Alcohol, allopregnanolone and aggression in mice

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 aggress ion (AHA) is its positive modulation of the GABA(A) receptor complex. Objec tive: The objective of this study was to investigate whether alcohol intera cts with an endogenous modulator of the GABA(A) receptor complex, the neuro steroid allopregnanolone, in stimulating/heightening aggressive behavior. M ethods ann results: The first experiment was designed to test the hypothesi s that neurosteroid modulators of the GABA(A) receptor complex will increas e 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. Modera te doses of alcohol and the neurosteroids increased aggression by ca. 50% a bove baseline; impaired locomotion was seen only at the highest doses. A se cond experiment compared AHA and ANA (i.e. alcohol-non-heightened aggressio n) mice by giving allopregnanolone (1-10 mg/kg) with a simultaneous oral in jection 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 aggressio n of AHA and ANA mice. Administration of the 1.0 g/kg dose of alcohol in AN A mice prevented allopregnanolone-heightened aggression. In AHA mice, addit ion of allopregnanolone to 1.0 g/kg alcohol dose-dependently reduced alcoho l-heightened aggression, suggesting potentiation of alcohol's suppressive e ffects on aggression. Conclusions: The neuroactive steroid allopregnanolone appears to play an important role in alcohol-heightened aggression. Moreov er, the upward shift of the aggression-heightening effects of alcohol and t he downward shift at the maximally effective alcohol dose by allopregnanolo ne point to a shared mechanism for both positive modulators of the GABA(A) receptor complex.