In the following study, we asked which steroid receptors regulate aggression and arginine vasopressin (AVP) immunoreactivity (-ir) in several limbic regions. Using spontaneous mutant and knockout mice, we generated a novel cross of mice whose offspring lacked estrogen receptor alpha (ERalpha), androgen receptor (AR) or both ERalpha and AR. The wild-type (WT) males and females were compared with ERalpha knockout (ERalphaKO) male, mutated AR (Tfm) male and ERalphaKO/Tfm (double knockout; DKO) male littermates. Animals were gonadectomized and treated with 17beta-estradiol (E2) prior to resident-intruder aggression tests. WT and Tfm males showed aggression whereas WT females, ERalphaKO and DKO males did not. In the lateral septum, WT and Tfm male brains had significantly denser AVP-ir as compared with WT females and DKO males. ERalphaKO male brains were intermediate in the amount of AVP-ir present. In the medial amygdala, brains from all genotypes had equivalent AVP-ir, except DKO males, which had significantly less AVP-ir. Overall, the expression of aggressive behavior coincided with AVP-ir in WT, Tfm and DKO males. However, in ERalphaKO males and WT females, the amount of AVP-ir was not associated with resident-intruder aggression. In sum we have shown that E2 acts via ERalpha to regulate aggression in male mice. In contrast both ERalpha and AR contribute to AVP-ir in limbic brain regions.
