Ethopharmacological studies of the effects of β-carbolines and benzodiazepines on murine aggression

The behavioral profiles generated by a benzodiazepine (BDZ) agonist (diazepam), an “inverse” agonist (β-carboline-3-carboxylate ethyl ester, βC-3-CEE), and dihydro-(DHβCs) and tetrahydro-β-carbolines (THβCs) were investigated on aggressive isolated mice using a computerized ethopharmacological technique. Augmentation of intraspecific sociability with a concurrent reduction of aggression are characteristic features of diazepam's effects, whereas βC-3-CEE exerts the opposite effects. βC-3-CEE countered the prosocial activity of diazepam and had intrinsic activities on intraspecific behaviour. Some DHβCs (harmalol and 6-methoxy-harmalan) and THβCs (1-methyl-6-hydroxy-THβC and tetrahydronorharmane) may exacerbate aggression at low (BDZ-negative) doses (1 mg/kg), and inhibit such behavior at higher (serotonin-positive) doses (10-15 mg/kg). The ethological profiles of DHβCs were different from the profiles of THβCs. Differences in ethological profiles of βC-3-CEE, DHβCs, and THβCs seem to reflect the neurochemical (mainly BDZ-and serotonergic) properties of these substances.     

Effects of NMDA receptor channel blockade on aggression in isolated male mice

N‐Methyl‐D ‐aspartate (NMDA) receptor antagonists are perspective candidates for medication development for a number of diseases/states that are associated with increased aggressiveness (e.g., opioid withdrawal). The prototypic NMDA receptor antagonist phencyclidine (PCP) itself is a widely abused substance and is known to elevate levels of aggression in drug users. The present study was aimed at testing several drugs that share with PCP the ability to block NMDA receptor–associated channel. The resident‐intruder procedure was used to assess drug effects on aggressive behavior in isolated male mice. Resident aggressive mice were administered NMDA channel blockers (PCP; 0.3–10 mg/kg), dizocilpine (MK‐801; 0.01–0.3 mg/kg), memantine (1–30 mg/kg), and MRZ 2/579 (0.1–5.6 mg/kg). The competitive NMDA receptor antagonist D CPPene (0.1–5.6 mg/kg) was also tested as a compound representing an alternative approach to reduce activity of NMDA receptor complex. PCP, dizocilpine, and memantine inhibited expression of aggressive behaviors only at doses that produced ataxia. The novel channel blocker MRZ 2/579 also produced ataxia at the highest dose level but failed to affect aggressiveness. Reduction in aggression with a corresponding increase in sociability was observed after administration of D ‐CPPene. Overall, the present results suggest that NMDA receptor channel blockers do not exert selective effects on aggressive behavior. Aggr. Behav. 25:381–396, 1999. © 1999 Wiley‐Liss, Inc.     

Self-Regulation Deficits Explain the Link between Reactive Aggression and Internalizing and Externalizing Behavior Problems in Children

Childhood aggression is often associated with significant psychosocial maladjustment; however, adjustment difficulties may vary based on the function of aggression. The present study used the Behavior Rating Inventory of Executive Function (BRIEF; Gioia et al. Child Neuropsychology 6:235–238, 2000) to examine whether difficulties in particular domains of self-regulation serve as common mechanisms in the association between reactive (versus proactive) aggression and internalizing or externalizing adjustment problems in clinic-referred children. Reactive aggression was associated with poorer behavioral regulation and metacognition, whereas proactive aggression was not associated with poorer self-regulation. Further, the association between reactive aggression and adjustment problems, both internalizing and externalizing, was accounted for by poorer behavioral regulation and metacognitive skills. Gender, age, ADHD diagnosis, IQ, and psychotropic medication status did not account for the results. These findings suggest that self-regulation skills influence adjustment problems in reactively aggressive youth and may be important targets of intervention for such children.     

Moderators of the association between relational aggression and perceived popularity

This study, which involved two waves of measurement over a period of 12 months, examined first whether the positive association between relational aggression and two types of high status was moderated by social self-efficacy, leadership, cooperation, and peer sociability. It was expected that relational aggressors are most likely to gain high peer group status when they are also self-efficacious or prosocial. Second, this study examined the reciprocal association between relational aggression and high peer status. It was anticipated that relational aggression would contribute to higher perceived popularity and vice versa. Third, we also examined and hypothesized reciprocal effects between social self-efficacy, leadership, cooperation, and peer sociability and perceived popularity. Youth were 540 13-15 year olds participating in Grade 7 (Time 1) and again 1 year later in Grade 8 (Time 2). Data were collected from peers, teachers, and the adolescents themselves. Consistent with expectations, relationally aggressive adolescents high in social self-efficacy, leadership, cooperation, and peer sociability were higher in status than relationally aggressive individuals with low levels of these characteristics. In addition, relational aggression and perceived popularity reciprocally influenced each other. Finally, social self-efficacy, leadership, cooperation, and peer sociability reciprocally influenced and were influenced by perceived popularity.     

Manipulations of vasopressin alter aggression differently across testing conditions in monogamous and non‐monogamous Peromyscus mice

Differences in the distribution of arginine vasopressin (AVP) and a subtype of AVP receptors, the V_1a receptor, may explain dissimilarities in social behavior of monogamous and non‐monogamous rodents. Intracerebroventricular infusions of AVP and a V_1a antagonist were used in sexually naive males of two mouse species, the monogamous and highly aggressive California mouse (Peromyscus californicus) and the non‐monogamous and less aggressive white‐footed mouse (P. leucopus), to begin testing the interaction between the social system of a species and the effects of AVP on aggression. Two testing conditions, the resident‐intruder aggression test (R‐I) and the neutral arena aggression test, were used because they may differ in function and underlying biological mechanisms. In the R‐I test, administration of the antagonist lengthened attack latencies in California mice. In contrast, blocking V_1a receptors did not alter attack latencies in the R‐I test in white‐footed mice or in the neutral arena aggression test in both species. AVP also did not alter aggression in either species in either behavioral test. Overall, these results suggest that AVP may be more likely to be associated with offensive aggression as measured in the R‐I test than with neutral arena aggression and that the effects of AVP manipulations may differ between monogamous and non‐monogamous rodents. Aggress. Behav. 31:000–000, 2005. © 2005 Wiley‐Liss, Inc.     

Pain‐induced aggression and changes in social behavior in mice

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

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

Severe 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.     

Mice: the initiation and maintenance of pregnancy-induced aggression following thelectomy

Two experiments were conducted in order to assess the effects of thelectomy (i.e., nipple removal) on the display of pregnancy-induced aggression in Rockland-Swiss (R-S) albino mice. Pregnant animals, thelectomized on Gestation Day (GD) 12, exhibit a high incidence and intensity of aggression toward adult R-S male intruders during tests conducted on GDs 14, 16, and 18 (i.e., during the last third of gestation in this species). Since thelectomized dams display levels of aggression (i.e., 63% incidence) equivalent to those of sham-operated and nonoperated animals (53 and 67% incidence, respectively), it would appear that nipple presence is not a critical factor for the maintenance of pregnancy-induced aggression in mice (Experiment 1). To examine the effects of nipple deprivation on the initiation of pregnancy-induced aggression, virgin animals were thelectomized prior to mating, then repeatedly tested for aggression at 2-day intervals of gestation. Unlike nipple-intact dams, pregnant mice, deprived of nipples prior to conception, rarely exhibit (less than 17% incidence) agonistic behaviors toward intruder males (Experiment 2). These findings suggest that the development and self-stimulation of nipples early in pregnancy may be important conditions for the display of heightened aggression with advancing pregnancy in mice.     

Reduction of appeasement‐related affect as a concomitant of diazepam‐induced aggression: evidence for a link between aggression and the expression of self‐conscious emotions

Aggressive responding following benzodiazepine ingestion has been recorded in both experimental and client populations, however, the mechanism responsible for this outcome is unclear. The goal of this study was to identify an affective concomitant linked to diazepam‐induced aggression that might be responsible for this relationship. Thirty males (15 diazepam and 15 placebo) participated in the Taylor Aggression Paradigm while covertly being videotaped. The videotapes were analyzed using the Facial Action Coding System with the goal of identifying facial expression differences between the two groups. Relative to placebo participants, diazepam participants selected significantly higher shock settings for their opponents, consistent with past findings using this paradigm. Diazepam participants also engaged in significantly fewer appeasement expressions (associated with the self‐conscious emotions) during the task, although there were no group differences for other emotion expressions or for movements in general. Aggr. Behav. 35:203–212, 2009. © 2008 Wiley‐Liss, Inc.     

AEDs and psychotropic drugs in children with autism and epilepsy

The efficacy of antiepileptic drugs (AEDs) and psychotropic medications in children with autism is limited to the treatment of seizures or to specific behaviors such as irritability, impulsivity, hyperactivity, repetitive behaviors, or aggression. The reliability and value of the available data--to determine the efficacy of these medications in autism--are limited by lack of controlled clinical trials, the small number of subjects, the heterogeneity of the population studied, and the brief duration of most drug trials. Indeed, few controlled clinical trials using AEDs in autism, with or without seizures, have been conducted. Because some AEDs also have a positive effect on mood, the benefits that children with autism sometimes obtain from these medications may not be due to the treatment of the abnormal electrical activity or the seizures per se but to an effect on common neuronal systems responsible for both behavior and epilepsy. The relationship between epilepsy and autism, and specifically the effects that abnormal electrical activity may have on the developing brain, may provide some valuable insights into the type of studies that are needed to help us understand the pathophysiology of autism.     

Repeated diazepam administration reversed working memory impairments and glucocorticoid alterations in the prefrontal cortex after short but not long alcohol-withdrawal periods

The study was designed to assess whether repeated administration of diazepam (Valium®, Roche)—a benzodiazepine exerting an agonist action on GABA_A receptors—may alleviate both the short (1 week, 1W) and long-term (6 weeks, 6W) deleterious effects of alcohol withdrawal occurring after chronic alcohol consumption (6 months; 12% v/v) in C57/BL6 male mice. More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels in the prefrontal cortex (PFC). In a subsequent experiment, diazepam was administered i.p. for 9 consecutive days (1 injection/day) during the alcohol withdrawal period at decreasing doses ranging from 1.0 mg/kg to 0.25 mg/kg. Diazepam was not detected in the blood of withdrawn mice at the time of memory testing, occurring 24 hours after the last diazepam injection. Repeated diazepam administration significantly improved alternation rates and normalized levels of glucocorticoids and pCREB activity in the PFC in 1W but not in 6W withdrawn mice. Thus, repeated diazepam administration during the alcohol-withdrawal period only transitorily canceled out the working memory impairments and glucocorticoid alterations in the PFC of alcohol-withdrawn animals.     

Does fear modulate defensive and offensive types of maternal attack in mice?

Swiss CD‐1 lactating mice show a different pattern of attack toward intruders of differing sex, displaying defensive attack against the male (bites on the head and ventrum associated with fear) and offensive attack against the female (bites on the back and flanks with no elicitation of fear). This dichotomy may reflect diverse functions of maternal aggression: the attack toward males (the more infanticidal gender in laboratory strains) has been interpreted as a counterstrategy to infanticide, whereas the attack toward females may serve to establish a social hierarchy or to space rivals of the same sex. In terms of proximal mechanisms, fear may be a key factor involved in the modulation of the different patterns of attack. In Experiment 1 we compared the pattern of attack of lactating females in Swiss CD‐1 and Wild mice toward male and female intruders in relation to fear components of behavior of the attacking dams. Results showed that in Swiss mice, male intruders were attacked with a defensive type of attack accompanied by high levels of fear, whereas female intruders did not elicit fear in the attacking animal but were attacked with an offensive pattern. In Wild mice, both types of intruders were attacked with a defensive pattern; notwithstanding, fear was evident only toward male intruders. This suggests that fear is not totally responsible for the expression of the defensive type of attack. To test the hypothesis that defensive attack toward male and female intruders may be related to the infanticidal potential of the intruder, Experiment 2 examined levels of infanticide in both male and female Swiss CD‐1 and Wild mice. Swiss female mice showed virtually no infanticidal behavior, whereas Swiss males and both sexes of Wild mice showed similarly high levels of infanticide (55%–75%). From a game theory perspective, the defensive pattern of maternal attack toward female intruders in Wild mice is discussed as “extreme” defense of a high value resource and thus, functionally, a competitive form of aggression. Aggr. Behav. 26:193–203, 2000. © 2000 Wiley‐Liss, Inc.     

An ethopharmacological assessment of agmatine's effects on agonistic encounters between male mice

The endogenous polyamine agmatine may be a new central neurotransmitter. Agmatine‐like immunoreactivity has been described in numerous brain regions (such as the hypothalamus and amygdala), long thought involved in the control of aggression. Consequently, the present study examined agmatine's (2.5–80 mg/kg, ip) effects on behavior directed by isolated male mice to anosmic partners in a neutral area. The videotaped encounters were analysed in terms of 10 broad behavioral categories. Agmatine did not appear to be involved in the modulation of aggression or anxiety in this test. Aggr. Behav. 31:000000, 2005. © 2005 Wiley‐Liss, Inc.     

Differential effect of handling on adult aggression in male mice bidirectionally selected for attack latency

Individual variation in intermale aggression is to a significant degree based upon genetic variation, but environmental factors can also exert their influence on the level of aggression. Moreover, genotype–environment interactions are a well‐known phenomenon. In the present experiment, I tested whether cage size or handling during development had an influence on adult attack latency scores. To be able to study a genotype–environment interaction, mice from two bidirectionally on attack latency selected lines were used. The size of the cage in which the mice grew up had no long‐term effect on aggression, neither in the high‐ nor in the low‐aggressive line. Handling, however, significantly increased the adult aggression of males from the low‐aggressive line. Despite the differential effect of handling on genetically high‐ and low‐aggressive mice, handling was not able to undo the marked differences in attack latencies between mice from both lines. Aggr. Behav. 25:365–368, 1999. © 1999 Wiley‐Liss, Inc.     

A daily diary investigation of self-reported alcohol-related direct and indirect aggression

Research supports the relationship between alcohol use and direct aggression, however, scant research has examined the association between alcohol use and indirectly aggressive behavior. Further, extant research has relied on retrospective reporting of behaviors, which may be subject to recall bias. The daily diary methodology enables the assessment of both the between- and within-subject variation, as well as reduces the likelihood of biased reporting. Consequently, the current study utilized a daily diary design to examine (a) associations between daily alcohol use and alcohol-related aggressive behaviors (i.e., direct and indirect); and (b) the co-occurrence of alcohol-related direct and indirect aggression. Participants were 105 (80% female) college student drinkers. Students completed baseline questionnaires and up to 14 consecutive, daily surveys regarding their previous day alcohol use, alcohol-related direct aggression, and alcohol-related indirect aggression. Findings revealed that alcohol use was associated with same day alcohol-related direct and indirect aggression, after controlling for baseline alcohol use. Self-reported alcohol-related direct aggression was more likely to occur on days in which self-reported alcohol-related indirect aggression occurred, after controlling for dispositional aggression, trait self-control, and baseline alcohol use. Results of the study suggest that, similar to alcohol-related direct aggression, alcohol use is associated with an increased likelihood of alcohol-related indirect aggression. Further, the co-occurrence of alcohol-related indirect and direct aggression supports that individuals may be engaging in multiple types of aggressive behaviors. Findings extend previous cross-sectional and qualitative research suggesting that indirect aggression may co-occur, perhaps increasing in severity.     

A behavior-analytic conceptualization of the side effects of psychotropic medication

A range of behavior-much deemed problematic by society-is treated with behavioral methods or psychotropic medications. Although the processes associated with behavioral interventions have been investigated using conceptual, experimental, and applied analyses, less is known about the behavioral processes associated with the use of psychotropic medication. Psychotropic drugs produce at least two types of effects of behavioral interest: (a) primary effects of drug action on target behaviors and (b) side effects that change the target or other behavior. Although an empirical literature exists regarding the former effects, little attention has been given to the latter topic. In this paper we offer a conceptual analysis of the side effects of psychotropic medication. We propose that the side effects of various drugs can influence behavior by functioning as motivating operations, conditional or discriminative stimuli, or by establishing new response-reinforcer relations. This conceptualization may facilitate the empirical analysis of how psychotropic drugs change behavior.     

Examining the relation between PTSD and insomnia on aggression

Posttraumatic stress disorder (PTSD) symptoms and poor sleep have been identified as potential causals factor in aggression, violence, and impulsive behavior. Given the high cost of aggression to society and public health, identifying modifiable factors related to aggression, such as insomnia, may guide treatment strategies to help decrease aggression. Participants were 143 Veterans seeking treatment for PTSD at a VA outpatient PTSD clinic. Linear and logistic regression analyses were used to examine the relation between PTSD and insomnia on aggression. Results from bivariate analyses indicated that while both PTSD and insomnia severity were associated with higher aggression scores independently, when PTSD and insomnia were examined together, PTSD severity was the only significant predictor of aggression. Interaction effects yielded nonsignificant results suggesting that poor sleep did not moderate the PTSD and aggression relation. Results suggest that addressing PTSD symptoms as a first treatment target may be more important for decreasing risk for aggression than targeting insomnia. More research is needed to understand whether treating PTSD and insomnia reduces aggression in Veterans.     

Violent phenotype in SAL mice is inflexible and fixed in adulthood

Violence was shown to be qualitatively different from functional hyper‐aggression in mice selected for high aggression namely Short Attack Latency (SAL), Turku Aggressive (TA) and North Carolina (NC900) strains. This study aimed at investigating whether this adulthood violent phenotype as seen previously in the SAL mice is fixed and hence behaviorally inflexible right from day 1 of the experiment or consequential, i.e., subject to gradual change from functional aggression to violence. The functionally hyper‐aggressive strains namely TA and NC900 strains served as controls for the study. Methodologically, behavioral (in)flexibility was studied using the overall sequential structure of agonistic behavior. In particular, intra‐individual variations in the overall agonistic behavior as well as offensive, pre‐ and post‐offensive behavior transitions, directly related to the resident–intruder interactions were investigated. The SAL mice showed the least intra‐individual variation in their overall sequential agonistic structure as well as a fixed offense‐oriented agonistic behavior of highest magnitude when compared with the other strains. Additionally, the pre‐ and post‐ offensive transitions were most salient in the functionally hyper‐aggressive TA and NC900 strains, whereas virtually absent in the SAL mice. Thus, the violent behavior of the adult SAL mice is behaviorally inflexible or fixed, whereas the functionally hyper‐aggressive behavior of the adult TA and NC900 mice is behaviorally flexible and constantly adaptive to the opponent behavior, over 3 days of repeated resident–intruder interaction. Aggr. Behav. 35:430–436, 2009. © 2009 Wiley‐Liss, Inc.     

Neuropharmacological aspects of adaptive pain inhibition in murine “victims” of aggression

This review outlines recent research on a subset of physiological responses in murine “victims” or aggression. In a typical resident-intruder paradigm, the detailed study of intruders has revealed that exposure to conspecific attack (and related stimuli) is associated with two forms of analgesia which appear to be integral components of the murine defensive repertoire. In response to intense/enduring attack, intruder mice display a profound, long-lasting and opioid-mediated analgesia. This reaction is highly correlated with defensive immobility and may function to reduce involuntary cues to further attack. In contrast, the inhibition of pain reactivity in mice tested immediately upon the display of defeat is less intense, shorter-lasting, non-opioid in nature and may function to facilitate active defenses such as escape. As this form of pain inhibition is also evident in intruders exposed to the scent of an aggressive male conspecific, a possible anticipatory defensive function linked to mechanisms of anxiety has been proposed. This hypothesis is supported by 1) the prevention of defeat analgesia by a range of antianxiety drugs (benzodiazepines, 5-hydroxytryptamine_1A [5-HT_1A] receptor agonists, and 5-HT₃ receptor antagonists) and 2) the effects of social defeat on behavior in the elevated plusmaze model of anxiety. These findings are discussed in relation to coping mechanisms in murine “victims” of aggression. © 1995 Wiley-Liss, Inc.     

Personality and risk-taking: common biosocial factors

The first part of this article describes a study of the relationships between personality and risk-taking in six areas: smoking, drinking, drugs, sex, driving, and gambling. The participants, 260 college students, were given self-report measures of risky behaviors in each of the six areas and the Zuckerman-Kuhlman five-factor personality questionnaire. Generalized risk-taking (across all six areas) was related to scales for impulsive sensation seeking, aggression, and sociability, but not to scales for neuroticism or activity. Gender differences on risk-taking were mediated by differences on impulsive sensation seeking. The second part discusses biological traits associated with both risk-taking and personality, particularly sensation seeking, such as the D4 dopamine receptor gene. the enzyme monoamine oxidase, and augmenting or reducing of the cortical evoked potential. Comparative studies show relationships between biological markers shared with other species and correlated behaviors similar to sensation seeking in humans. A biosocial model of the traits underlying risk-taking is presented.