Effects of topiramate on morphological and structural alterations of the anterior cingulate cortex in aggressive socially isolated mice.

RATIONALE: Topiramate, an approved antiepileptic drug, was found effective in treating aggressive symptoms in humans and rodents. However, the effects and mechanisms of Topiramate on aggressive behavior are still unclear. Our previous study indicated that intraperitoneal administration of Topiramate successfully decreased aggression and reinforced sociability in socially aggressive mice, and increased cFos-expressing neurons in the anterior cingulate cortex (ACC). In addition to its pharmacological properties, previous studies have approved the neuroprotective effects of Topiramate. These suggest a potential effect of Topiramate on ACC's structure and function. OBJECTIVES AND RESULTS: In the present study, we first investigated the structural characteristics of ACC in the social isolation-induced aggression paradigm. The results showed that hyper-aggressive behavior in socially aggressive mice was associated with several structural alterations in ACC: increased neuron death combined with decreased neuron density, increased damaged neuronal morphology and increased neuroinflammation markers. Based on these observations, we next investigated the potential neuroprotective effect of Topiramate against structural alterations of ACC observed in socially aggressive mice. Results indicated that intraperitoneal administration of Topiramate (30 mg/kg) decreased aggression and enhanced sociability without affecting locomotor activity. Interestingly, the anti-aggressive effect of Topiramate was associated with decreased neuronal death, ameliorated damaged neuronal morphology, and decreased reactive microglia markers in ACC. CONCLUSIONS: Our results provide insights into the structural alterations of ACC in aggressive socially aggressive mice. Moreover, the present study suggested that the anti-aggressive effect of Topiramate could be related to its neuroprotective effects against the structural alterations of ACC.

The role of the anterior cingulate cortex in aggression and impulsivity.

Aggression is a complex social behavior that evolved in the context of defending a territory, fighting for limited resources, and competing for mates and protection. Although aggression considered as a negative or undesirable emotion is an essential part of many species' repertoire of social behaviors. For humans, the motivations, actions, and limits of aggressive acts are not always clear. However, uncontrolled aggression may have destructive consequences, and it develops inappropriately into violence. At the neural level, several studies demonstrated that aggression is related to cortical abnormalities, including the anterior cingulate cortex (ACC). This review summarizes the state of the literature regarding the involvement of ACC in the neurobiology of aggression and impulsivity. We will first review structural and neuroanatomical studies, including volumetric and functional investigations of aggression. Next, we will discuss the neurochemical and neuropharmacological studies of aggression related to the ACC. We will focus mainly on the gamma-aminobutyric acid/glutamate balance, as well as the serotoninergic system. Finally, we will try to integrate these results and reconcile discrepancies in the field and suggest recommendations for future studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

GABA-A receptor signaling in the anterior cingulate cortex modulates aggression and anxiety-related behaviors in socially isolated mice.

Dysfunctional modulation of brain circuits that regulate the emotional response to potentially threatening stimuli is associated to an inappropriate representation of the emotional salience. Reduced top-down control by cortical areas is assumed to underlie several behavioral abnormalities including aggression and anxiety related behaviors. Previous studies have identified disrupted GABA signaling in the anterior cingulate cortex (ACC) as a possible mechanism underlying the top-down regulation of aggression and anxiety. In this study, we investigate a role for GABA-A receptor in the ACC in the regulation of aggression and anxiety related behaviors in socially isolated mice. We evaluated the effects of site directed injections of the GABA-A receptor agonist, muscimol or the GABA-A receptor antagonist, bicuculline into the ACC on these behaviors. Results showed that hyper-aggressive behavior, the anxiety and avoidance behavior in socially isolated mice were increased by muscimol microinfusion into ACC, while the sociability was not affected. In contrast, hyper-aggressive behavior in socially isolated mice was inhibited following bicuculline microinfusion without affecting anxiety. Furthermore, microinfusion of bicuculline into ACC decreased avoidance intensity and significantly reinforced social behavior, suggesting that GABA-A receptor inhibition in ACC specifically regulated aggression and sociability. Together, our results confirm a role for GABA-A receptor signaling in the ACC in the regulation of aggressive, social and anxiety related behaviors in socially isolated mice.

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.

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

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