Animal Models Of Aggression Research Articles

Bidirectional effects of Topiramate on anterior cingulate cortex region related aggressive behavior

Topiramate, an antiepileptic drug, has been found to be useful for the treatment of aggression in clinical populations as well as in animal models of aggression. However, increases in aggression were also observed under lower doses of Topiramate. Subsequently, Topiramate produced an inverted U-shaped dose response curve, with increases in aggression at low doses, whereas higher doses engendered anti-aggressive effects. In our previous study, we demonstrated that Topiramate modulates brain activity in the prefrontal areas involved in the modulation of the subcortical circuit mediating aggression, and we found indirect evidence that the anterior cingulate cortex (ACC) could be a key site where Topiramate may exert its dose-response effects on aggression. In this study, we performed site-directed injections of Topiramate (0.1 and 0.3 mM) into the ACC on offensive behaviors in isolation-inducedaggression paradigm. By using the resident-intruder test, we demonstrated that Topiramate microinfusion into the ACC at low doses produced increases in aggression, as evidenced by shorter attack latencies (p < 0.01) and increased attack duration (p < 0.01), without affecting the social behavior. In contrast, higher doses engendered anti-aggressive effects, by increasing the attack latencies (p < 0.001), decreasing attack number (p < 0.001) and decreasing attack duration (p < 0.001), as well as an increase in the social behavior. Our findings supported that Topiramate at higher concentrations appeared more efficient to decrease aggression in treated mice. Therefore, we suggest that the ACC is a key brain region in which Topiramate may exert its dose-response effects on aggressive and antisocial behaviors observed in populations with psychotic disorders.

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.

Purpose: A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation.Experimental Design: We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically.Results: This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease.Conclusions: Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. Clin Cancer Res; 24(6); 1389-401. ©2017 AACR.

The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications

The matrix metalloproteinases (MMP) MMP-2 and MMP-9 are physiological regulators of vascular remodelling. Their dysregulation could contribute to vascular calcification. We examined the role of the MMP-2 and MMP-9 in uraemic vascular calcification in vivo and in vitro. The impact of pharmacological MMP inhibition on the development of media calcifications was explored in an aggressive animal model of uraemic calcification. In addition, the selective effects of addition and inhibition, respectively, of MMP-2 and MMP-9 on calcium-/phosphate-induced calcifications were studied in a murine cell line of vascular smooth muscle cells (VSMCs). High-dose calcitriol treatment of uraemic rats given a high phosphate diet induced massive calcifications, apoptosis and increased gene expressions of MMP-2, MMP-9 and of osteogenic transcription factors and proteins in aortic VSMC. The MMP inhibitor doxycycline prevented the VSMC transdifferentiation to osteoblastic cells, suppressed transcription of mediators of matrix remodelling and almost completely blocked aortic calcifications while further increasing apoptosis. Similarly, specific inhibitors of either MMP-2 or -9, or of both gelatinases (Ro28-2653) and a selective knockdown of MMP-2/-9 mRNA expression blocked calcification of murine VSMC induced by calcification medium (CM). In contrast to MMP inhibition, recombinant MMP-2 or MMP-9 enhanced CM-induced calcifications and the secretion of gelatinases. These data indicate that both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodelling and the initiation of vascular calcification. Their inhibition seems a promising strategy in the prevention of vascular calcifications.

TL-118 and Gemcitabine Drug Combination Display Therapeutic Efficacy in a MYCN Amplified Orthotopic Neuroblastoma Murine Model – Evaluation by MRI

Neuroblastoma (NB) is the most common extra-cranial pediatric solid tumor with up to 50% of NB patients classified as having high-risk disease with poor long-term survival rates. The poor clinical outcome and aggressiveness of high-risk NB strongly correlates with enhanced angiogenesis, suggesting anti-angiogenic agents as attractive additions to the currently insufficient therapeutics. TL-118, a novel drug combination has been recently developed to inhibit tumor angiogenesis. In the current study, we used the SK-N-BE (2) cell line to generate orthotopic NB tumors in order to study the combinational therapeutic potential of TL-118 with either Gemcitabine (40 mg/kg; IP) or Retinoic acid (40 mg/kg; IP). We show that TL-118 treatment (n = 9) significantly inhibited tumor growth, increased cell apoptosis, reduced proliferation and extended mouse survival. Moreover, the reciprocal effect of TL-118 and Gemcitabine treatment (n = 10) demonstrated improved anti-tumor activity. The synergistic effect of these drugs in combination was more effective than either TL or Gemcitabine alone (n = 9), via significantly reduced cell proliferation (p<0.005), increased apoptosis (p<0.05) and significantly prolonged survival (2-fold; p<0.00001). To conclude, we demonstrate that the novel drug combination TL-118 has the ability to suppress the growth of an aggressive NB tumor. The promising results with TL-118 in this aggressive animal model may imply that this drug combination has therapeutic potential in the clinical setting.

Preclinical investigations into the relationship between adolescent SSRI exposure and aggressive behavior: Response to commentary by Rubin and Walkup (2012).

A Commentary published in the October 2012 issue of Behavioral Neuroscience entitled "SSRIs, Adolescents, and Aggression: Tempering Human Implications Regarding SSRI-Induced Aggression in Hamsters: Comment on Ricci and Melloni (2012)", presents an interpretation of findings from our report published in the same issue of Behavioral Neuroscience entitled "Repeated Fluoxetine Administration During Adolescence Stimulates Aggressive Behavior and Alters Serotonin and Vasopressin Neural Development in Hamsters". The commentary was informative, especially in its review of the prescribing demographics for SSRIs in youth and its review of human and animal aggression subtypes, and in several instances offered alternative explanations and interpretations of evidence cited in our report, particularly regarding putative relationships between human and animal models of aggression. In our response, we reply to comments made by the authors regarding the animal model of choice for our studies, the methodologies employed and the greater implication(s) of our published study as well as offer a disparate view of the evidence cited by the authors in their commentary as they pertain to the relevance of the models of aggression used in our study.

Aggressive behavior: A comprehensive review of its neurochemical mechanisms and management

Aggression is a deliberate series of actions that lead to harm, injury, or destruction of another organism, and is the most common factor promoting violent crimes. Beyond being the immediate cause of physical injury, aggressive behavior also produces profound long term emotional disabilities in its victims. When outburst of aggression is comorbid with DSM-IV-defined neuropsychiatric disorders, the offenders are usually given psychiatric care; however, when they appear normal or healthy, their most likely fate is punishment by the law. This punitive approach often increases aggression, thereby promoting the propensity for violent crimes. Antipsychotics are the drugs commonly used for treatment of aggression and violent outbursts. However, the uses of these drugs have serious side effects of catalepsy or impairment of sensorimotor performance. They also affect the defense or flight capabilities of organisms, which further limit their usefulness in aggression. Thus, there is a critical need to search for agents that can selectively reduce aggression without affecting other behaviors or causing any serious unwanted side effects. This review focuses on the types, neurochemical bases, and animal models of aggression, with a comprehensive appraisal of the pharmacological approach to the treatment of the disorder.

Handbook of Behavior Genetics: From Greeks to Geeks

Handbook of Behavior Genetics: From Greeks to Geeks

Comparison of Pretargeted and Conventional CC49 Radioimmunotherapy Using 149Pm, 166Ho, and 177Lu

The therapeutic efficacies of radiolabeled biotin, pretargeted by monoclonal antibody (mAb)-streptavidin fusion protein CC49 scFvSA, were compared to those of radiolabeled mAb CC49, using the three radiolanthanides in an animal model of human colon cancer. The purpose of the present study was to compare antibody pretargeting to conventional radioimmunotherapy using (149)Pm, (166)Ho, or (177)Lu. Nude mice bearing LS174T colon tumors were injected sequentially with CC49 scFvSA, the blood clearing agent biotin-GalNAc(16), and (149)Pm-, (166)Ho-, or (177)Lu-DOTA-biotin. Tumor-bearing mice were alternatively administered (149)Pm-, (166)Ho-, or (177)Lu-MeO-DOTA-CC49. Therapy with pretargeted (149)Pm-,(166)Ho-, and (177)Lu-DOTA-biotin increased the median time of progression to a 1 g tumor to 50, 41, and 50 days post-treatment, respectively. Therapy with (149)Pm-,(166)Ho-, and (177)Lu-MeO-DOTA-CC49 increased the median time to progression to 53, 24, and 67 days post-treatment, respectively. In contrast, saline controls showed a median time to progression of 13 days postinjection. Treatment with pretargeted (149)Pm-, (166)Ho-, and (177)Lu-biotin or (149)Pm-, (166)Ho-, and (177)Lu-CC49 increased tumor doubling time to 18-36 days, compared to 3 days for saline controls. Among treated mice, 23% survived >84 days post-therapy, and 11% survived 6 months, but controls survived <29 days. Long-term survivors showed tumor growth inhibition or partial regression, extensive necrosis in residual masses, and no evidence of nontarget tissue toxicity at necropsy. Both pretargeted and conventional RIT demonstrated considerable efficacy in an extremely aggressive animal model of cancer. Our results identified (177)Lu as an optimal radiolanthanide for future evaluation of these agents in toxicity and multiple-dose therapy studies.

Differential regulation of catechol-O-methyltransferase expression in a mouse model of aggression

This study was designed to understand molecular and cellular mechanisms underlying aggressive behaviors in mice exposed to repeated interactions in their homecage with conspecifics. A resident-intruder procedure was employed whereby two males were allowed to interact for 10 min trials, and aggressive and/or submissive behaviors (e.g., degree of attacking, biting, chasing, grooming, rearing, or upright posture) were assessed. Following 10 days of behavioral trials, brains were removed and dissected into specific regions including the cerebellum, frontal cortex, hippocampus, midbrain, pons, and striatum. Gene expression analysis was performed using real-time quantitative polymerase-chain reaction (qPCR) for catechol-O-methyltransferase (COMT) and tyrosine hydroxylase (TH). Compared to naive control mice, significant up regulation of COMT expression of residents was observed in the cerebellum, frontal cortex, hippocampus, midbrain, and striatum; in all of these brain regions the COMT expression of residents was also significantly higher than that of intruders. The intruders also had a significant down regulation (compared to naive control mice) within the hippocampus, indicating a selective decrease in COMT expression in the hippocampus of submissive subjects. Immunoblot analysis confirmed COMT up regulation in the midbrain and hippocampus of residents and down regulation in intruders. qPCR analysis of TH expression indicated significant up regulation in the midbrain of residents and concomitant down regulation in intruders. These findings implicate regionally- and behaviorally-specific regulation of COMT and TH expression in aggressive and submissive behaviors. Additional molecular and cellular characterization of COMT, TH, and other potential targets is warranted within this animal model of aggression.

Trastuzumab mimotope vaccination of HER-2/neu transgenic mice results in prolonged tumor-free survival and reduced tumor load

12510 Background: Passive immunotherapy with the humanized monoclonal antibody trastuzumab (Herceptin) to date is the most effective treatment for patients with HER-2/neu overexpressing breast cancer. In previous studies we could show that active immunization with peptide mimotopes, i.e. structural mimics of the epitope recognized by trastuzumab, leads to formation of antibodies again recognizing HER-2/neu in mice. Functional in vitro analyses of the induced antibodies demonstrated “trastuzumab-like” properties, such as receptor internalization, inhibition of signaling, and antibody-mediated cytotoxicity against HER-2/neu overexpressing breast cancer cells. The aim of the present study was to test the effects of trastuzumab mimotope vaccination in vivo, namely in a HER-2/neu transgenic mouse model. Methods: We used BALB-neuT mice, which carry the activated neu oncogene on the BALB/c background. These mice constitute the most aggressive animal model for HER-2/neu driven carcinogenesis, as all females uniformly develop mammary carcinomas at the age of 12 weeks. One group of mice was immunized with the previously described trastuzumab mimotope - KLH conjugate, a control group with the carrier protein KLH alone, and a further control group was left naïve. Mice were palpated weekly to monitor tumor development and size, and blood samples were taken at regular intervals to follow up the induced immune responses. Results: Trastuzumab mimotope immunizations lead to delayed tumor development and thus to an increase in tumor-free survival. When tumors occurred, they were smaller and grew more slowly than in the control mice. In contrast, control KLH immunizations did not affect tumor growth kinetics as compared to the naïve mice. Serum analysis demonstrated that all immunized animals had mounted an anti-KLH immune response, so we accredit the observed tumor-inhibitory effects in the mimotope group to the biologic properties of induced anti-HER-2/neu antibodies. Conclusion: These results indicate that epitope-specific vaccination with mimotopes elicits trastuzumab-like antibodies that are effective in vivo against HER-2/neu overexpressing tumor cells also in HER-2/neu expressing organisms. [Table: see text]

Diversity of animal models of aggression: their impact on the putative alcohol/aggression link.

Many attempts have been made to "model" the putative link between alcohol and "aggression" using a variety of situations employing a wide range of animal species. In general, these attempts have proved somewhat disappointing. One reason for this appears to be the fact that the different "aggression" tests tap varied mixtures of offensive, defensive and predatory motivations (i.e., they are not homogenous). Indeed, one can make the claim that the majority of examples of "aggression" associated with alcohol-ingesting humans are inappropriate (nonadaptive) responses whereas many animal models tap adaptive territorial or socially competitive actions. A further problem is that alcohol has very wide-ranging effects on neurophysiology and endocrine functioning. Recent evidence from studies on infra-human animals and clinical situations suggests that some of alcohol's effects on social conflict are expressed by actions in signaling and perception rather than motivation. This aspect is briefly examined in some studies with laboratory mice.

Pain-induced aggression: An ethological perspective

Pain-induced aggression has been studied mainly in animals, but generalizations are made to human aggression, noteably in Berkowitz’s “aversive-stimulation” view. This review reevaluates the motivational basis of pain-induced attack by considering it from an ethological perspective. Studies supporting the view that shock-induced attack is fear-motivated are briefly reviewed before consideration of evidence that does not support this view, from naturally-ocurring examples of pain-induced attack, and from examples of sex and hormonal effects. A reconcilliation between the apparently conflicting views is suggested by distinguishing between the functional (competitive-protective) dimension and the causal (offensive-defensive) dimension. It is proposed that pain-induced attack is protective in function but can be offensive or defensive (or both) in its form; the offensive form is only rarely observed under laboratory conditions. The implications of this view are discussed (1) for the use of shock-induced fighting as an animal model of aggression; and (2) for studies of human pain-induced aggression. Ethical issues surrounding shock-induced aggression research are considered.

Central Serotonin and Impulsive Aggression

The role of central serotonergic (5-HT) system dysfunction in the regulation of aggression in both animals and man has been investigated for more than the past two decades. Evidence for reduced central 5-HT in the mediation of aggression comes from both behavioural and correlative studies. Functional reduction and augmentation of 5-HT activity is respectively associated with increased and decreased aggression in various animal models of aggression. While similar studies in man have not been performed, strong and consistent associations between indices reflecting reduced pre-synaptic 5-HT activity and aggression have been reported. Evidence of post-synaptic receptor upregulation in the brains of suicide victims has also been reported leaving the functional status 5-HT activity in such patients an open question. However, reduced neuroendocrine (i.e. prolactin) responses to fenfluramine, a 5-HT uptake inhibitor/releaser, which activates both pre- and post-synaptic sides of the 5-HT synapse, strongly suggest that overall central 5-HT activity is reduced in mood and/or personality disorder patients with history of suicidal and/or impulsive aggressive behaviour. Preliminary data with the 5-HT receptor agonist m-chlorophenylpiperazine further suggest that reduced activity of post-synaptic 5-HT receptors may be an important correlate of impulsive aggressive behaviour. Pharmacological agents with potent 5-HT pre- and/or post-synaptic augmenting effects should be tested clinically to determine their efficacy in the treatment of impulsive aggressive behaviour in psychiatric patients.

Reflections on experimental and human pathology of aggression

o 1. On the basis of the already proposed distinction between “normal” and “pathological” aggression in laboratory animals, it is essayed an integration of the experimental findings derived from a specific animal model of aggression with the available clinical information on human violent behavior. 2. The too disregarded importance of the role played by the inhibitory control of brain functions, appears instead reportedly essential in the regulation of emotions and behavior, and is of great relevance in explaining the behavioral changes that follow induced or spontaneous impairment of the serotonergic system of the brain. 3. As a matter of fact, the numerous evidences indicate that genetic predisposition and induced or acquired defects of serotonergic inhibitory control greatly concur to precipitate anomalous strong aggression. 4. Interestingly, the cluster of symptoms presented by laboratory rats in consequence of the serotonergic discontrol, has many unexpected similarities with several pathological conditions of man. 5. This fact confers to laboratory experiments the value of a tool aimed at a better understanding of the biological mechanisms which underlie corresponding alterations of human conduct, with special reference to pathological aggression and violence. 6. In this line, some specific nutrient defects and/or malabsorption conditions can be important in the facilitation or elicitation of mental illness including human aggression. 7. In addition, the efficacy and neurochemical action of those substances capable to partially or completely block or prevent experimental aggression, will likely assume equal relevance in the management or prevention of human violent behavior.

Alterations in trace amine and trace acid concentrations in isolated aggressive mice.

We have used an animal model of aggression, the isolation syndrome in mice, to examine the possible role of the trace amines, beta-phenylethylamine (PEA), meta-tyramine (m-TA) and para-tyramine (p-TA) in aggressive behaviour. The brain, plasma and urinary levels of PEA, m-TA and p-TA, and their respective major acid metabolites, phenylacetic acid (PAA), meta-hydroxyphenylacetic acid (m-HPA) and para-hydroxyphenylacetic acid (p-HPA) were measured in isolated aggressive mice (after fighting), and in group housed controls. The urinary levels of PEA, m-TA, PAA, m-HPA and p-HPA, and the plasma levels of PAA and p-HPA were significantly lower in isolated aggressive mice. Similarly, the whole brain levels of PEA, p-TA, PAA and p-HPA tended to be reduced. In contrast, the brain levels of m-TA and m-HPA tended to increase. It should be noted, however, that the present procedure did not dissociate the stress and aggression components of the isolation syndrome, and, therefore, further experiments are required to determine whether the observed neurochemical changes are functionally related to increased aggression.

Effect of noise on shock-elicited aggression in rats.

ONLY a limited number of experiments have been designed to evaluate the effects of noise on aggression. As animal models of aggression are amenable to pharmacological and physiological analysis we have investigated the effect of noise on aggression in rats and have found an interesting non-monotonic relationship, with an increase in aggression at moderate noise levels but a decrease at high levels. The aggressive behaviour chosen for the present experiments was shock-elicited aggression in the rat. Two rats were paired in a small enclosure and subjected to a series of footshocks which elicit fighting, depending on the intensity, frequency and duration of electric shock1,2. This is a well documented and highly reliable form of aggressive behaviour that is usually considered a form of irritable aggression3.

The effects of benzodiazepines on aggression: reduced or increased?

The effects of various benzodiazepines on animal models of aggression are presented. The differences in response noted after single dose or after chronic drug administrations are stressed. The implications for predicting responses to these drugs in humans are discussed.

Aggression. Summing up.

o1.On the basis of the already proposed distinction between “normal” and “pathological” aggression in laboratory animals, it is essayed an integration of the experimental findings derived from a specific animal model of aggression with the available clinical information on human violent behavior.2.The too disregarded importance of the role played by the inhibitory control of brain functions, appears instead reportedly essential in the regulation of emotions and behavior, and is of great relevance in explaining the behavioral changes that follow induced or spontaneous impairment of the serotonergic system of the brain.3.As a matter of fact, the numerous evidences indicate that genetic predisposition and induced or acquired defects of serotonergic inhibitory control greatly concur to precipitate anomalous strong aggression.4.Interestingly, the cluster of symptoms presented by laboratory rats in consequence of the serotonergic discontrol, has many unexpected similarities with several pathological conditions of man.5.This fact confers to laboratory experiments the value of a tool aimed at a better understanding of the biological mechanisms which underlie corresponding alterations of human conduct, with special reference to pathological aggression and violence.6.In this line, some specific nutrient defects and/or malabsorption conditions can be important in the facilitation or elicitation of mental illness including human aggression.7.In addition, the efficacy and neurochemical action of those substances capable to partially or completely block or prevent experimental aggression, will likely assume equal relevance in the management or prevention of human violent behavior.