Aggressive Behavior In Male Mice Research Articles

Brain site specific knockdown of estrogen receptor α in the medial preoptic area reduced sexual but not aggressive behavior in male mice

Brain site specific knockdown of estrogen receptor α in the medial preoptic area reduced sexual but not aggressive behavior in male mice

Major Urinary Protein-1 Increases Energy Expenditure and Improves Glucose Intolerance through Enhancing Mitochondrial Function in Skeletal Muscle of Diabetic Mice

Major urinary protein-1 (MUP-1) is a low molecular weight secreted protein produced predominantly from the liver. Structurally it belongs to the lipocalin family, which carries small hydrophobic ligands such as pheromones. However, the physiological functions of MUP-1 remain poorly understood. Here we provide evidence demonstrating that MUP-1 is an important player in regulating energy expenditure and metabolism in mice. Both microarray and real-time PCR analysis demonstrated that the MUP-1 mRNA abundance in the liver of db/db obese mice was reduced by approximately 30-fold compared with their lean littermates, whereas this change was partially reversed by treatment with the insulin-sensitizing drug rosiglitazone. In both dietary and genetic obese mice, the circulating concentrations of MUP-1 were markedly decreased compared with the lean controls. Chronic elevation of circulating MUP-1 in db/db mice, using an osmotic pump-based protein delivery system, increased energy expenditure and locomotor activity, raised core body temperature, and decreased glucose intolerance as well as insulin resistance. At the molecular level, MUP-1-mediated improvement in metabolic profiles was accompanied by increased expression of genes involved in mitochondrial biogenesis, elevated mitochondrial oxidative capacity, decreased triglyceride accumulation, and enhanced insulin-evoked Akt signaling in skeletal muscle but not in liver. Altogether, these findings raise the possibility that MUP-1 deficiency might contribute to the metabolic dysregulation in obese/diabetic mice, and suggest that the beneficial metabolic effects of MUP-1 are attributed in part to its ability in increasing mitochondrial function in skeletal muscle.

Effects of neonatal maternal separation (MS) on peri-pubertal onset of aggressive behavior in male mice

Effects of neonatal maternal separation (MS) on peri-pubertal onset of aggressive behavior in male mice

5-HT1B receptors, ventral orbitofrontal cortex, and aggressive behavior in mice

Systemic injections of 5-HT(1B) receptor agonists have been shown to have specific anti-aggressive effects in aggressive individuals. One site of action for these drugs is the 5-HT(1B) receptors in the ventral orbitofrontal cortex (VO PFC), an area that has been implicated in the inhibitory control of behavior and is a terminal region for 5-HT projections. To assess the anti-aggressive effects of the 5-HT(1B) receptor agonist CP-94,253 when microinjected into the VO PFC (0.1, 0.56, and 1.0 microg/0.2 microl) or into the infralimbic prefrontal cortex (IL PFC; 1.0 microg/0.2 microl) in separate groups of aggressive resident male mice. To confirm the 5-HT(1B) receptor as the critical site of action for the anti-aggressive effects, the 5-HT(1B/D) antagonist GR-127,935 was microinjected at 10.0 microg/0.2 microl into the VO PFC. After recovery from surgery, the anti-aggressive effects of microinjected CP-94,253 were studied during 5-min resident-intruder confrontations that were recorded and analyzed. Microinjections of CP-94,253 (0.56 and 1.0 microg/0.2 microl) dose-dependently reduced the frequency of attack bites and sideways threats. This effect was behaviorally specific because non-aggressive motor activities were not significantly altered by the drug. In the IL vmPFC or in an area lateral to the VO PFC, CP-94,253 (1.0 microg/0.2 microl) did not have significant behavioral effects. The results highlight the 5-HT(1B) receptors in the VO PFC as a particularly important site for the inhibition of species-typical aggressive behavior in male mice.

The effects of the D1 receptor antagonist SCH-23390 on individual and aggressive behavior in male mice with different experience of aggression

The dopaminergic systems of the brain are known to be involved in the mechanisms of aggression. The present report describes studies of the effects of acute administration of the dopamine D1 receptor antagonist SCH-23390 (0.1 mg/kg, i.p., over 30 min) on the individual and aggressive behavior of male mice of the line C57BL/6J with different experience of aggression. A group of animals with no previous experience of aggression responded to administration of this agent with decreases in direct aggression (attacks), though the total time of hostile behavior, i.e., the sum of the durations of attacks, aggressive grooming, and scattering of foreign litter, showed no change. The agent had no effect on the aggressivity of animals with 20 days of experience of agonistic confrontations. The discussion addresses the possible development of pharmacological densensitization of dopamine D1 receptors in aggressive males in response to prolonged activation of the dopaminergic systems in conditions of repeated experience of aggression, as demonstrated previously.

Perinatal exposure to genistein alters reproductive development and aggressive behavior in male mice

Exposure to endocrine disrupting chemicals adversely affects reproductive development and behavior in males. The goal of this study was to determine if exposure to genistein, an isoflavone found in soy, during early periods of sex differentiation alters reproductive development and behavior in male mice. Female C57BL/6 mice were fed a phytoestrogen-free diet supplemented with 0, 5 or 300 mg/kg of genistein throughout gestation and lactation. Anogenital distance (AGD) and body mass of male offspring was measured weekly from postnatal days 2–21, timing of preputial separation was assessed at puberty, and in adulthood, reproductive organ masses, sperm and testosterone production, and reproductive and aggressive behaviors were assessed. Exposure to genistein resulted in smaller AGD are reduced body mass, with the low-dose diet exerting a greater effect. Timing of preputial separation, adult reproductive behavior, sperm concentrations and testosterone production were not influenced by genistein treatment at either dose. Aggressive behaviors were decreased, whereas defensive behaviors were increased, in males that received the low-dose genistein diet. Exposure to genistein during critical periods of sex differentiation results in concurrent and persistent demasculinization in male mice. Phenotypic and behavioral abnormalities induced by genistein showed a non-monotonic response, where treatment with a low dose exerted a greater effect than treatment with a high dose of genistein. Given the popularity of soy infant formulas, the influence isoflavone exposure on reproductive and behavioral health in boys and men should be considered.

Aggressive behavior increases after termination of chronic sildenafil treatment in mice

Recent reports to the U.S. Food and Drug Administration Adverse Event Reporting System implicate sildenafil citrate in adverse emotional and aggressive behaviors. Sildenafil citrate (Viagra™) is widely prescribed for erectile dysfunction and acts by inhibiting phosphodiesterase Type-5, resulting in accumulation of cyclic-guanosine monophosphate (cGMP). Cyclic-GMP is synthesized by guanylyl cyclase that is directly activated by the messenger molecule, nitric oxide (NO), formed throughout the CNS by the enzyme nitric oxide synthase (NOS). Elevated concentrations of cGMP have been associated with increased aggressive behavior. In addition, the potential effect of cGMP accumulation on NO-mediated behavioral and neuroendocrine function through possible feedback mechanisms remains unspecified; however, neuronal NOS (nNOS) inhibition by pharmacologic agents or ablation of the gene encoding nNOS increases aggressive behavior in male mice. We tested the hypothesis that sildenafil citrate may increase aggression via its actions on cGMP and potential feedback inhibition of NO concentrations. Male C57BL/6 mice were injected with saline vehicle (0), 2, 5, 8, or 10 mg/kg of sildenafil citrate thrice weekly for 4 weeks. Latency to display aggressive behavior, frequency, and duration of aggressive behavior were recorded during neutral-arena aggression tests. No change in agonistic behavior was observed in mice during treatment with sildenafil citrate. However, sildenafil-treated mice given the highest dose were generally more aggressive 1 week post-cessation of drug treatment as compared to vehicle-treated mice. Additional investigation into potential withdrawal effects or abuse doses seems warranted.

Motor and neurochemical correlates of aggressive behavior in male mice

Motor and neurochemical correlates of aggressive behavior in male mice

Male urinary chemosignals differentially affect aggressive behavior in male mice.

Chemical signals modulate aggressive behavior in mice. For example, male urinary cues enhance aggression against other adults: a resident mouse attacks a male but not a castrated intruder, unless it is anointed with male urine. Our purpose was to understand whether molecules excreted with urine also act as aggression triggers in a different context. Therefore, the effect of urine, or molecules purified from urine, voided by different animals (males or females), was tested on the aggression of male mice against pups. Latency to the first attack, percentage of pups receiving the first attack, and percentage of attacked pups after 5 and 15 min were recorded. At variance with intermale aggression, male urinary chemosignals sprayed on pups reduced infanticide, while female urine did not. Male urine also delayed infanticide when compared to female urine. Pups anointed with low molecular weight dialyzed urine and with the high molecular weight protein fraction were attacked later than controls. Pups anointed with Major Urinary Proteins (MUPs) also were attacked later. The volatiles retained by MUPs act in the same way as adult male urine. MUPs and their ligands did not modify biting of food items. The results show that mice do not perceive male chemosignals as compulsory aggression triggers but rather can consistently and differentially shape their behavior in response to the same molecules according to different contextual events.

Motor and neurochemical correlates of aggressive behavior in male mice

We tested aggressive behavior in male albino mice by placing two individuals in one cage. Three successive tests with one-day-long intervals were performed; pairs were formed in a randomized order. Three animal groups, I-III, were classified according to the test results. These were absolute dominants, an intermediate group (animals were sometimes winners in conflicts, sometimes were defeated, or demonstrated no aggressive behavior), and submissive individuals (defeated in all cases). One day before testing and 1 h after each test, the intensity of motor activity (duration and velocity of running in a “locomotion wheel ”) was measured in all animals. Three days after testing, we measured the levels of noradrenaline (NA)and serotonin (ST) in the hypothalamus and those of NA and adrenaline (A) in the blood. Mice of groups I and II demonstrated high background indices of locomotor activity, while in group III these indices were comparatively low. In the course of testing, these indices in group I were in general preserved, while in groups II and III they dropped significantly. In mice of group I, the highest levels of NA in the hypothalamus and blood, high NA/ST ratio in the hypothalamus, and high NA/A ratio in the blood were observed. Animals of group II were characterized by intermediate levels of NA and ST in the hypothalamus together with rather high concentrations of A and the lowest NA/A ratio in the blood. In mice of group III, the highest level of ST and the lowest NA/ST ratio in the hypothalamus, as well as an intermediate NA/A ratio in the blood, were observed. We conclude that, generally, the response of an animal to emotional stress related to an antagonistic conflict can be classified into three types. These are an NA-ergic type in dominants, an intermediate A-ergic type, and an ST-ergic (vagotonic) type in submissive individuals. These types correlate with the three ethological models of behavior, “struggle,” “escape,” and catatonia.

Strain‐specific aggressive behavior of male mice submitted to different husbandry procedures

AbstractSevere aggression within groups of male laboratory mice can cause serious welfare problems. Previous experiments have shown that the transfer of specific olfactory cues during cage cleaning and the provision of nesting material decrease aggression and stress in group‐housed male mice. In this study, the combined effect of these husbandry procedures was tested for their long‐term effect on aggression in two strains of male mice (BALB/c and CD‐1). We used postcleaning aggressive behavior, wound counts, and testosterone levels as indicators of aggressiveness. Physiological responses to social challenge were investigated through urinary corticosterone and adrenal tyrosine‐hydroxylase measurements. Furthermore, the aggression‐modulating effects of two enrichment items (ShepherdShack/DesRes and PVC tube) were explored. Marked differences were found between the two strains. CD‐1 mice were more aggressive, had higher testosterone levels but lower corticosterone levels, and had fewer wounds than BALB/c mice. However, in neither of the two strains was long‐term enrichment with nesting material and its transfer after cage cleaning effective in lasting reduction of intermale aggression. This may be explained by the fact that aggression levels were generally low. It seems that housing mice in small, socially stable groups or keeping social disturbances to a minimum considerably modulates aggression in group‐housed male mice. Mice of both strains housed in cages enriched with nesting material had lower urinary corticosterone levels than standard‐housed mice. We therefore conclude that the long‐term provision of nesting material, including the transfer of nesting material during cage cleaning, may enhance the welfare of laboratory mice. Aggr. Behav. 29:69–80, 2003. © 2002 Wiley‐Liss, Inc.

Vasopressin V1b receptor knockout reduces aggressive behavior in male mice.

Increased aggression is commonly associated with many neurological and psychiatric disorders. Current treatments are largely empirical and are often accompanied by severe side effects, underscoring the need for a better understanding of the neural bases of aggression. Vasopressin, acting through its 1a receptor subtype, is known to affect aggressive behaviors. The vasopressin 1b receptor (V1bR) is also expressed in the brain, but has received much less attention due to a lack of specific drugs. Here we report that mice without the V1bR exhibit markedly reduced aggression and modestly impaired social recognition. By contrast, they perform normally in all the other behaviors that we have examined, such as sexual behavior, suggesting that reduced aggression and social memory are not simply the result of a global deficit in sensorimotor function or motivation. Fos-mapping within chemosensory responsive regions suggests that the behavioral deficits in V1bR knockout mice are not due to defects in detection and transmission of chemosensory signals to the brain. We suggest that V1bR antagonists could prove useful for treating aggressive behavior seen, for example, in dementias and traumatic brain injuries.

Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice: Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist

Experiments with social instigation or the omission of scheduled reinforcement show that serotonergic mechanisms may be involved in escalated aggression in animals. 5-HT1B receptor agonists have anti-aggressive effects in individuals who show moderate as well as high levels of aggression. The present study compared the effects of the 5-HT1B agonist anpirtoline (0.125–1.5 mg/kg) on (1) species-typical aggressive behavior in male mice, (2) aggression “instigated” or primed by prior exposure to the opponent, and (3) aggression heightened by “frustration” caused by omission of scheduled reinforcement. The effects of anpirtoline on species-typical behavior were also assessed after pretreatment with the 5-HT1B/1D receptor antagonist GR127935 (10 mg/kg). Anpirtoline, like other 5-HT1B agonists (CP-94,253, zolmitriptan), decreased both instigated and frustration-heightened aggression, while motor behavior was unaffected. The aggression-inhibiting effects of anpirtoline were blocked by pretreatment with GR127935. The current results indicate that the 5-HT1B receptor is critically involved in the modulation of escalated aggression.

Behavioral correlates of learned aggression in male mice

The aims of this paper are to study the aggressive behavior in male mice with consecutive experience of victories in 2, 10, and 20 days (T2, T10, and T20 winners) of daily agonistic confrontations under the sensory contact model and to determine the most probable behavioral domains that should be used as animal models for learned aggression in humans. It has been shown that the structure of winners' behavior changes from test to test: the attacking behavior prevailed (81% of the total time) in the behavior of T2 winners. Attacks and diggings (herein: digging up and scattering the litter on the partner' territory) prevailed in the behavior of T10 winners (each approximately 40%). T20 winners demonstrated aggressive grooming half of the testing time and digging behavior 25% of the time. Correlational analysis revealed that the number of significant correlations between the behavioral domains (attacking, digging, aggressive grooming, self-grooming, threats, rotations) and between different behavioral parameters (latency, number, total and average time) of one behavioral domain are growing from the second test to twentieth test, and the relationships between the behavioral domains change qualitatively. The following may be regarded as elements of learned aggression in male mice: (1) appearance of aggressive grooming instead of the intensive attacking behavior and (2) involvement of the digging behavior in the hostile behavior together with the threats and attacking behavior. Negative correlations between parameters of the behavioral domains may testify to the replacement of one behavioral pattern by another and reflect learned behavior. Positive correlations between certain behavioral domains may reflect the formation of a common motivational background for the winners' behavior. Aggr. Behav. 26:386–400, 2000. © 2000 Wiley-Liss, Inc.

Elimination of Aggressive Behavior in Male Mice Lacking Endothelial Nitric Oxide Synthase

Male mice with targeted deletion of the gene encoding the neuronal isoform of nitric oxide synthase (nNOS(-/-)) display increased aggressive behavior compared with wild-type (WT) mice. Specific pharmacological inhibition of nNOS with 7-nitroindazole also augments aggressive behavior. We report here that male mice with targeted deletion of the gene encoding endothelial NOS (eNOS(-/-)) display dramatic reductions in aggression. The effects are selective, because an extensive battery of behavioral tests reveals no other deficits. In the resident-intruder model of aggression, resident eNOS(-/-) males show virtually no aggression. Latency for aggression onset is 25-30 times longer in eNOS(-/-) males compared with WT males in the rare instances of aggressive behaviors. Similarly, a striking lack of aggression is noted in tests of aggression among groups of four mice monitored in neutral cages. Although eNOS(-/-) mice are hypertensive ( approximately 14 mmHg blood pressure elevation), hypertension does not appear responsible for the diminished aggression. Reduction of hypertension with hydralazine does not change the prevalence of aggression in eNOS(-/-) mice. Extensive examination of brains from eNOS(-/-) male mice reveals no obvious neural damage from chronic hypertension. In situ hybridization in WT animals reveals eNOS mRNA in the brain associated exclusively with blood vessels and no neuronal localizations. Accordingly, vascular eNOS in the brain appears capable of influencing behavior with considerable selectivity.

Monoamine Oxidase in Neuropsychiatry and Behavior

Monoamine oxidase (MAO) catalyzes the oxidative deamination of a number of biogenic amines, including the key neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and the neuromodulator phenylethylamine (PEA). Two forms of MAO, designated “MAO A” and “MAO B,” have been identified on the basis of biochemical properties and, subsequently, by cloning the relevant genes. Of the two, MAO A exhibits a higher affinity for 5-HT and NE and for the inhibitor clorgyline (Johnston 1968), whereas MAO B has a higher affinity for PEA, benzylamine, and the inhibitor deprenyl (Knoll and Magyar 1972).

Effects of Haloperidol on Communicative and Aggressive Behavior in Male Mice with Different Experiences of Aggression

Effects of two doses of haloperidol (0.1 and 0.4 mg/kg, 30 min and 24 h, IP) on communicative and aggressive behavior in C57BL/6J male mice have been studied. Some of the mice were without prior experience of aggression (“recruits”); the others had been victorious in 20 daily aggressive confrontations (“experienced winners”). Communicative behavior was estimated as the behavioral reaction to a standard tester (loser) in the partition test. Haloperidol in either dose significantly reduced communicative behavior in the “recruits,” but not in the “experienced winners.” Significantly fewer attacks, less total attacking time, and total time of aggressive behavior (aggressive grooming + attacks) were demonstrated by the “experiences winners,” than by the “recruits,” while the latency of the first attack, the number, the total and average duration of aggressive grooming events were significantly higher. In the “recruits,” haloperidol dose dependently increased the latency and decreased the number of attacks, the total attacking time, and the total time of aggressive behavior 30 min and 24 h after injection. However, haloperidol did not affect the average or total time of aggressive grooming. Neither dose significantly affected any measure of aggressive behavior in the “experienced winners.” It has been concluded that repeated aggression experience reduces the pharmacological sensitivity of the dopamine receptors.

Differential effects of chlordiazepoxide on aggressive behavior in male mice: the influence of social factors.

The present study examined the influence of prior social experience on the effects of chlordiazepoxide (CDP; 5.0, 10.0 and 20.0 mg/kg) on intrasexual aggression in male mice. Prior to drug testing, animals were either individually housed or screened in dyadic encounters in a neutral cage. This novel method yielded four experimental groups comprising animals with different social experiences and different aggressive/defensive characteristics: 1) individually-housed males (I): 2) aggressive males (A); 3) counter-attacking males (C), which actively responded to but did not initiate attack; and 4) defeated males (D). Twenty-four hours after screening, animals were treated with CDP and subjected to a resident-intruder test with untreated intruders. Results indicated that the lowest dose of CDP (5 mg/kg) increased aggressive behaviour but only in A males. At higher doses (10-20 mg/kg), CDP reduced attacks towards intruders in A, C and I, but not D, males. In A and C males, the antiaggressive action of CDP was associated with a prosocial effect (increased social investigation), whereas in I males, reduced aggression was associated with an increase in fear-related behaviours. As these differential effects of CDP on intermale aggression cannot be fully explained by differences in behavioural baselines, present data highlight the importance of experiential background as a powerful variable in determining behavioural responses to benzodiazepines. Present findings therefore suggest that an understanding of drug effects on social behaviour demands consideration of biological variability in phenotype.

Aggressive behavior in male mice lacking the gene for neuronal nitric oxide synthase requires testosterone

Nitric oxide acts as a neural messenger in both the central and peripheral nervous systems. Mice with targeted disruption of the neuronal isoform of nitric oxide synthase (nNOS−/−) are extremely aggressive relative to wild-type (WT) mice. Male nNOS−/− mice exhibit an increase in the number and duration of aggressive encounters compared to WT animals when tested in a variety of paradigms used to test rodent aggression. This inappropriate aggressive behavior has only been observed in male nNOS−/− mice; nNOS−/− females, like female WT mice, exhibit little or no aggression. The present study sought to test the dependence of increased aggressive behavior in nNOS−/− males on testosterone. Intact nNOS−/− males exhibited elevated levels of aggression relative to intact WT males. Castration reduced aggression in both WT and nNOS−/− males to equivalent low levels. Testosterone replacement restored aggression to precastration levels in both genotypes. These data provide evidence that increased aggressive behavior of nNOS−/− mice, like aggression in WT mice, is testosterone-dependent.

Interaction of Morphine and Haloperidol on Agonistic and Motor Behaviors of Male Mice

RODRÍGUEZ-ARIAS, M., J. MIÑARRO AND V. M. SIMÓN. Interaction of morphine and haloperidol on agonistic and motor behaviors of male mice. PHARMACOL BIOCHEM BEHAV 58 [1]153–158, 1997.—To further clarify the interaction between opioid and dopaminergic systems, the effects of simultaneous administration of morphine hydrochloride (1.25 or 2.5 mg/kg) and haloperidol (0.1 mg/kg) on aggressive behavior of male mice were explored. Isolated male mice (experimental animals) were confronted in a neutral area with anosmic, group-housed conspecifics (standard opponents) 30 min after injection of both compounds, and aggression was evaluated by estimation of times allocated to 11 different behavioral categories. In the first experiment (which functioned as a pilot study), the two doses of morphine were explored. In the second one, incorporating a more complete experimental design, only the lowest morphine dose was used and the animals were preselected by a previous aggression test. In attack behavior, morphine added to haloperidol counteracted, at least partially, the antiaggressive effect of the neuroleptic. In contrast, the impairing effects of haloperidol on motor activity were increased by the addition of morphine. These results show that the behavioral effects of dopaminergic antagonists are modulated by opioid influences and that opiates and dopaminergic agents interact in a different manner on motor and on aggressive behaviors.