Isolation-induced Aggressive Behavior 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.

Effects of Testicular and Non-Testicular Testosterone on Territorial and Isolation-induced Aggressive Behavior of Male Layer Chicks.

Testosterone (T) is known to induce aggressive behavior, particularly in male animals. However, our recent results showed that a certain kind of aggressive behavior is T-independent; moreover, the role of T in chicken territorial and isolation-induced aggressive behavior has not yet been investigated. In addition, castration alone is insufficient to evaluate the role of T in aggressive behavior because we found that non-testicular T concentration, probably derived from the adrenal gland, in the blood of castrated chicks was low, but not zero. In the present study, therefore, the role of testicular T in chicken aggressive behavior was evaluated through castration, and the role of nontesticular T was assessed using the subcutaneous implantation of flutamide, a non-steroidal antiandrogen, in the castrated male layer chicks. Resident-intruder (R-I) and social interaction (SI) tests were used to quantitatively monitor territorial and isolation-induced aggressive behavior, respectively. Castration and drug implantation of the chicks were performed at 14 days of age. The R-I test was performed at 29 and 30 days of age, and the SI test was performed at 31 and 32 days of age. The total aggression frequencies (TAFs) and aggression establishment rate (AER) were used as indices of chick aggressive behavior. In the R-I test, castration significantly decreased the TAFs but the AER was not affected by castration or flutamide implantation. In the SI test, on the other hand, there were no significant differences in the TAFs, but the AER tended to increase in the intact chicks and decrease in the flutamide-implanted, castrated male chicks. These results suggest that the role of T in chicken aggression depends on the differences in social context of the behavior, and that both testicular and non-testicular T play an important role in the occurrence of isolation-induced aggression in male layer chicks.

The neuropeptide Drosulfakinin regulates social isolation-induced aggression in Drosophila.

Social isolation strongly modulates behavior across the animal kingdom. We utilized the fruit fly Drosophila melanogaster to study social isolation-driven changes in animal behavior and gene expression in the brain. RNA-seq identified several head-expressed genes strongly responding to social isolation or enrichment. Of particular interest, social isolation downregulated expression of the gene encoding the neuropeptide Drosulfakinin (Dsk), the homologue of vertebrate cholecystokinin (CCK), which is critical for many mammalian social behaviors. Dsk knockdown significantly increased social isolation-induced aggression. Genetic activation or silencing of Dsk neurons each similarly increased isolation-driven aggression. Our results suggest a U-shaped dependence of social isolation-induced aggressive behavior on Dsk signaling, similar to the actions of many neuromodulators in other contexts.

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.

Blood Testosterone Concentration and Testosterone-induced Aggressive Behavior in Male Layer Chicks: Comparison between Isolated- and Grouped-Raising.

Testosterone (T) is known to induce aggressive behavior, mainly in male animals. Subcutaneous implantation of T-filled silastic tubes, rather than intramuscular injection of T, is generally recommended for long-term treatment using exogenous T. However, the effect of T implantation on chicken aggressive behavior has not been investigated. In addition, the concentration of T required to induce aggressive behavior or whether rearing conditions such as isolated- or grouped-raising affect T-induced aggressive behavior in chickens is not known. The present study aimed to examine the relationship between the lengths of T-filled tubes, blood T concentration, and aggressive behavior in group- and isolation-raised male layer chicks. The testes were bilaterally removed and silactic tubes of various lengths filled with crystalline T were subcutaneously implanted at 14 days of age. A social interaction test was performed to quantitatively assess chick aggressive behavior at 32 days of age. Comb weight and size were used to assess the activation of endogenous androgen receptors. Total aggression frequencies (TAF) and aggression establishment rate (AER) were used to evaluate aggressiveness. Significant positive correlations (P<0.001) were observed between the comb parameters and plasma T concentration. In the isolation-raised chicks, the TAF and AER were high irrespective of the lengths of the implanted T tubes or the corresponding plasma T concentrations. However, in the group-raised chicks, the AER tended to differ between the T-implanted aggressors (P=0.0902), and the AER significantly increased with implantation of 1.0-cm-long T-filled tubes (P<0.05), which corresponded to approximately 47 pg/mL plasma T concentration. These results suggest that both grouped raising and approximately 47 pg/mL plasma T concentration are required for the induction of T-dependent aggressive behavior, and that isolation-induced aggressive behavior is T-independent in male layer chicks.

5-HT2CR antagonist/5-HT2CR inverse agonist recovered the increased isolation-induced aggressive behavior of BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing.

IntroductionSocial isolation enhances the aggressive behavior of animals, but the detailed mechanism remains unclear. Epigenetic studies have suggested that Htr2c RNA editing is closely related to aggressive behavior. This study aims to obtain a fundamental understanding of how social isolation impacts adenosine deaminase acting on RNA 1 (ADAR1, RNA editing enzyme) and Htr2c RNA editing, leading to aggressive behavior, and explore the effective solutions for the recovery of this behavior.MethodsWe evaluated 21‐day‐old BALB/c mice with and without isolation for aggressive behavior using a resident‐intruder test. Immune‐reactivity and protein expression of ADAR1 (p110) were measured using immunohistochemistry and Western blotting. Htr2c RNA editing was evaluated using pyrosequencing. In addition, the 5‐HT 2C R antagonist SB243213/5‐HT 2C R inverse agonist SB206553 was used to treat the isolated mice, and the performance of both treatments on the behavior, ADAR1 (p110) expression, and Htr2c RNA editing in isolated mice was examined.ResultsBoth the protein expression and immune‐reactivity of ADAR1 (p110) in the amygdala decreased, but the percentage of Htr2c RNA editing at A and B sites of amygdala only showed a moderate increase in isolated BALB/c mice with enhanced aggressive behavior compared to the age‐matched group‐housed BALB/c mice. Additionally, treatment with the 5‐HT 2C R antagonist SB243213/5‐HT 2C R inverse agonist SB206553 recovered the enhanced aggressive behavior of isolated mice and returned the protein expression and immune‐reactivity of ADAR1 (p110) back to the normal level. Moreover, compared to the age‐matched isolated mice treated with physiological saline, isolated mice treated with 5‐HT 2C R inverse agonist SB206553 showed a lower percentage of Htr2c RNA editing at both A and B sites, and the same result occurred in isolated mice treated with 5‐HT 2C R antagonist SB243213 at B site of Htr2c RNA editing.ConclusionsThe 5‐HT 2C R antagonist SB243213/5‐HT 2C R inverse agonist SB206553 recovered increased aggressive behavior of isolated BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing.

Methamidophos, an Organophosphorus Insecticide, Induces Pro-aggressive Behaviour in Mice.

Although evidence indicates that exposure to organophosphorus (OP) pesticides induces neurobehavioral disorders, little is known about the effects of OP on aggressive behaviour. Our study investigated the effects of repeated exposure to an OP pesticide, methamidophos, on the isolation-induced aggressive behaviour in mice. Forty seven male mice were individually housed for a month. Socially isolated animals were then confronted with a standard non-isolated opponent for 15min (pre-treatment trial), and the latency and frequency of aggressive and general exploratory behaviours were recorded. Based on the presence of attack behaviour in the pre-treatment trial, mice were classified as isolation-induced aggressive and non-aggressive. All mice were then treated for 7days with methamidophos (3.5mg/kg/day, n=22, intraperitoneal (i.p.)) or saline (1mL/kg/day, control group, n=25, i.p.), and a second trial was performed. Repeated exposure to methamidophos induced attack behaviour in non-aggressive mice. The treatment with methamidophos also decreased plasma butyrylcholinesterase and brain acetylcholinesterase activity. These results suggest that methamidophos has a pro-aggressive effect on socially isolated mice.

Evaluation of Anti-Aggressive Activity of Kyllinga brevifolia in Rodent Model of Aggression

Kyllinga brevifolia Rottb, Cyperaceae, rhizomes are used in the Paraguayan folk medicine as sedative and tonic for nervous system. The aim of this study was to determine the anti-aggressive activity of hydro-ethanolic (rhizomes) extract (CEKb), hexane (KbF-hex), chloroform (KbF-chlo), ethyl acetate (KbF-ethyl-ac) and aqueous (KbF-aq) fractions of K. brevifolia on the aggressive behavior assessed in the isolation - induced aggression model in male mice. The effect on aggressive behavior was observed during a ten minute resident-intruder confrontation. Oral doses of CEKb (10 and 100 mg/kg; p< 0.05), KbF-hex (0.1, p<0.01; 1, p<0.001 and 10 mg/kg, p< 0.01)) and KbF-ethyl-ac (0.1, p<0.01; 1, p< 0.05 and 10 mg/kg, p< 0.05) from K. brevifolia reduced fighting time of isolation-induced aggressive behavior, respectively, in male mice. In conclusion, our results make evident that CEKb, Hex Kb and KbF-ethyl-ac obtained from K. brevifolia possesses anti aggressive-like property in mice. These finding give further support to the traditional use of Kyllinga brevifolia as sedative and tonic in Paraguayan folk medicine. Taken together, these findings suggest that Kyllinga brevifolia exhibits a general anti-offensive aggressive activity and may be relevant in the treatment of reactive aggression in humans.

Effect of Jobelyn® on intruder- and isolation-induced aggressive behavior in mice

Aggression is a violent behavior emitted against another organism that may lead to its harm or death and thus is of public health significance, which necessitates the search for agents with anti-aggressive property. This study investigated the effect of Jobelyn® (JB), a unique African polyherbal formulation, on intruder- and isolation-induced aggressive behaviors in mice. Male mice that showed aggression after being housed individually with female counterparts for 3 weeks or kept in isolation for 4 weeks were treated orally (p.o.) with JB (5, 10 or 50 mg/kg), haloperidol (HP) (1 mg/kg), fluoxetine (FL) (10 mg/kg), p-chlorophenylalanine (PCPA) (20 mg/kg), mianserin (MS) (50 mg/kg) or distilled water (10 mL/kg) 60 min before being tested for aggression. Interaction studies involving oral administration of PCPA (20 mg/kg), FL (10 mg/kg) or MS (50 mg/kg) to aggressive mice that had received JB (5 or 10 mg/kg, p.o.) 30 min earlier were assessed. The effect of JB (5, 10 or 50 mg/kg, p.o.) on defensive behaviors was also evaluated. JB (5, 10 or 50 mg/kg) decreased aggressive behaviors without impairing the defensive mechanisms of mice. PCPA (20 mg/kg), an inhibitor of 5-hydroxytryptamine (5-HT) biosynthesis, increased aggressive responses and reduced the anti-aggressive effect of JB. FL (10 mg/kg), a 5-HT reuptake inhibitor, significantly suppressed aggression but did not alter the effect of JB on aggression. MS (50 mg/kg), a 5-HT receptor antagonist, reduced aggression and enhanced the effect of JB on aggression. These findings suggest that JB has anti-aggressive activity, which may be related to the enhancement of serotonergic system.

Therapeutic effect of Yokukansan on social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice

In patients with dementia including Alzheimer's disease, hallucinations, agitation/aggression and irritability are known to frequently occur and as distressing behavioral and psychological symptoms of dementia (BPSD). On the basis of the evidence on clinical efficacy and safety of Yokukansan, a traditional Japanese herbal medicine, on BPSD, in the present study, Yokukansan was examined in the therapeutic effects on social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice. Yokukansan was p.o. administered for 7 days as a drinking water to isolated mice fed a zinc-deficient diet for 10 days, which exhibited aggressive behavior, and isolated pair-fed mice fed a control diet of the amount consumed by zinc-deficient mice for 10 days, which exhibited aggressive behavior. Aggressive behavior was evaluated by the resident-intruder test. Yokukansan (312 mg/kg/day) attenuated both aggressive behaviors of zinc-deficient and pair-fed mice. Because Yokukansan can suppress abnormal glutamatergic neuron activity, MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, and aminooxyacetic acid (AOAA), a γ-amino butyric acid (GABA) transaminase blocker, were also examined in the effects on social isolation-induced aggressive behavior. MK-801 (0.1 mg/kg) or AOAA (23 mg/kg) was i.p. injected into isolated aggressive mice. Thirty minutes later, the resident-intruder test was performed to evaluate the effect of the drugs. Both drugs attenuated aggressive behavior of zinc deficient mice, but not that of pair-fed mice. These results suggest that Yokukansan ameliorates social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice through the action against glutamatergic neurotransmitter system and other neurotransmitter systems.

Effects of GH deficiency and GH replacement on inter-male aggressiveness in mice

Objective Growth hormone (GH) has been suggested to influence aggressive behavior in several species, but no data are presently available in GH-deficient (GHD) animals. The aim of this study was to elucidate the effects of GHD on aggressive behavior in a mouse model of isolated GHD due to removal of the GHRH gene (GHRH knock out, GHRHKO), and to evaluate the effects of GH replacement. Design We studied two groups of adult male mice: Ten GH-sufficient animals heterozygous for GHRHKO allele (HTZ), and 30 GHRHKO animals. Behavior was measured by scoring several aggression parameters after isolation, when the animal was challenged against an intruder both in neutral and home cage. Animals were then re-studied after the GHRHKO mice were left untreated (control, Ctrl), or were treated for 2 weeks with daily subcutaneous recombinant GH or with vehicle (Veh). Blood samples were collected before and after GH or Veh treatment, and assayed for serum IGF-I and testosterone. Results The GHRHKO mice showed significantly reduced aggressiveness compared to HTZ animals. GH (but not Veh) administration normalized isolation-induced aggressive behavior in GHRHKO mice, despite lack of full serum IGF-I normalization. No difference was noted in serum testosterone levels among all groups at any of the time points. Conclusions These findings show that GHD reduces aggressive behavior in GHRHKO mice, that GH replacement normalizes aggressiveness, and that this behavior change is not related to an increase in serum testosterone.

Ameliorative effect of Yokukansan on social isolation-induced aggressive behavior of zinc-deficient young mice

Yokukansan, a traditional Japanese medicine has been used to cure neuropsychological disorders. In the present study, the effect of Yokukansan on social isolation-induced aggressive behavior was examined in zinc-deficient mice, which were fed a zinc-deficient diet and a drinking water containing Yokukansan for 2 weeks. In the resident–intruder test, the rate of mice that exhibited aggressive behavior in zinc-deficient mice, which was significantly higher than that in the control mice, was significantly decreased by administration of Yokukansan. The basal level of serum glucocorticoid, which was significantly higher in zinc-deficient mice, was lowered by administration of Yokukansan. On the other hand, serum glucocorticoid levels after the resident–intruder test were almost the same between the control and zinc-deficient mice. However, administration of Yokukansan to zinc-deficient mice significantly increased serum glucocorticoid level after the resident–intruder test and the significant difference in the rate of serum corticosterone level after the test to the basal level between the control and zinc-deficient mice was abolished. Dietary zinc deficiency increases the basal levels of serum glucocorticoid, while may insufficiently increase serum glucocorticoid levels in the resident–intruder test. The concentrations of glutamate and GABA (γ-aminobutyric acid) in the brain were significantly higher in zinc-deficient mice, while Yokukansan ameliorated the significant increases. These results indicate that Yokukansan ameliorates social isolation-induced aggressive behavior of zinc-deficient mice, probably via amelioration of abnormal glucocorticoid secretion. The ameliorative effect seems to be linked to the modification of glutamatergic neuron activity after administration of Yokukansan.

Anxiolytic-like profiles of histamine H3 receptor agonists in animal models of anxiety: a comparative study with antidepressants and benzodiazepine anxiolytic

Histamine H3 receptor functions as a presynaptic auto- and hetero-receptor on histaminergic and non-histaminergic neurons in the brain regulating the synaptic release of numerous neurotransmitters. Therefore, the ligands for this receptor have been proposed to be of therapeutic interest for the treatment of various neuropsychiatric disorders. At present, however, the psychopharmacological profiles of H3 ligands, particularly H3 agonists, have not been extensively studied. The present study investigated the anxiolytic-like profiles of H3-selective agonists in a variety of classical (benzodiazepine-sensitive) and atypical (antidepressant-effective) animal models of anxiety. Comparator drugs used were diazepam and both fluvoxamine and desipramine in the former and latter models, respectively. H3 agonist R-alpha-methylhistamine and immepip were inactive in rat elevated plus maze test and Vogel type conflict test where diazepam (5 mg/kg) produced significant anxiolytic-like effects. Meanwhile, these H3 agonists (10-30 mg/kg) significantly reduced isolation-induced vocalizations in guinea pig pups and isolation-induced aggressive behavior in mouse resident-intruder test. Moreover, in rat conditioned fear stress test, R-alpha-methylhistamine (30 mg/kg) and immepip (10 mg/kg) significantly decreased freezing time, which were completely reversed by concomitant treatment with H3 antagonist, thioperamide (10 mg/kg). In contrast to the limited efficacy obtained with desipramine (30 mg/kg), fluvoxamine (20-60 mg/kg) exhibited anxiolytic-like effects in all the latter three atypical models. These data suggest that the H3 agonists may have anxiolytic-like effects similar to those of selective serotonin reuptake inhibitors but not benzodiazepine anxiolytics and represent a novel strategy for the treatment of some anxiety disorders in which selective serotonin reuptake inhibitors are prescribed.

Yokukansan Inhibits Social Isolation-Induced Aggression and Methamphetamine-Induced Hyperlocomotion in Rodents

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as on that of their caregivers. However, effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD, such as aggression, agitation, irritability, and hallucinations, in a randomized, single-blind, placebo-controlled study. However, the psychopharmacologic effects of YKS remain unexplored. In the present study, we investigated the effects of YKS on social isolation-induced aggressive behavior and methamphetamine- or MK-801-induced hyperlocomotion in rodents. Social isolation markedly induced aggressive behavior in male Wistar rats. Quetiapine at a dose of 10 mg/kg (per os (p.o.)) significantly inhibited this social isolation-induced aggressive behavior. YKS (100, 300 mg/kg, p.o.) also significantly inhibited the aggressive behavior. Moreover, risperidone (0.1 mg/kg, p.o.) significantly inhibited methamphetamine- or MK-801-induced hyperlocomotion in mice. YKS (300 mg/kg, p.o.) inhibited methamphetamine-induced hyperlocomotion, while YKS at the same dose had no effect on MK-801-induced hyperlocomotion. These findings suggest that YKS may be useful for the treatment of aggression and agitation, and that the psychopharmacologic effects of YKS might be mediated, in part, by inhibiting the activity of the dopaminergic system.

Enhancement of social isolation-induced aggressive behavior of young mice by zinc deficiency

Neuropsychological behavior via activation of the hypothalamic-pituitary-adrenal (HPA) axis was analyzed using young mice fed a zinc-deficient diet for 2 weeks. Serum corticosterone concentration was significantly increased after 2-week zinc deprivation, whereas zinc concentration in the brain was not decreased. In the resident-intruder test, the rate of mice that exhibited aggressive behavior to the total mice was significantly higher in isolated zinc-deficient mice than in isolated control mice. The duration of aggressive behavior was more in isolated zinc-deficient mice. These results indicate that aggressive behavior of young mice elicited by social isolation is enhanced by zinc deficiency. On the other hand, social isolation-induced aggressive behavior was enhanced in isolated pair-fed mice with food restriction that can activate the HPA axis. Serum corticosterone concentration was also significantly higher in isolated zinc-deficient mice. To see the effect of the increased serum corticosterone on behavioral abnormality, neurotransmitter concentrations in brain tissue were checked. The concentrations of glutamate and GABA in brain tissue were significantly higher in both grouped and isolated zinc-deficient mice. Furthermore, the concentration of extracellular glutamate in the amygdala before the resident-intruder test was significantly higher in isolated zinc-deficient (aggressive) mice and the higher concentration was maintained during the test. The changes in neurotransmitter homeostasis, probably via the increase in serum corticosterone, seem to be linked to aggressive behavior elicited by social isolation in zinc deficiency.

Prolonged prenatal exposure to low-level ozone affects aggressive behaviour as well as NGF and BDNF levels in the central nervous system of CD-1 mice

The long-term effects on isolation-induced aggressive behaviour and central NGF and BDNF levels of gestational exposures to ozone (O 3) were evaluated in adult CD-1 mice. Females were exposed to O 3, at the dose of 0.0, 0.3 or 0.6 ppm from 30 days prior the formation of breeding pairs until gestational day 17. Litters were fostered at birth to untreated dams and, at adulthood, male offspring underwent five successive daily encounters (15 min each) with a standard opponent of the same strain, sex, weight and age. The encounters on day 1, 3 and 5 were videotaped and agonistic and non-agonistic behavioural items finely scored. O 3-exposed mice showed a significant increase in freezing and defensive postures, a decrease in nose-sniffing behaviour and reduced progressively the aggressive behavioural profile displayed on day 1. Reduced NGF levels in the hippocampus and increased BDNF in the striatum were also found upon O 3 exposure.

Selective reduction by isolation rearing of 5-HT1A receptor-mediated dopamine release in vivo in the frontal cortex of mice.

Serotonin (5-HT)1A receptors modulate in vivo release of brain monoaminergic neurotransmitters which may be involved in isolation-induced aggressive behavior. The present study examined the effect of isolation rearing on the 5-HT1A receptor-mediated modulation of dopamine (DA), 5-HT and noradrenaline (NA) release in the frontal cortex of mice. The selective 5-HT1A receptor agonist (S)-5-[-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) increased the release of DA and NA and decreased the release of 5-HT in the frontal cortex of mice. The effect of MKC-242 on DA release was significantly less in isolation-reared mice than in group-reared mice, while effects of the drug on NA and 5-HT release did not differ between both groups. The effect of the other 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin on cortical DA release was also less in isolation-reared mice than in group-reared mice, and that of the drug on cortical 5-HT release did not differ between both groups. In contrast to MKC-242-induced DA release, amphetamine-induced increase in cortical DA release in vivo was greater in isolation-reared mice. The present findings suggest that isolation rearing enhances the activity of cortical dopaminergic neurons and reduces selectively the 5-HT1A receptor-mediated release of DA in the cortex.

Modulation by 5-HT2A Receptors of Aggressive Behavior in Isolated Mice

The present study examines whether isolation-rearing affects sensitivity of 5-hydroxy-tryptamine (5-HT)2A receptors and the functional interaction between 5-HT1A and 5-HT2A receptors in mice. The 5-HT2A-receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)-induced head twitch response was significantly greater in isolated mice than in grouped mice. DOI increased isolation-induced aggressive behavior, and the 5-HT2A-receptor antagonist ritanserin decreased it. The 5-HT1A-receptor agonist (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242) inhibited the DOI-enhanced aggressive behavior. MKC-242 inhibited DOI-induced head twitch response. These findings suggest that 5-HT2A receptors play a role in aggressive behavior in isolated mice and imply that the antiaggressive effect of MKC-242 may be mediated partly by the inhibition of 5-HT2A-receptor function.

Involvement of benzodiazepine binding sites in an antiaggressive effect by 5-HT 1A receptor activation in isolated mice

The effect of the benzodiazepine receptor antagonist flumazenil was examined on an antiaggressive effect of ( S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3- benzodioxole HCl (MKC-242), a 5-HT 1A receptor agonist. MKC-242 (0.1–1.0 mg/kg, p.o.) selectively reduced isolation-induced aggressive behavior in a dose-dependent manner. Flumazenil (10 mg/kg, i.p.) antagonized the antiaggressive effects of MKC-242 and diazepam, although it alone did not affect the behaviors of isolated mice. These findings suggest that a γ-aminobutyric acid A (GABA A) receptor system is involved in the antiaggressive effect by 5-HT 1A receptor activation.

Behavioral profiles of SSRIs in animal models of depression, anxiety and aggression. Are they all alike?

The behavioral profiles of five clinically used selective serotonin reuptake inhibitors (SSRIs) citalopram, paroxetine, sertraline, fluvoxamine and fluoxetine, have been compared in animal models of antidepressant (mouse forced swim test), anxiolytic (exploration of black and white test box and foot-shock-induced ultrasonic vocalization in the rat) and antiaggressive (isolation-induced aggressive behavior in the mouse) activity. the results are discussed in relation to receptor binding data from the literature. Furthermore, affinities for the sigma 1 and sigma 2 binding sites are presented. Citalopram reversed the immobility induced by forced swimming with a potency similar to that of imipramine. Paroxetine, fluvoxamine and fluoxetine reversed swim-induced immobility less potently and with a maximum of 40-50% reversal. Citalopram produced a mixed anxiogenic-/anxiolytic-like response in rats tested in the two-compartment black and white box. Paroxetine induced an anxiogenic-like response at low doses and the other SSRIs were without major effects. Citalopram and paroxetine inhibited footshock-induced ultrasonic vocalization with high potencies. The dose-response curve was biphasic for citalopram with a maximum of 64% inhibition. Sertraline and fluvoxamine inhibited the vocalization less potently, and fluoxetine induced a weak inhibitory effect corresponding to a maximum of 32%. Sertraline, fluvoxamine and fluoxetine inhibited isolation-induced aggressive behavior, whereas citalopram and paroxetine were inactive. Both 5-HT1 and 5-HT2 receptors are involved, and there was a functional interaction between 5-HT1A and 5-HT2A or 5-HT2C receptors, as ritanserin potentiated the antiaggressive effect of 1,5-HTP as well as that of 8-OH-DPAT.