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 experiments 1 and 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 experiment 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 experiments 1 and 2, we observed strong motivation to acquire operant self-administration of opportunities to aggress and relapse vulnerability during abstinence. In experiment 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.

Conclusions: 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 compulsive aggression.

Keywords: Addiction; Aggression; Mice; Motivation; Relapse; Reward.

Figure 1. Relapse to aggression seeking after forced abstinence

(A) Time course schematic for training and testing (top) and for individual trials (bottom). Vertical red lines within the “lever extended” and “intruder” bars indicate an active lever press and removal of an intruder following an attack bout, respectively, relative to total possible durations. (B) Number of rewarded and attack trials over 9 days (80-min session/d) of aggression self-administration under a trial-design fixed-ratio-1 (FR1) reinforcement schedule (n=26). (C) Number of nonreinforced “active”-lever and inactive-lever presses during a 30-min relapse to aggression seeking test under extinction conditions on Day 1 (n=13) or Day 15 (n=13) of forced abstinence. Individual data denoted with circles. Data are mean±SEM.

Figure 2. Relapse to aggression seeking after punishment-induced suppression

(A) Time course schematic for training, punishment, and testing (top) and for individual trials (bottom). (B) Number of rewarded and attack trials over 9 days (80-min session/d) of aggression self-administration under a trial-design FR1 reinforcement schedule (n=31). (C) Number of rewarded and attack trials over 10 days (80-min session/d) of aggression self-administration during the punishment phase (n=31). The mice received response-contingent shocks in sessions 1–6 (0.1 mA increase every other day), and 0.4 mA on sessions 7–10 on 50% of reinforced active-lever presses. (D) Number of nonreinforced “active”-lever and inactive-lever presses during a 30-min test of relapse to aggression seeking in cohort 1 (left, n=16) and cohort 2 (right, n=15) under extinction conditions. Individual data denoted with circles. * Different from day 1 and 15 (left) or day 15 (right), p < 0.05. Data are mean±SEM.

Figure 3. Relapse to aggression seeking after choice-based voluntary suppression, and differences in propensity to aggression in a large cohort of CD-1 mice

(A) Schematic of overall the time course for training, choice-based voluntary suppression, progressive-ratio testing, and punishment testing. (B) Schematic for individual trials. Self-administration trials and punishment trials were identical to those described in Fig. 1A and 2A. (C) Left: Number of food rewards, aggression rewards, and attack trials (left) over 9 days (80-min session/d) of food and aggression self-administration under an FR1 reinforcement schedule (n=43). Right: Number of food and aggression rewards earned over 10 days (80-min session/d) of the voluntary suppression choice phase (n=43). (D) Number of nonreinforced “active”-lever and inactive-lever presses during a 30-min test of relapse to aggression seeking. Left: between-subjects comparison, day 1 (n=9) versus day 15 (n=8). Right: within-subjects comparison (n=26). (E) Number of rewards earned during three 2-h progressive-ratio tests for aggression (left) and palatable food (right) (n=43). (F) Number of rewarded trials over 10 days (80-min session/day) of aggression self-administration during the punishment phase (n=43). The mice received response-contingent shocks (0.1 mA on days 1–3, 0.2 mA on days 4–5, and 0.25 mA on days 6–7) on 50% of reinforced active-lever presses. Individual data denoted with circles in corresponding panels. * Different from day 1, p<0.05; C = choice test. Data are mean±SEM.

Figure 4. Cluster analysis of aggression-related behaviors

(A) Schematic of measures used in cluster analysis. (B) Distributions of individual responses (n=41) for each of the five measures: attacks, relapse, aggression choice, aggression progressive ratio, and punishment (see text). (C) Cluster analytical pipeline. Two clustering algorithms were used independently to provide unbiased optimal group assignments and establish cluster assignment overlap. (D) Scatterplot of normalized punishment and resilience ratio scores, colored by cluster assignment. Red circles denote compulsive aggression seeking mice (Cluster 1, n=11) and blue circles denote typical aggression seeking mice (Cluster 2, n=30). Right: Final phenotype assignments under TwoStep clustering. (E) Visual representation of clusters using projection of data onto the first 3 principal components of the 5 original measures. Asterisk denotes the single mouse differentially assigned between clustering algorithms in 4D and 4E. Right: Pie chart showing the variance of the 3 principal components by which the data are displayed. (F) Breakdown, by cluster, of the measures shown in 4B. Individual data denoted with circles. * Different from the typical aggression group, p < 0.05; PC = principal component; BIC = Bayesian Information Criterion; C–H = Calinski-Harabasz criterion; MAD; mean absolute deviation. Group data are mean±SEM.