Isolation-induced Aggression In Mice Research Articles

The effects of Topiramate on isolation-induced aggression: a behavioral and immunohistochemical study in mice.

Topiramate, an antiepileptic drug, has been found to be useful for the treatment of aggression in clinical populations. Most preclinical studies related to Topiramate have been focused exclusively on the quantitative aspects of the aggressive behavior between mice. However, there is still limited knowledge regarding the effects of Topiramate on neuronal mechanisms occurring in aggressive mice. The present work aims to understand further the effects of the antiepileptic drug Topiramate on aggressive behaviors, and on the neural correlates underlying such behaviors. To achieve this, we combined the resident-intruder model of isolation-induced aggression in mice with two drug regimens of Topiramate administration (30.0 mg/kg; acute and sub-chronic treatments). Our data showed that both acute and subchronic treatments decreased the intensity of agonistic encounters and reinforced social behavior. By using C-fos immunoreactivity, we investigated the neuronal activation of several brain regions involved in aggressive behavior following subchronic treatment. We found that Topiramate produced activation in several cortical areas and in the lateral septum of resident brain mice compared with their controls. However, Topiramate induced inhibition in the medial nucleus of the amygdala, the dorsomedial nucleus of the periaqueductal gray, and especially in the anterior hypothalamic nucleus. Finally, we performed microinfusion of Topiramate (0.1 and 0.3 mM) into the lateral septum and anterior hypothalamus on offensive behaviors in isolation-induced-aggression paradigm. Interestingly, the microinfusion of Topiramate into the lateral septum has the capacity to alleviate aggressive behavior, without affecting social behavior. However, the microinfusion of Topiramate into the anterior hypothalamus decreased aggressive behavior and slightly reinforced social behavior. Our observations supported that the dose of 0.1 mM of Topiramate appeared more efficacy to treat aggression in adult mice. These pharmacological characteristics may account for Topiramate efficacy on aggressive symptoms in psychiatric patients.

Effects of acute administration of nicotine and lobeline on agonistic encounters in male mice

The effects of acute administration of two nicotinic ligands, (-)-nicotine and (-)-lobeline were examined on isolation-induced aggression in mice. Individually housed male mice confronted anosmic “standard opponents” in a neutral arena 10 min after drug administration. Encounters were videotaped and evaluated using an ethologically based analysis facilitating estimation of time allocated to 11 broad behavioral categories. Nicotine did not have significant effects on threat or attack but significantly diminished time allocated to digging. The lowest dose of lobeline significantly diminished attack and induced a slight increase of immobility without significantly diminishing other behaviors with motor components. The intermediate and highest dose of lobeline reduced time allocated to all behaviors with motor components. It is concluded that these two nicotinic agonists produce different behavioral profiles during agonistic encounters in mice but that this test may not facilitate assessing the impact of such drugs on irritability. Aggr. Behav. 26:376–385, 2000. © 2000 Wiley-Liss, Inc.

Isolation-induced aggression in mice: effects of 5-hydroxytryptamine uptake inhibitors and involvement of postsynaptic 5-HT1A receptors.

The inhibitory potencies of selective serotonin (5-hydroxytryptamine, 5-HT) uptake inhibitors on isolation-induced aggressive behaviour in male mice were studied. Furthermore, the role of postsynaptic 5-HT1A receptors in the mediation of aggressive behaviour was studied. The selective 5-HT uptake inhibitors, sertraline, floxetine, femoxetine and fluvoxamine, showed weak antiaggressive effects, and citalopram and paroxetine were ineffective. This rank of potencies corresponded with neither uptake inhibitory potencies in vitro nor potentiation of 1-5-hydroxytryptophan (1,5-HTP)-induced motor effects in vivo, as citalopram and paroxetine were among the most potent compounds in these tests. A subeffective dose of 1,5-HTP (110 mumol/kg = 25 mg/kg, s.c.) potentiated the antiaggressive effect of citalopram and paroxetine more than 110 and 1600 times, respectively. The effects of sertraline, fluvoxamine, fluoxetine and femoxetine were only potentiated 3, 36, 4 and 16 times, respectively. The 5-HT releasing compound fenfluramine inhibited the aggressive behaviour dose dependently, and depletion of 5-HT by treatment with p-chloro-phenylalanine methyl ester attenuated this effect significantly. p-Chloro-phenylalanine methyl ester was ineffective itself, but potentiated the antiaggressive effect of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamin)tetralin (8-OH-DPAT). The beta-adrenoceptor/5-HT1A receptor antagonist, (-)-penbutolol, reversed the antiaggressive effects of 8-OHDPAT. In conclusion, selective 5-HT uptake inhibitors act in different ways on isolation-induced aggressive behaviour, and postsynaptic 5-HT1A receptors are involved in mediating the aggressive behaviour.

Selective, centrally acting serotonin 5-HT2 antagonists. 1. 2- and 6-substituted 1-phenyl-3-(4-piperidinyl)-1H-indoles.

A series of 1-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2-imidazolidinones has been synthesized. The 1-position of the indole is substituted with phenyl groups and in the 2- or 6-positions are additional substituents. An analogous series with the imidazolidinone ring opened to corresponding urea derivatives was also prepared. High potency and selectivity for 5-HT2 receptors (as compared with D2 and alpha 1 receptor affinities) were obtained with medium-large substituents such as 6-chloro, 6-methyl, and 6-trifluoromethyl or a 2-methyl substituent. Larger 6-substituents such as isopropyl considerably reduced activity, while the smaller 6-fluoro substituent afforded unselective compounds. Selective 5-HT2 antagonists were found by combining 6-substitution with both unsubstituted 1-phenyl and substituted 1-phenyl groups (2-F, 4-F, 4-Cl). However, 3-substitution of the phenyl group markedly reduced 5-HT2 receptor affinity, especially with a 3-trifluoromethyl substituent. Introduction of a 3-(2-propyl) substituent in the imidazolidinone ring reduced binding to alpha 1 adrenoceptors with a factor of 3-8. Practically no influence on 5-HT2 and D2 receptor affinities were found by the presence of this substituent compared to the 3-unsubstituted derivatives. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and they had a long duration of action (> 24 h). Especially urea derivatives were found to be considerably more potent at 24 h than at 2 h after subcutaneous administration. Some of the compounds potently inhibited isolation-induced aggression in mice, an effect which, however, did not correlate to 5-HT2 receptor-mediated activities. On the basis of these structure-activity studies 1-[2-[4-[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1- piperidinyl]ethyl]-3-(2-propyl)-2-imidazolidinone (Lu 26-042, compound 4c) was selected for further pharmacological and toxicological investigations.

Test-specific effects of FG-7142 on isolation-induced aggression in mice

Treatment with FG-7142 decreased isolation-induced attack, but not defense, by male mice when the residents' home cages contained only a sawdust substrate. When a small wooden nesting box was added to the cage (Experiment 2), however, FG-7142 somewhat increased levels of attack. Time spent in the nesting box was also increased, while overall levels of social interaction were decreased, by drug treatment in Experiment 2. The latter findings are consistent with FG-7142's well-documented anxiogenic properties and indicate that this drug is probably proaggressive in its actions. The antiaggressive effects of FG-7142 in Experiment 1 may have resulted from drug-induced fear behaviors that were incompatible with attack. Alternatively, Experiment 2 suggests the possibility that species-typical attack may be defensively motivated under some circumstances. Although the antiaggressive properties of eltoprazine and yohimbine were unaffected by the addition of the nest box (Experiment 3), the provision of some sort of refuge within the testing apparatus may be an important methodological consideration for studies employing resident-intruder paradigms.

Acute and chronic effects of cocaine on isolation-induced aggression in mice

The purpose of the present study was to investigate the effects of acute and chronic cocaine administration on aggressive behaviour in mice. The animals were made more aggressive by individual housing for a period of 6 weeks. Group-housed anosmic conspecifics which were not aggressive were used as intruder controls. In acute studies, cocaine induced no significant change in aggressive behaviour at low doses (0.5-5 mg/kg) but significantly decreased aggressive behaviour after doses of 10 and 20 mg/kg. Cocaine increased the isolation-induced aggressive behaviour in mice when they were injected twice daily for a week with low doses of 0.5 or 1 mg/kg. In particular, the latency to first attack was significantly decreased by the drug and the frequency of attack towards the non-aggressive intruder was dramatically increased. Higher cocaine doses (10 or 20 mg/kg) under the described treatment regimen decreased these agonistic repertories. Tolerance did not develop to the anti-aggressive effects of high doses of cocaine on continued treatment.

The cholecystokinin-like peptide, ceruletide, reduces isolation-induced aggression in mice

Ceruletide, a non-mammalian decapeptide related to cholecystokinin octapeptide, reduced the aggressiveness of isolated NMRI mice. In this respect, its ED 50, (μmol/kg, s.c.) was 0.024 (95% confidence range, 0.0133–0.0447) and that of haloperidol 3.38 (1.488–7.669). An approximately equipotent dose of diazepam was 17.5 μmol/kg.

Benzodiazepine-receptor mediated inhibition of isolation-induced aggression in mice

The effects of a benzodiazepine receptor agonist (diazepam), antagonist (Ro 15-1788), and an “active” antagonist [inverse agonist] (3-carboethoxy-β-carboline) were examined in an isolation-induced model of aggression. Diazepam (4 mg/kg) and 3-carboethoxy-β-carboline (10 mg/kg), but not Ro 15-1788, significantly inhibited aggressive behavior in this model. Ro 15-1788 (10 mg/kg) reduced the anti-aggressive actions of both diazepam and 3-carboethoxy-β-carboline, while mice treated with a combination of diazepam and 3-carboethoxy-β-carboline had aggression scores increased to values not significantly different from vehicle treated mice. These findings suggest that both diazepam and 3-carboethoxy-β-carboline have anti-aggressive properties in the isolation-induced model of aggression which are mediated through CNS benzodiazepine receptors.

Antagonism by propranolol of isolation-induced aggression in mice: Correlation with 5-hydroxytryptamine receptor blockade

The effects of β-adrenoceptor antagonists, (±)-propranolol, pindolol, metroprolol, atenolol and (+)-propranolol, and of 5-HT receptor antagonists, methysergide and cyproheptidine, were studied on the aggressive behaviour induced in male mice by prolonged isolation. A close correlation was found between the dose of drug required to antagonize 5-HTP-induced head twitches in mice and that which prevented fighting in previously isolated mice. Metroprolol, atenolol and (+) -propranolol were inactive in both tests, while the other agents all reduced aggressive behaviour in doses of 0.5–4 mg/kg. In a dose of 10 mg/kg, 5-HTP increased aggressive behaviour in isolated mice. It is suggested that fighting behaviour is associated with an increased activation of 5-HTP pathways in the C.N.S. β-Adrenoceptor antagonists prevent this behaviour because of their blockade of 5-HT receptors rather than those of nor-adrenaline.

Effects of phencyclidine on isolation-induced aggression in mice.

Mice, isolated 6 to 8 wk. to induce aggression, were injected with either saline, 1.0, or 3.0 mg/kg phencyclidine (PCP) i.p. After 30 min., an untreated, group-housed mouse (intruder) was introduced into the home cage of each isolated mouse (resident) for a 3-min. period. The frequency of resident mouse attack bites, tail rattles, nasal contacts, locomotions, and rearings was recorded by time sampling. The 1.0 mg/kg PCP dose increased the attack bites and decreased nasal contacts while the high dose produced no change in these behaviors. Locomotions were increased at both doses of PCP. This drug's effects on agonistic and related behaviors are similar to the reported bi-phasic effects of d-amphetamine on aggression.

Selective antagonism of isolation-induced aggression in mice by diazepam following chronic administration

Benzodiazepines are non-selective (i.e., they only inhibit aggression at doses producing concurrent neuromuscular impairment) antagonists of isolation-induced aggression in mice following acute administration. However, in the present study diazepam was shown to be a selective antagonist of fighting in isolated mice following chronic administration for 5 days. When administered chronically, selective tolerance rapidly developed to the general CNS depression produced by diazepam whereas the antifighting activity was not diminished and, in fact, tended to be enhanced following multiple drug administrations. Thus, the antagonism of fighting in isolated mice by diazepam does not appear to be due solely to general CNS depressant properties.

Piperoxane reduces the effects of clonidine on aggression in mice and on noradrenaline dependent hypermotility in rats

Aggression in isolated male mice and hypermotility in rats produced by the noradrenaline releaser H 77/77 were studied after the s.c administration of the α-adrenergic agonist clonidine and the α-antagonist piperoxane. Clonidine 0.005–0.5 mg/kg inhibited both behaviours while piperoxane showed a weak and short-lasting anti-aggressive aggressive effect and no 77/77 antagonism. Inactive doses of piperoxane reduced the inhibitory effects of clonidine. The results indicate that isolation-induced aggression in mice and H 77/77-induced hypermotility in rats are behavioural signs related to the availability of noradrenaline at the receptor.

Antagonism of isolation-induced aggression in mice by thyrotropin-releasing hormone (TRH)

TRH was shown to be an extremely potent (ED50 = 0.04 mg/kg, IP) antagonist of isolation-induced aggression in male mice. The antifighting activity of TRH was selective in that it did not produce concurrent neurological impairment or significant alterations in spontaneous locomotor activity at antiaggressive doses. This activity of TRH appeared to be a direct affect on CNS structures since neither triiodothyronine nor any of the constituent amino acids of TRH antagonized aggression in isolated mice. The results are discussed in terms of the recent clinical effectiveness of TRH in some cases of mental illness (e.g., depression and schizophrenia).

The role of serotonergic pathways in isolation-induced aggression in mice

Male mice that became aggressive following four weeks of social isolation were treated with seven known serotonin receptor antagonists. All of the antiserotonergic drugs selectively antagonized the fighting behavior of the isolated mice; the antiaggressive activity was selective since, at antifighting doses, none of the drugs either significantly altered spontaneous motor activity or impaired inclined-screen performance. Antagonism of 5-HTP-induced head-twitch was used as an in vivo measure of antiserotonergic activity and a statistically significant correlation existed beteen potency as an antiserotonergic and potency as an antiaggressive. PCPA, a serotonin depletor, also significantly antagonized isolation-induced aggression for at least 24 hr postdrug administration. The interrelationship between cholinergic and serotonergic mechanisms in the mediation of isolation aggression was investigated. The involvement of serotonergic systems in isolation-induced aggression is discussed.

Catecholamine correlates of isolation-induced aggression in mice

Drugs differentially affecting catecholaminergic neurotransmission mechanisms were injected into isolated mice to assess effects on aggression. L-DOPA in combination with a peripheral decarboxylase inhibitor produced a dose-dependent decrease in the number of fights and average fight durations accompanied by an increase in attack latencies. Central dopamine levels were increased whilst brain noradrenaline and 5-hydroxytryptamine were reduced. Virtually identical effects on aggression were observed after apomorphine. Pimozide decreased fighting, but neither attack latencies nor average fight durations were affected. All doses of disulfiram virtually abolished all components of aggressive responses. The effect of D-amphetamine on number of fights was biphasic; lower doses potentiated aggression, but higher doses reduced fighting accompanied by increased attack latencies and reduced average fight durations. We conclude that catecholamines may be intimately involved in mediating certain components of aggressive responses but that balance relationships among various putative neurotransmitters may be a more meaningful correlate of this behavior.

Lithium in the treatment of aggression.

Lithium has become a widely accepted treatment for manic-depressive psychosis. It is dramatically effective for many cases of mania and is useful in the prevention of manic and depressive episodes. Hyperaggressiveness and hypersexuality are frequent components of manic-depressive illness and abate under the influence of lithium. A brief review is presented of the behavioral and biochemical pharmacology of lithium. This documents the inhibitory role which lithium can play in several examples of animal aggressive behavior including pain-elicited aggression, mouse killing in rats, isolation-induced aggression in mice, p-chlorophenylalanine-induced aggression in rats, and hypothalamically induced aggression in cats. The use of lithium to control human aggressive behavior has resulted in controversial findings. In epileptic conditions, improvement has been reported in interseizure aggressivity, but other reports indicate the possibility of increased seizures. Improvement in aggressive behavior in childhood has occasionally been reported as well as in emotionally unstable character disorders in young female patients. Te was a single blind study and the other a large but uncontrolled study. Both studies reported an improvement in aggressiveness as indicated by fewer recorded reports (tickets) for fighting. The final study reported is a study of 12 male delinquents age 16 to 23. They received lithium or placebo for 4 months inside an institution and then a trial of lithium for 1 to 12 months on an outpatient basis. Analysis of results in terms of the number of aggressive antisocial acts showed fewer serious aggressive episodes when the lithium level was between 0.6 and 1 meq/liter than when it was between 0.0 and 0.6 meq/liter. These results must be viewed with caution and are only suggestive since the study was not double blind.

5-Hydroxytryptamine correlates of isolation-induced aggression in mice

Drug regimens designed to enhance or impair serotonergic functioning were found to differentially affect isolation-induced fighting in mice. Male albino mice were isolated for at least 4 weeks. Number of fights, attack latencies, and average fight durations were recorded for 15 min every other day. On intervening days, the locomotor activity of each mouse was measured in stabilimeters. After the baseline for aggression and activity stabilized, drug procedures were instituted. While motility remained unaffected, mice injected with D,L-5-hydroxytryptophan in combination with a peripheral decarboxylase inhibitors (seryltrihydroxybenzine) engaged in fewer fights of shorter average duration which were precede by longer attack latencies. Biochemical analyses indicated that although serotonin levels were increased, catecholamine levels were reduced. A putative inhibitor of tryptophan hydroxylase, p-chloro-N-methylamphetamine (PCMA), was found to increase fighting frequency; attack latencies, average fight durations, and motility measurements did not differe significantly from non-injection performance. At time periods in which fighting was increased, levels of brain serotonin were reduced while catecholamine levels remained unaltered. Although PCMA did not affect motility at time intervals when fighting was increased, locomotor activity was increased for the first 8 hr after administration. Notwithstanding contributions by other putative neurotransmitters, these results suggest that serotonergic mechanisms are involved in the control of isolation-induced aggression in mice.

The effect of nitrites on isolation-induced aggression in mice

Chronic administration of sodium nitrite (1 g/1) in drinking water of pregnant mice and their offspring caused a significant increase in the isolation-induced aggression of the male young. The cessation of administration of sodium nitrite reduced the aggressive behavior of the experimental group to the control level.

The behavioral pharmacology of Sch 12679. A new psychoactive agent.

Sch 12679, N-methyl-l-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-3-benzazepine maleate, is active in a broad spectrum of laboratory models of aggressive behavior without producing any signs of neurologic impairment up to lethal doses. Sch 12679 is an effective inhibitor of isolation-induced aggression in mice, muricide and septal lesion-induced aggression in rats and spontaneous aggression in Rhesus monkeys. Sch 12679 also antagonizes methamphetamine aggregate toxicity in mice and hypothalmic self-stimulation in rats as do major tranquilizers; however, it differs from major tranquilizers in that it does not affect conditioned avoidance response (CAR) performance or produce catalepsy, ptosis or hypothermia. Sch 12679 does not fit into established profiles for either minor or major tranquilizers or other existing types of psychopharmacological agents. Initial clinical studies have confirmed that Sch 12679 reduces aggressive behavior without producing concomitant sedation.