Flunitrazepam in combination with alcohol engenders high levels of aggression in mice and rats

Abstract

Rationale: Higher doses of benzodiazepines and alcohol induce sedation and sleep; however, in low to moderate doses these drugs can increase aggressive behavior.

Objectives: To assess firstly the effects of ethanol, secondly the effects of flunitrazepam, a so-called club drug, and thirdly the effects of flunitrazepam plus alcohol on aggression in mice and rats.

Methods: Exhaustive behavioral records of confrontations between a male resident and a male intruder were obtained twice a week, using CF-1 mice and Wistar rats. The salient aggressive and non-aggressive elements in the resident's repertoire were analyzed. Initially, the effects of ethanol (1.0g/kg), and secondly flunitrazepam (0; 0.01; 0.1; and 0.3mg/kg) were determined in all mice and rats; subsequently, flunitrazepam or vehicle, given intraperitoneally (0; 0.01; 0.1; and 0.3mg/kg) was administered plus ethanol 1.0g/kg or vehicle via gavage.

Results: The most significant finding is the escalation of aggression after a moderate dose of ethanol, and a low dose of flunitrazepam. The largest increase in aggressive behavior occurred after combined flunitrazepam plus ethanol treatment in mice and rats.

Conclusions: Ethanol can heighten aggressive behavior and flunitrazepam further increases this effect in male mice and rats.

Figure 1

A Frequency of aggression in male mice (n=28) and B frequency of aggression in male rats (n=10) administered 3 times with vehicle or 1.0 g/kg ethanol each. Vertical bars represent the mean ± SEM and asterisks indicate the statistical difference between the groups, p≤ 0.05.

Figure 2

Histogram rank-ordering the bars according to the frequency of aggressive behaviour after water (clear bars) vs. ethanol (grey bars) in individual male mice (n=28) in A, and male rats (n=10) in B.

Figure 3

A Frequency of aggression in resident male mice (n=28) and the right side of the figure shows the effects of flunitrazepam (0.01-0.3 mg/kg) and the left side the effects of ethanol 1.0 g/kg plus flunitrazepam (0.01-0.3 mg/kg). B Frequency of aggression in resident male rats (n=10). The frequency of attack bites towards the male intruder are depicted. Vertical bars represent the mean ± SEM and * statistical difference from vehicle; ## statistical difference from all other groups, p≤ 0.05.

Figure 3

A Frequency of aggression in resident male mice (n=28) and the right side of the figure shows the effects of flunitrazepam (0.01-0.3 mg/kg) and the left side the effects of ethanol 1.0 g/kg plus flunitrazepam (0.01-0.3 mg/kg). B Frequency of aggression in resident male rats (n=10). The frequency of attack bites towards the male intruder are depicted. Vertical bars represent the mean ± SEM and * statistical difference from vehicle; ## statistical difference from all other groups, p≤ 0.05.