Compulsive Addiction-like Aggressive Behavior in Mice

Abstract

Background Some people are highly motivated to seek aggressive encounters, and among those who have been incarcerated for such behavior, recidivism rates are high. These observations echo two core features of drug addiction: high motivation to seek addictive substances, despite adverse consequences, and high relapse rates. Here we used established rodent models of drug addiction to determine whether they would be sensitive to “addiction-like” features of aggression in CD-1 mice. Methods In Exp. 1–2, we trained older CD-1 mice to lever-press for opportunities to attack younger C57BL6/J mice. We then tested them for relapse to aggression seeking after forced abstinence or punishment-induced suppression of aggression self-administration. In Exp. 3, we trained a large cohort of CD-1 mice, and tested them for choice-based voluntary suppression of aggression seeking, relapse to aggression seeking, progressive ratio responding, and punishment-induced suppression of aggression self-administration. We then used cluster analysis to identify patterns of individual differences in compulsive “addiction-like” aggressive behavior. Results In Exp. 1–2, we observed strong motivation to acquire operant self-administration of opportunities to aggress, and relapse vulnerability during abstinence. In Exp. 3, cluster analysis of the aggression-related measures identified a subset of “addicted” mice (~19%) that exhibited intense operant-reinforced attack behavior, decreased likelihood to select an alternative reinforcer over aggression, heightened relapse vulnerability and progressive ratio responding, and resilience to punishment-induced suppression of aggressive behavior. Conclusion Using procedures established to model drug addiction, we showed that a subpopulation of CD-1 mice demonstrate “addiction-like” aggressive behavior, suggesting an evolutionary origin for pathological aggression.

Reward Mechanisms Across Aggressive and Addictive Forms of Externalizing Psychopathology

“…The experiments reported by Golden et al (4) underscore the important role of appetitive processes in certain aggressive phenotypes. Using well-validated rodent models of addiction involving operant conditioning procedures, the authors report compelling evidence for “addiction-like” reward mechanisms in aggressive behavior after forced abstinence, punished abstinence, and in preference for learned aggression over other rewards (palatable food).…”

“…As such, there is a clear parallel to draw between our currently limited abilities to effectively treat either form of externalizing. As discussed next, the research reported by Golden et al (4) has important implications for neurobehavioral models of externalizing psychopathology in humans.…”

“…By contrast, theoretical perspectives on impulsive-aggressive behavior have emphasized the role of frontal-executive systems of the brain that regulate negative affectivity (anger and distress) and guide behavioral output (3). The article by Golden et al (4) in this issue of Biological Psychiatry describes a series of studies that eloquently highlight the understudied role of reward mechanisms in aggressive-externalizing behaviors. Their findings suggest that appetitive processes seen in problematic substance use are also implicated in certain forms of aggressive behavior.…”

“…A particularly important element of the approach taken by Golden et al (4) was their focus on individual difference characteristics and identifying distinct aggressive phenotypes. While the majority of mice behaved in line with the hypothesis that aggression can be rewarding, a notable minority (~29%) were not trainable to self-administer access to an intruder and the opportunity to attack.…”

“…Aggressive and substance using outcomes are in turn shaped in one direction and/or the other by etiological influences separate from the core disinhibitory liability. The findings of Golden et al (4) suggest that an important etiological mechanism for the callous-aggressive expression of externalizing liability may involve an instinctual preference for aggressive action. Given that most animals in their research (~70%) acquired aggressive behavior through reward training, it can be theorized that the degree of linkage between reward circuitry and circuitry for agonistic action comprises a continuum, with some individuals possessing a higher degree of linkage between these systems.…”