Cox staining technique and analyzed with ImageJ and Reconstruct software. Results: Administration of pCPA induced aggressive behavior in mice, evidenced by increased attack behaviors (increased number and duration of attacks), which positively correlated with squeaking and tail rattling. MOE treatment significantly reduced these characteristics of aggression in comparison with vehicle (non-aggressive) and untreated pCPA groups (p < 0.001), and also reduced social exploration behavior. Although the behavioral effects of MOE were comparable to those of fluoxetine and tryptophan, these effects were quicker compared to fluoxetine and tryptophan. Additionally, MOE also markedly increased 5-HT concentration and dendritic spine density in the prefrontal cortex relative to vehicle and untreated pCPA groups (p < 0.05). Interestingly, these behavioral effects were produced without compromising locomotor activity. GC-MS analysis of the MOE identified 17 known compounds from different chemical classes with anti-inflammatory, antioxidant, neuroprotective and antidepressant activities, which may have contributed to its anti-aggressive effect. Conclusion: MOE decreased depression-associated aggressive behavior in mice via increased 5-HT concentration and dendritic spine density in the prefrontal cortex. The MOE-mediated effects were faster than those of fluoxetine and tryptophan. Our finding suggests that MOE may have clinical promise in decreasing aggressive and depressive behaviors.

Lateral habenula glutamatergic neurons projecting to the dorsal raphe nucleus promote aggressive arousal in mice

The dorsal raphe nucleus (DRN) is known to control aggressive behavior in mice. Here, we found that glutamatergic projections from the lateral habenula (LHb) to the DRN were activated in male mice that experienced pre-exposure to a rival male mouse (“social instigation”) resulting in heightened intermale aggression. Both chemogenetic and optogenetic suppression of the LHb-DRN projection blocked heightened aggression after social instigation in male mice. In contrast, inhibition of this pathway did not affect basal levels of aggressive behavior, suggesting that the activity of the LHb-DRN projection is not necessary for the expression of species-typical aggressive behavior, but required for the increase of aggressive behavior resulting from social instigation. Anatomical analysis showed that LHb neurons synapse on non-serotonergic DRN neurons that project to the ventral tegmental area (VTA), and optogenetic activation of the DRN-VTA projection increased aggressive behaviors. Our results demonstrate that the LHb glutamatergic inputs to the DRN promote aggressive arousal induced by social instigation, which contributes to aggressive behavior by activating VTA-projecting non-serotonergic DRN neurons as one of its potential targets.

Deletion of the P/Q-Type Calcium Channel from Serotonergic Neurons Drives Male Aggression in Mice.

Aggressive behavior is one of the most conserved social interactions in nature and serves as a crucial evolutionary trait. Serotonin (5-HT) plays a key role in the regulation of our emotions, such as anxiety and aggression, but which molecules and mechanisms in the serotonergic system are involved in violent behavior are still unknown. In this study, we show that deletion of the P/Q-type calcium channel selectively from serotonergic neurons in the dorsal raphe nuclei (DRN) augments aggressive behavior in male mice, while anxiety is not affected. These mice demonstrated increased induction of the immediate early gene c-fos and in vivo serotonergic firing activity in the DRN. The ventrolateral part of the ventromedial hypothalamus is also a prominent region of the brain mediating aggression. We confirmed a monosynaptic projection from the DRN to the ventrolateral part of the ventromedial hypothalamus, and silencing these projections with an inhibitory designer receptor exclusively activated by a designer drug effectively reduced aggressive behavior. Overall, our findings show that deletion of the P/Q-type calcium channel from DRN neurons is sufficient to induce male aggression in mice and regulating its activity may serve as a therapeutic approach to treat violent behavior.SIGNIFICANCE STATEMENT In this study, we show that P/Q-type calcium channel is mediating aggression in serotonergic neurons from the dorsal raphe nucleus via monosynaptic projections to the ventrolateral part of the ventromedial hypothalamus. More importantly, silencing these projections reduced aggressive behavior in mice and may serve as a therapeutic approach for treating aggression in humans.

Decaffeinated Tea Extract and its Fractions attenuate Clonidine- induced Aggressive Behavior in Mice

Introduction: Considerable data have been generated on anti-aggressive drugs of different pharmacological profiles. Present study was based on research findings that caffeine produced inverted ‘U’ shaped aggressive behavior in mice, lower and very higher doses reducing aggressive behavior and moderate doses increasing aggressive behavior. Therefore, we studied effect of decaffeinated tea and its fractions on clonidine- induced aggression in mice. Objective: Objective was to evaluate the effect of polyphenol rich Decaffeinated Tea Extract (DTE) and its fractions namely chloroform fraction (DTCf), ethyl acetate fraction (DTEa), diethyl ether fraction (DTDe) and acetone- water fraction (DTAw) against clonidine- induced aggressive behavior in mice. Methods: Mice were pretreated with caffeine (10 mg/Kg, i.p.), DTE (100- 300 mg/kg) or its fractions (100, 200 mg/kg) and clonidine (30 mg/Kg, i.p.) was administered after 30 min. Diazepam (2.5 mg/kg, i.p.) was used as reference standard. Aggressive behaviour viz: latency to first attack and total no. of attacks were observed in transparent activity chamber for1hr duration. Results: DTE 300 mg/Kg, i.p. increased latency to first attack and decreased total no. of attacks significantly (P&lt; 0.0001) as compared to control group. DTCf, DTDe and DTAw at doses 100 &amp; 200 mg/kg significantly decreased number of attacks (P&lt;0.0001) while DTEa in doses of 100 and 200 mg/kg, significantly increased latency to first attack (P&lt;0.0001) as compared to control group.

Ethanol enhanced MDPV- and cocaine-induced aggressive behavior in mice: Forensic implications

BackgroundReports concerning the causal link between aggressive behavior and use and abuse of different substances (i.e., alcohol, MDPV) can be found in the literature. Nonetheless, the topic concerning the effects of acute ethanol administration on MDPV and cocaine induced aggressive behavior has yet to be thoroughly investigated. The aim of this study was to investigate such synergistic effects. Materials and methodsA total of 360 male mice were employed in the study. Ethanol was diluted with saline solution and administered 10 min before MDPV or cocaine injection via oral gavage needles. Similarly, MDPV and cocaine were dissolved in saline solution and administered by intraperitoneal injection. Different associations of specific drug doses were then tested. To investigate the acute effects of MDPV and cocaine and their interaction with ethanol on aggression in mice, a resident–intruder test was used. ResultsEthanol alone was ineffective at dosages of 0.05 g/kg and 0.25 g/kg but increased the aggressiveness of the mice at 0.125 g/kg. Similarly, the injection of both cocaine alone and MDPV alone did not significantly increase the aggressiveness of the mice; conversely, the combination of ethanol and cocaine and ethanol and MDPV enhanced aggression at specific ethanol dosages (0.05 g/kg and 0.125 g/kg). ConclusionThis study demonstrated that acute ethanol administration enhances MDPV- and cocaine-induced aggressive behavior in mice. This aggressive response is particularly enhanced when MDVP and cocaine are coupled with specific ethanol dosages, proving that psychostimulant drugs may act synergistically under certain conditions.

Sansoninto attenuates aggressive behavior and increases levels of homovanillic acid, a dopamine metabolite, in social isolation-reared mice

Background and aimEarly-life stress is thought to affect aggressive behavior in humans and rodents. Laboratory experiments have demonstrated that Sansoninto (SST; 酸棗仁湯 suān zǎo rén tāng), a traditional herbal medicine, attenuates stress-induced abnormal behavior in rodents. However, it is unknown whether SST attenuates stress-induced aggressive behavior. The current study examined the effects of SST on aggressive behavior of mice who suffered from social isolation (SI) stress in adolescence. Experimental procedureFive-week old mice were socially isolated for 6 weeks, and SST administration was started at 4 weeks after starting SI. Aggressive behavior and locomotor activity were examined in SST-treated mice. The content of dopamine and its metabolites in the hypothalamus were examined using high-performance liquid chromatography analysis. Gene expression analyses of monoamine oxidase-B (MAO-B), catechol-O-methyltransferase (COMT), and tyrosine hydroxylase in the hypothalamus were performed using quantitative reverse transcription polymerase chain reaction. Results and conclusionSST attenuated SI-induced aggressive behavior and increased levels of homovanillic acid, a metabolite of dopamine. However, SST did not affect dopamine levels. SI enhanced locomotion in a novel environment and increased COMT mRNA levels. In contrast, SST-treated mice showed no significant enhancement of locomotion. SST attenuated the increase in COMT mRNA levels. Given that the dopaminergic system has been implicated in aggressive behavior, these findings suggest that SST toned down dopaminergic signaling, resulting in amelioration of aggression. SST may be useful for treatment of aggressive behavior in patients with neurotic symptoms.

Low-normal doses of methiopropamine induce aggressive behaviour in mice.

Recreational use of illicit methiopropamine (MPA) is a public health concern because it produces neurochemical effects comparable with those induced by methamphetamine (METH). The present study investigated the effects of MPA on the expression of an aggressive behaviour. Eighty CD-1 male mice, after receiving intraperitoneal injection of saline, MPA (0.01-10 mg/kg), METH (0.01-10 mg/kg), or AMPH (0.01-10 mg/kg), once a week over a 5-week period, underwent the resident-intruder test and spontaneous locomotor activity measurement. Results showed that all psychostimulants induce aggressive behaviour even at low doses, with a dose-dependent increase and a time-dependent sensitisation. MPA potency was similar to METH and superior to AMPH. Therefore, MPA-induced aggressive behaviour may appear even at MPA dosages free of cardiovascular or other behavioural adverse effects and could become a non-intentional side effect that users experience after increasing and repeating MPA consumption.

Effect of gut microbiota early in life on aggressive behavior in mice

Recent reports have indicated that gut microbiota modulates the responses to stress through the microbiota-gut-brain axis in mice, suggesting a connection between gut microbiota and brain function. We hypothesized that the gut microbiota early in life would have an effect on aggressiveness, and examined how gut microbiota affect aggressive behaviors in mice. BALB/c mice were housed in germ-free (GF) and ex-germ-free (Ex-GF) isolators. An aggression test was performed between castrated and a non-castrated mice at 8 weeks of age; the mice were allowed to confront each other for 10 min in strictly contamination-free environments. To evaluate aggressive behavior related to gut microbiota, we orally administered diluted Ex-GF mouse feces to the offspring of GF mice at 0, 6, and 10 weeks. GF mice showed more aggression than Ex-GF mice. Furthermore, GF mice who were administered feces of the Ex-GF group at 0-week-old were less aggressive than the GF mice. These findings suggested that the gut microbiota in the early stages of development was likely to have an effect on aggressiveness. Maintenance of healthy gut microbiota early in life can affect the mitigation of aggressive behavioral characteristics throughout the lifetime.

Chronic social defeat stress in female mice leads to sex-specific behavioral and neuroendocrine effects

Over the years, it has become increasingly clear that males and females respond differently towards environmental stressors, highlighting the importance of including both sexes when studying the effects of stress. This study aims to provide further insight into the detailed consequences of exposing female mice to 21 days of chronic social defeat stress (CSDS). We used a protocol that relies on the ability of odorants and pheromones in male urine to trigger male mouse aggressive behavior. Collected male C57Bl/6n urine was applied to female C57Bl/6n mice who were then attacked by a novel male CD1 mouse each day according to the CDSD protocol. Control females were pair-housed and handled daily. Physiological, neuroendocrine and behavioral changes were evaluated during the experiment. CSDS exposure resulted in number of physiological changes, such as body weight gain, enlarged adrenals and reduced thymus weight, exaggerated HPA-axis negative feedback and increased anxiety-like behavior. However, no generalized social avoidance behavior was observed. This study provides important insights in the physiological, neuroendocrine and behavioral responses of female mice to CSDS, which are partially dependent on estrous cycle stage. This protocol will allow direct comparison of male and female responses to CSDS and enable sex-specific study of mechanisms underlying individual stress resilience. Lay summary In this study we found that there are differences in the way that female and male mice respond towards chronic social stress conditions when it comes to behavior and hormonal changes.

Pain‐induced aggression and changes in social behavior in mice

The effects of neuropathic, formalin, and acetic acid-induced visceral pain were investigated on the social and aggressive behaviors in the Swiss male mice. Neuropathic pain was induced by tibial nerve transection (TNT). Also, somatic and visceral pain was conducted by intraplantar injection of diluted formalin (1%, 20 μl) and intraperitoneal administration of acetic acid (0.6%, 200 μl), respectively. Fourteen and twenty one days after the TNT surgery, and also, 1 and 7 days following formalin and acetic acid administration, the three-chambered test was used to determine sociability and preference for social novelty and resident/intruder test was used for the evaluation of the aggressive behaviors. In the sociability phase of the three-chambered test, all the three models of pain did not change the animal's sociability. However, in the social novelty preference phase, the animals in pain showed deficits in social novelty preference by a significant increase in the time spent with the familiar mice compared to the control groups. Also, animals in pain significantly showed more aggressive behaviors like biting and clinching and have much less attack latency in comparison to the control groups. Pain-induced changes in the social novelty preference and aggressive behaviors continued in the neuropathic group until the end of the experiment. However, 7 days following the induction of both formalin and visceral pain, animals' social memory, and aggression almost returned to the standard value. These results suggest that long-lasting pain could lead to social memory impairment and increase aggressive behaviors in mice.

Are Baseline Glucocorticoid Levels Linked to Aggressive Behaviour in Wild Wood Mice?

Defensive strategies of prey species constitute a key element to survive and maximise biological fitness in natural environments. However, some of the mechanisms underlaying antipredator behaviours are not clear. Despite previous studies had attempted to unravel the relationship between aggressiveness and glucocorticoids (GC), this association remains uncertain. Our study aimed to find an explicit link between the aggressive behaviour in the wood mice (Apodemus sylvaticus) and the GC release. For this, a live-trapping study was conducted in the Montes do Invernadeiro Natural Park (NW Spain). We collected faecal samples from 76 captures to measured free-ranging mice baseline faecal corticosterone metabolites (FCM) levels using an enzyme immunoassay. Moreover, we determined the aggressive behaviour of each mice by measuring the number of bites perpetrated upon the researcher while handling. Results of the statistical model showed that aggressive behaviour in mice was not explained by FCM concentrations. On the other hand, a better body condition was associated with the individual's aggressiveness. Moreover, it seems that recaptured individuals tended to be more aggressive, probably because previous experience with this life-threatening event improved the individual's defensive performance in order to successfully escape again.

Divergent pathways mediate 5-HT1A receptor agonist effects on close social interaction, grooming and aggressive behaviour in mice: Exploring the involvement of the oxytocin and vasopressin systems.

5-HT1A receptor (5-HT1AR) abnormalities are implicated in aggression, and there has been considerable interest in developing 5-HT1AR agonists for treating aggression. Endogenous oxytocin (OXT) released upon stimulation of 5-HT1ARs in the hypothalamus mediates at least some of the effects of 5-HT1AR agonists on social behaviour. Given 5-HT1AR, OXT receptor (OXTR) and vasopressin V1a receptor (V1aR) agonists can all reduce aggression, the current study aimed to determine whether the anti-aggressive effects of 5-HT1AR stimulation can also be explained by downstream actions at OXTRs and/or V1aRs in a mouse model of non-territorial, hyper-aggressive behaviour. Male Swiss mice (N=80) were socially isolated or group housed for six weeks prior to the start of testing. Testing involved placing two unfamiliar weight- and condition-matched mice together in a neutral context for 10 minutes. Social isolation led to a pronounced increase in aggressive behaviour, which was dose-dependently inhibited by the 5-HT1AR agonist 8-OH-DPAT (0.1, 0.3 and 1 mg/kg intraperitoneally (i.p.)), with accompanying increases in close social contact (huddling) and grooming. The effects of 8-OH-DPAT on aggression, huddling and grooming were blocked by pretreatment with a selective 5-HT1AR antagonist (WAY-100635; 0.1 mg/kg i.p.). The anti-aggressive effects of 8-OH-DPAT were unaffected by an OXTR antagonist (L-368,899; 10 mg/kg i.p.), whereas the effects on huddling and grooming were inhibited. Pretreatment with a V1aR antagonist (SR49059; 20 mg/kg i.p.) had no effect. Our study suggests that stimulation of endogenous oxytocin is involved in the effects of 5-HT1AR activation on close social contact and grooming but not aggression.

Effect of Yokukansan and Yokukansankachimpihange on Aggressive Behavior, 5-HT Receptors and Arginine Vasopressin Expression in Social Isolation-Reared Mice.

The traditional herbal medicines yokukansan (YKS) and yokukansankachimpihange (YKSCH) are prescribed for neurosis, insomnia or night crying and irritability in children. YKSCH comprises YKS and two additional herbs, a chimpi and a hange, and is used to treat digestive function deficiencies. However, the differences between the effects of YKS and YKSCH on brain function are unclear. The present study examined the effects of YKS and YKSCH on aggressive behavior in mice reared under a social isolation (SI) condition. Mice were housed individually for 6 weeks. YKS and YKSCH were administered orally for 2 weeks before aggression tests. SI increased aggressive behavior against naïve mice, and YKS, but not YKSCH, significantly attenuated this aggressive behavior. Because serotonin (5-HT)2A and 5-HT3A receptor antagonists are reported to have anti-aggressive effects, the mRNA levels of these receptors were examined. YKS attenuated the SI-induced increase in 5-HT2A and 5-HT3A receptor mRNA in the amygdala. On the other hand, YKSCH attenuated the SI-induced increase in 5-HT1A receptor mRNA. YKS and YKSCH did not affect 5-HT and its metabolite 5-hydroxyindoleacetic acid content in the amygdala. However, YKSCH increased the mRNA level of arginine vasopressin (AVP), which is a neuropeptide that has been implicated in aggression, in the amygdala. These results suggest that YKS ameliorates aggressive behavior by decreasing 5-HT2A and 5-HT3A receptor expression. The YKSCH-induced increase in AVP may disrupt the anti-aggressive effect of YKS. YKS may be more effective than YKSCH for treating irritability if digestive function deficiencies are not considered.

Cannabidiol attenuates aggressive behavior induced by social isolation in mice: Involvement of 5-HT1A and CB1 receptors

Long-term single housing increases aggressive behavior in mice, a condition named isolation-induced aggression or territorial aggression, which can be attenuated by anxiolytic, antidepressant, and antipsychotic drugs. Preclinical and clinical findings indicate that cannabidiol (CBD), a non-psychotomimetic compound from Cannabis sativa, has anxiolytic, antidepressant, and antipsychotic properties. Few studies, however, have investigated the effects of CBD on aggressive behaviors. Here, we investigated whether CBD (5, 15, 30, and 60 mg/kg; i.p.) could attenuate social isolation-induced aggressive behavior in the resident-intruder test. Male Swiss mice (7–8 weeks) were single-housed for 10 days (resident mice) to induce aggressive behaviors, while conspecific mice of same sex and age (intruder mice) were group-housed. During the test, the intruder was placed into the resident's home-cage and aggressive behaviors initiated by the resident, including the latency for the first attack, number of attacks, and total duration of aggressive encounters, were recorded. The involvement of 5-HT1A and CB1 receptors (CB1R) in the effects of CBD was also investigated. All tested CBD doses induced anti-aggressive effects, indicated by a decrease in the number of attacks. CBD, at intermediary doses (15 and 30 mg/kg), also increased latency to attack the intruder and decreased the duration of aggressive encounters. No CBD dose interfered with locomotor behavior. CBD anti-aggressive effects were attenuated by the 5-HT1A receptor antagonist WAY100635 (0.3 mg/kg) and the CB1 antagonist AM251 (1 mg/kg), suggesting that CBD decreases social isolation-induced aggressive behaviors through a mechanism associated with the activation of 5-HT1A and CB1 receptors. Also, CBD decreased c-Fos protein expression, a neuronal activity marker, in the lateral periaqueductal gray (lPAG) in social-isolated mice exposed to the resident-intruder test, indicating a potential involvement of this brain region in the drug effects. Taken together, our findings suggest that CBD may be therapeutically useful to treat aggressive behaviors that are usually associated with psychiatric disorders.