Experimental Social Stress: Dopaminergic Receptors, Oxidative Stress, and c-Fos Protein Are Involved in Highly Aggressive Behavior

Abstract

Aggression is defined as hostile behavior that results in psychological damage, injury and even death among individuals. When aggression presents itself in an exacerbated and constant way, it can be considered escalating or pathological. The association between social stress and the emergence of exacerbated aggressiveness is common and is suggested to be interconnected through very complex neurobiological factors. For example, alterations in the expression of the dopaminergic receptors D1 and D2, reactive oxygen species (ROS) and the c-Fos protein in the cortex have been observed. Our objective was to analyze which factors are involved at the neurobiological level in the highly aggressive response of Swiss Webster adult male mice in a vivarium. In this work, we investigated the relationship among dopaminergic receptors, the production of ROS and the expression of c-Fos. Mice with exacerbated aggression were identified by the model of spontaneous aggression (MSA) based on the grouping of young mice and the regrouping of the same animals in adulthood. During the regrouping, we observed different categories of behavior resulting from social stress, such as (i) highly aggressive animals, (ii) defeated animals, and (iii) harmonic groups. To evaluate the dopaminergic system and the c-Fos protein, we quantified the expression of D1 and D2 dopaminergic receptors by Western blotting and fluorescence immunohistochemistry and that of the c-Fos protein by fluorescence immunohistochemistry. The possible production of ROS was also evaluated through the dihydroethidium (DHE) assay. The results showed that aggressive and subordinate mice showed a reduction in the expression of the D1 receptor, and no significant difference in the expression of the D2 receptor was observed between the groups. In addition, aggressive mice exhibited increased production of ROS and c-Fos protein. Based on our results, we suggest that exacerbated aggression is associated with social stress, dysregulation of the dopaminergic system and exacerbated ROS production, which leads to a state of cellular oxidative stress. The overexpression of c-Fos due to social stress suggests an attempt by the cell to produce antioxidant agents to reduce the toxic cellular concentration of ROS.

Associations between Omega-3 Index, Dopaminergic Genetic Variants and Aggressive and Metacognitive Traits: A Study in Adult Male Prisoners

“…Considering that rs686 is a functional SNP located in the promoter region of the DRD1 gene and its A allele is linked with an increased transcriptional gene activity compared with the G allele [ 47 ], a difference in the DRD1 density number may occur in the tested cohort compared with the general population. Since these receptors mediate aggressive behaviour [ 9 , 10 ], this hypothesis is supported by a previous study reporting higher levels of aggressive behaviour in this cohort of prisoners when compared with university students [ 43 ]. The DRD2 genetic variant did not show any genetic association with a measurement of aggression through the AQ in accordance with a previous study looking at DRD2 rs1800479’s (located in the downstream of the gene) association with criminal behaviour and self-reported aggression in violent prison inmates [ 48 ].…”

“…In studies on both adults and children, dopamine (DA) hyperactivity in brain regions linked to reward-related motivation (such as the limbic system and prefrontal cortex) has been associated with increases in impulsive and aggressive behaviours [ 7 , 8 ]. Levels of extracellular DA present in the synaptic cleft can act on dopaminergic receptors, such as dopamine receptors 1 ( DRD1 ) and 2 ( DRD2 ), which are involved in the development of aggressive behaviour [ 9 , 10 ]. Furthermore, pharmacological blockage of the DRD2 receptors by antipsychotic treatment revealed an anti-aggression effect in individuals [ 11 ].…”

Altered gut microbiota and its metabolites correlate with plasma cytokines in schizophrenia inpatients with aggression

“…Clarifying the pathophysiological changes of aggression behaviors in specific comorbidity is a continuing need and efforts are in progress. Inflammation and oxidative stress disturbances are critical biological events in aggression pathogenesis in healthy or neuropsychiatric disorders including personality disturbance and intermittent explosive disorder [ 12 , 20 , 21 ]. We and other colleagues previously showed definitive evidence that systemic pro-inflammation phenotype characterizes aggression in ScZ cases [ 8 ].…”

Analysis of the Mice Activity Profile in the Model of Spontaneous Aggression (MSA)

“…The model was created to investigate the evolution and causes of aggressive behavior in mice of the Swiss Webster lineage in our housing facilities. The MSA was validated (Fragoso et al, 2016) and used in others our group's works (Mendonça et al, 2019;Felippe et al, 2021). It is based on the grouping of these animals around weaning and on regrouping in adulthood, and the regrouping is a stressor that may cause aggressive behavior (Fragoso et al, 2016).…”