Alcohol, allopregnanolone and aggression in mice

Abstract.

Rationale: Aggressive behavior of certain individual animals can be greatly increased when under the influence of low doses of alcohol. One of alcohol's neurochemical actions that may be relevant to alcohol-heightened aggression (AHA) is its positive modulation of the GABA_A receptor complex. Objective: The objective of this study was to investigate whether alcohol interacts with an endogenous modulator of the GABA_A receptor complex, the neurosteroid allopregnanolone, in stimulating/heightening aggressive behavior. Methods and results: The first experiment was designed to test the hypothesis that neurosteroid modulators of the GABA_A receptor complex will increase aggression and to compare these effects with alcohol. Male CFW mice were injected with allopregnanolone, alphaxalone (3–30 mg/kg, IP), or alcohol (1.0 g/kg, PO) 15 min prior to a 5-min confrontation with an intruder. Moderate doses of alcohol and the neurosteroids increased aggression by ca. 50% above baseline; impaired locomotion was seen only at the highest doses. A second experiment compared AHA and ANA (i.e. alcohol-non-heightened aggression) mice by giving allopregnanolone (1–10 mg/kg) with a simultaneous oral injection of alcohol (0.6 or 1.0 g/kg) or water. When administered with water and the 0.6 g/kg dose of alcohol, allopregnanolone increased the aggression of AHA and ANA mice. Administration of the 1.0 g/kg dose of alcohol in ANA mice prevented allopregnanolone-heightened aggression. In AHA mice, addition of allopregnanolone to 1.0 g/kg alcohol dose-dependently reduced alcohol-heightened aggression, suggesting potentiation of alcohol's suppressive effects on aggression. Conclusions: The neuroactive steroid allopregnanolone appears to play an important role in alcohol-heightened aggression. Moreover, the upward shift of the aggression-heightening effects of alcohol and the downward shift at the maximally effective alcohol dose by allopregnanolone point to a shared mechanism for both positive modulators of the GABA_A receptor complex.