Fighting In Mice Research Articles

Chronic methamphetamine increases fighting in mice

A propensity for violent behaviors to develop in chronic methamphetamine (METH) abusers has been noted. The idea that increased aggressiveness might result from chronic METH administration was tested in mice after chronic (long-term intermittent, 8 weeks) or single exposures to the drug. A single injection of METH (6 mg/kg) did not augment fighting. In contrast, chronic METH administration significantly increased the number of animals that initiated bite attacks. This regimen also shortened the latency before the first attack. Latency before the first attack was shorter at 20 h after the METH injection than at 15 min after injection. Locomotor activity was not different at 20 h after METH injection, indicating that increased fighting was not secondary to METH-induced hyperactivity. METH-induced increases in fighting were not related to the duration of persistent sniffing after the initial encounter with an intruder since the duration of this behavior was significantly increased at 15 min after METH but not at 20 h post drug. These results indicate that repeated injections of METH can increase fighting behaviors and also alter social interactions in mice. Thus, intermittent administration of METH might be useful as a pharmacological model to study the biochemical and molecular bases of aggressiveness.

The developmental onset of a rudimentary form of play fighting in C57 mice

Play fighting in its most elaborate form involves nonagonistic wrestling between pairmates, where one partner grabs, holds, bites, or otherwise contacts the other. Such play occurs in the absence of the functional consequences associated with serious fighting (e.g., resource acquisition or protection). Typically, the biting, nosing, or grooming contact during play fighting is directed at specific body targets. House mice have been classified as a species that lacks such play, even though play fighting is present in closely related species such as the rat. In this study, six litters of C57 mice were observed daily from the week before weaning until the week after weaning (15-30 days postnatally). Thirty-min videotaped records were collected daily for each litter. Consistent with other studies, over 85% of all play involved locomotor play, and most of the social play involved noncontact locomotion (86%). However, a rudimentary pattern of the "attack and defense" typical of play fighting was found to occur, albeit at a low frequency (2% of all play). Most playful attacks involved snout contact with the partner's rump, but evidence is provided that suggests that this rump contact may be transitory, with the nape area being the primary target for play. Most of the playful attacks elicited playful defense (97%), which in all cases involved the defender evading such contact by leaping or running away, or by dodging laterally away from the attacker. Therefore, there appears to be directed playful attacks in this species, with defense limited to evasion. Defensive tactics leading to wrestling were never observed. That is, play fighting in mice involves only a small subset of what other species, such as rats, exhibit. Nonetheless, the basic components of attack and defense are present in mice.

The developmental onset of a rudimentary form of play fighting in C57 mice

Play fighting in its most elaborate form involves nonagonistic wrestling between pairmates, where one partner grabs, holds, bites, or otherwise contacts the other. Such play occurs in the absence of the functional consequences associated with serious fighting (e.g., resource acquisition or protection). Typically, the biting, nosing, or grooming contact during play fighting is directed at specific body targets. House mice have been classified as a species that lacks such play, even though play fighting is present in closely related species such as the rat. In this study, six litters of C57 mice were observed daily from the week before weaning until the week after weaning (15–30 days postnatally). Thirty-min videotaped records were collected daily for each litter. Consistent with other studies, over 85% of all play involved locomotor play, and most of the social play involved noncontact locomotion (86%). However, a rudimentary pattern of the “attack and defense” typical of play fighting was found to occur, albeit at a low frequency (2% of all play). Most playful attacks involved snout contact with the partner's rump, but evidence is provided that suggests that this rump contact may be transitory, with the nape area being the primary target for play. Most of the playful attacks elicited playful defense (97%), which in all cases involved the defender evading such contact by leaping or running away, or by dodging laterally away from the attacker. Therefore, there appears to be directed playful attacks in this species, with defense limited to evasion. Defensive tactics leading to wrestling were never observed. That is, play fighting in mice involves only a small subset of what other species, such as rats, exhibit. Nonetheless, the basic components of attack and defense are present in mice. © 1999 John Wiley & Sons, Inc. Dev Psychobiol 34: 175–182, 1999

Isolation-induced fighting in mice and regional brain monoamine utilization

The utilization of norepinephrine, dopamine and serotonin was measured in ten brain regions of isolated fighting mice and resting control animals. Fighting produced a markedly significant change in the utilization of dopamine ( P > 0.006), but not in norepinephrine or serotonin. However, important trends were identified in the latter systems which warrant further testing. This study highlights the importance of dopaminergic participation in fighting behavior.

On fighting in mice: is there a sensitive period for isolation effects?

To investigate the differential age-duration effects of isolation in promoting attacks and fighting in male laboratory mice ( Mus musculus), a factorial study of five different isolation intervals (0, 4 0, 4 1, 4 2, 4 3 days) initiated at five different ages (21, 28, 35, 56, 84 days since birth) was completed. Five hundred ICR mice (250 experimental isolates; 250 control partners) were studed in a procedure that yielded detailed information on the interactional processes that led up to attacks and fighting. In addition, measures of non-social reactivity and weight were taken for all animals. The results provide strong support for the time of isolation, the duration of isolation, and the developmental status of the partner. Beyond the notion of a sensitive period, the results indicate that the effects of isolation are superimposed upon species-typical developmental changes in both the subject and the partner.

The relationship between blood alcohol levels and aggression in mice

Previous reports of the impact of ethanol on murine aggression have produced inconsistent findings; some workers have found that low doses of ethanol increase aggression whereas others have reported either no effect or a suppression. The present study examined one variable that may help to account for these inconsistencies, namely the level of blood alcohol at various times after administration. Acute doses of 0.5, 1, 2 g/kg ethanol all potently suppressed fighting in mice. However, there was no simple relationship between blood alcohol levels and fighting. It appeared that the level of blood alcohol, whether these levels were falling and the time since alcohol was cleared from the blood were all factors that influenced the drugs anti-aggressive influence.

The benzodiazepine receptor ligand CL218,872 has both anxiolytic and sedative properties in rodents

The triazolopyridazine, CL218,872, inhibited the binding of [ 3H]flunitrazepam in the cerebellum more potently than in cortex, both in vitro and in vivo. The relationship between this phenomenon and the selectivity of benzodiazepine receptor subtypes is considered. In a range of behavioural tests the overall profile of CL218,872 was similar to that of diazepam in the rat and mouse, although CL218,872 was half as potent as diazepam in the rat and some 20-fold weaker in the mouse. In particular contrast to published observations, CL218,872 reduced locomotor activity in rats and mice at doses only slightly larger than those required to inhibit conflict in rats and footshock-induced fighting in mice. The only qualitative difference between the compounds that could be detected was in the mouse where large doses of CL218,872 did not produce the marked degree of motor incoordination seen after diazepam. However, no such difference was observed in the rat. The presently held view than CL 218,872 is a non-sedative anxiolytic agent needs to be revised in the light of these observations.

Influence of substance P and fragments on passive avoidance behavior.

N-terminal and C-terminal fragments of substance P (SP) have been shown to exert opposite effects on antinociception, grooming and fighting in mice. The present experiments explored whether these findings could be generalized to passive avoidance behavior. Substance P (SP-(1-11] and the C-terminal fragment pyroglutamyl-SP-(7-11) attenuated passive avoidance behavior when picogram amounts were injected into the nucleus accumbens. In contrast, the N-terminal fragment SP-(1-7) had an opposite effect and facilitated passive avoidance behavior.

Modulation of isolation-induced fighting by N- and C-terminal analogs of substance P: Evidence for multiple recognition sites

Substance P (SP) significantly reduced fighting in mice made aggressive by prolonged isolation. The N-terminal heptapeptide fragment SP (1–7) also reduced fighting. The C-terminal fragment SP(4–11) was without activity, while the shorter C-terminal fragment analog <E-SP(7–11) significantly increased isolation-induced fighting. The aggression-enhancing effect of <E-SP(7–11) was antagonized by naloxone, which by itself had no significant effect. The aggression-reducing effect of SP(1–11) was significantly enhanced by naloxone, while the effect of SP(1–7) was unchanged. These results demonstrate that a behavioral effect of SP may be duplicated by an N-terminal fragment of the SP molecule, and that peptide fragments or analogs of the N- and C-terminal portions of the SP molecule can exert opposing effects on a specific behavior. These findings represent a structure/activity relationship that is strikingly different from any previously described for SP. The differeing effects of naloxone on N- and C-terminal fragment analogs suggest that these two effects may be mediated by different mechanisms.

Influence of isolation and training on fighting in mice with olfactory bulb lesions

Isolation-induced aggressive mice receiving total bilateral bulbectomy failed to fight after chronic training. Animals receiving sub-total olfactory bulbectomy were capable of being trained to attack but the latency to attack was increased. When mice were bulbectomized before being isolated they were incapable of attack regardless of training or completeness of the lesion. These results indicated that isolation influences aggressive behavior in bilaterally bulbectomized mice.

Dopamine: Mesocortical vs nigrostriatal uptake in isolated fighting mice and controls

Acute isolation-induced fighting in mice produced a striking ‘dose-dependent’ increase in K m and V max for DA uptake in mesocortical nerve endings (synaptosomes) but no significant changes for these uptake constants in nigrostriatal terminals. The selective response of the mesocortical system to fighting is similar to that reported for other affective paradigms and stress. Several controls were carried out simultaneously to sort out neurotransmitter responses due to aggressive behavior from those due to secondary behaviors which accompany fighting. Non-significant or borderline increases in K m and V max for mesocortical DA uptake were noted in (i) animals permitted to witness fighting but prevented from participating, (ii) those subjected to the stress of a mock-fighting situation and (iii) animals simply handled by the investigator, but in no case were the control values increased to the magnitude produced by fighting. (iv) Group-housed animals showed no mesocortical response when placed in the arena with isolated mice. They retired to the corners and would not fight. These mild to negative control findings indicate that the marked cortical responses seen in the fighting animals are not due to (i) anticipation of the fight, (ii) physical stress and motor activity, (iii) placing the animals in the combat arena, or (iv) isolation. Significant changes in nigrostriatal DA reactivity were noted only in the isolated animals prevented from fighting where there was a decrease in K m and V max for DA uptake.

Cocaine increases isolation-induced fighting in mice.

Abstract Isolated male mice were treated with IP cocaine (10 or 35 mg/kg), saline, or received no injections. Groups of four identically-treated animals were placed in a small arena where fighting behavior was observed. Cocaine produced a marked dose-dependent increase in fight duration. The results are discussed in terms of possible catecholaminergic mechanisms.

Gonadal hormones and the induction of intraspecific fighting in mice

Recent data pertaining to the influence of gonadal hormones upon intraspecific fighting behavior of mice are reviewed. Contrary to previous findings, exposure to testosterone during the neonatal period of development is not necessary for the activation of fighting later in life by testosterone treatment provided that the adult treatment regime is chronic. Rather than ‘organizing’ the central nervous system, neonatal exposure to testosterone appears to render it more ‘sensitive’ to the aggression-activating property of that steroid; animals exposed to it early in life fight more quickly following the commencement of adult testosterone treatment. Other data have revealed that the position in utero of female fetuses relative to males determines to a significant extent the sensitivity of the adult female to testosterone. The responsiveness to the hormone of females contiguous to two male fetuses is enhanced. And finally, although estrogen does not activate fighting in normal adult females, it will do so if the female has been administered either estrogen or testosterone during early life. Females exposed to low levels of estrogen as neonates also will display aggression in adulthood when estrogen titres normally are high. These data suggest that for normal female-like behavior to develop, it is essential that the neonatal ovary be relatively quiescent.

The role of the catecholaminergic system in footshock-induced fighting in mice

The role of the catecholaminergic system in foot shock-induced fighting aggression in mice was studied with the help of behavioral tests and biochemical experiments. The administration of the catecholamine precursor l-dopa combined with enzymatic decomposition inhibitors (nialamide or Ro4-4602) produced a significant increase in the number of fighting episodes in mice. The administration of the dopamine agonists amantadine, apomorphine, and nomifensine also increased aggression in mice. Catecholamine synthesis inhibitors, alpha-MT and compounds blocking catecholamines receptors (pimozide and haloperidol), reduced the number of fighting epidoses in mice. Clonidine, a noradrenergic agonist, potentiated the aggressive behavior of mice while the noradrenergic antagonists aceperone and phenoxybenzamine, the alpha-adrenergic receptor blockers, suppressed aggression. The noradrenaline synthesis inhibitor FLA-63 also depressed the number of fighting episodes in mice. A comparison of two effective doses (ED50) for antiaggressive action and for the inhibition of motor activity showed that alpha-MT, FLA-63, and aceperone reduced the number of fighting episodes in mice most selectively. The interaction between catecholamine agonists and antagonists showed that an increase of aggression induced by nialamide plus l-dopa was abolished both by haloperidol and by phenoxybenzamine. Clonidine effects were also partially weakened by phenoxybenzamine. Studies on noradrenaline and dopamine levels in the brains of mice, after the synthesis of those catecholamines was inhibited, showed a higher noradrenaline utilization in the brains of aggressive mice than in nonaggressive mice. The present results suggest a significant role of noradrenaline dopamine in producing the foot shock-induced fighting aggression in mice.

Role of corticosterone in the control of post-shock fighting behaviour in male laboratory mice

Two experiments were conducted to examine the role of corticosterone in controlling fighting subsequent to electric foot-shock in male mice. It was found that (1) treatment with corticosterone restores post-shock fighting in adrenalectomized males but not in castrated-adrenalectomized males; (2) raising cortieosterone levels induces post-shock fighting in castrated-adrenalectomized males treated with testosterone but not in castrated-adrenalectomized controls treated with a placebo; and (3) preventing corticosterone responses to shock occludes the increasing in fighting which normally follow shock in intact males. These findings suggest that (1) corticosterone plays an important role in the control of post-shock fighting in mice; (2) this importance of corticosterone is dependent on the presence of circulating testosterone, or other androgens; and (3) corticosterone responses to the experience of shock may be involved in the mediation of the facilitatory effects of this experience on subsequent fighting behaviour.

Temporal relationships between shock treatment and intermale fighting behaviour in laboratory mice. Effects of modifying testicular and adrenal functions

The three experiments of this series were conducted to (1) examine subsequent effects of electric shock on intermale fighting in previously isolated mice, and (2) determine to what extent post-shock fighting is affected by manipulations of the pituitary-gonadal and pituitary-adrenocortical axes. In experiment 1 it was found that shock treatment significantly increases fighting 1 2 to 1 h later. Experiment 2 showed that castration alone does not affect post-shock fighting, whereas adrenalectomy and castration combined with adrenalectomy both inhibit such fighting. Experiment 3 showed that pretreatment with testosterone increases fighting in intact males, but fails to restore post-shock fighting in adrenalectomized and castrated-adrenalectomized males. These findings suggest that (1) the pituitary-adrenocortical axis plays an important role in controlling post-shock fighting in mice, and (2) the inhibition of post-shock fighting by adrenalectomy and castration combined with adrenalectomy is not a result of the loss of adrenal testosterone which accompanies these operations.

Acute influences of some ACTH-related peptides on fighting and adrenocortical activity in male laboratory mice

A number of corticotrophin preparations when given acutely enhanced fighting behavior, an event which may be consequent upon elevation of circulating corticosterone. A series of short ACTH analogues (ACTH 11–24, ACTH 4–10) had slight influences on circulating plasma corticosterone values and on fighting behavior. However, 20 μg ACTH 1–10 given 12 hr before testing did increase fighting c.f. controls. As this compound only caused a slight stimulation of plasma corticosterone titers, the possibility exists of an extra-adrenal influence. One cannot, it appears, eliminate glucocorticoid influences using these preparations in the mouse. Acutely, ACTH 1–24 had virtually no influences on Animex-assessed motor activity but did enhance fighting in castrated mice maintained with either androgen or estrogen. It is tentatively concluded that the ACTH influences on aggression in the mouse are partially mediated via glucocorticoid influences on the CNS combined with an extra adrenal influence of part of the ACTH molecule. A possible reason for the differing acute and chronic influences of ACTH on fighting in mice is presented.

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.

Effects of isolation and fighting in mice on the rate of synthesis of noradrenaline, dopamine and 5-hydroxytryptamine in the brain.

Male mice were isolated or housed in groups for 6–8 weeks. Some of the isolated mice were thereafter brought together in groups of 25–30 animals for 30 min, during which period they fought each other intensively. The brain concentration of 5-HIAA was lower in isolated than in grouped animals. 30 min after administration of the aromatic amino acid decarboxylase inhibitor 3-hydroxybenzyl-hydrazine HCl (NSD 1015) the amount of Dopa accumulated in the brain was lower in isolated than in grouped animals. There was no corresponding difference in the accumulation of 5-HTP. The accumulation of Dopa and 5-HTP after NSD 1015 was accelerated during fighting. The effects of isolation and fighting on DOPA accumulation were similar in NA- and DA-dominated areas of the brain. The brain concentrations of tryptophan and tyrosine were increased and the concentration of NA was decreased in fighting NSD 1015 treated animals. The brain concentrations of HVA was lower in isolated and higher in fighting animals than in grouped animals.

Effects of antihistamines on isolation-induced fighting in mice

A series of antihistamines representing many structural types and pharmacological spectra antagonized isolation-induced fighting in mice. Antagonism of fighting by these compounds was correlated with anti-cholinergic potency as measured by prevention of physostigmine-induced lethality but did not correlate with antihistaminic or anti-tetrabenazine potency. Antagomism of fighting was not related to effects of these drugs on spontaneous motor activity.