Modifications of Testosterone-dependent Behaviors by Estrogen Receptor-␣ Gene Disruption in Male Mice*

The role of the ␣ form of estrogen receptor (ER␣) gene expression in the regulation of testosterone-dependent male reproductive behaviors was investigated using ER knockout mice (ERKO), which are specifically deficient in functional ER␣, but not ER␤, gene expression. Previous studies in gonadally intact ERKO mice revealed that male aggressive behavior was greatly reduced by the lack of a functional ER␣ gene. In the present study the almost complete suppression of male-typical offensive attacks was further confirmed in ERKO mice that had been singly housed since weaning. Regarding aggression, it was also found that ER␣ gene disruption virtually abolished the propensity to initiate offensive attacks, even though ERKO mice could elicit attacks from resident C57BL/6J mice as wild-type (WT) and heterozygous littermates. Daily injection of testosterone propionate (TP) was completely ineffective in inducing aggressive behavior in gonadectomized ERKO mice, whereas it successfully restored aggression in WT mice. In contrast, male sexual behaviors, mounts and intromissions, were induced by daily injection of TP in both gona-dectomized ERKO and WT mice. In addition to TP, dihydrotestos-terone propionate (DHTP) was also effective in restoring mounts in ERKO mice, although DHTP was much more potent in WT mice than in ERKO mice. Neither TP nor DHTP, however, ever induced ejaculation in ERKO mice. These results together with previous findings in gonadally intact ERKO mice suggest that ER␣ may be responsible for the regulation by testosterone of consummatory, but not motiva-tional, aspects of male sexual behavior. Finally, ERKO male mice retrieved newborn pups placed in their home cage with similar la-tencies to males of the two other genotypes. During parental behavior tests, however, a higher percentage of ERKO mice (70%) showed infanticide compared with WT mice (35%). The latter result was interpreted as showing that ER␣ activation by testosterone during the perinatal period may exert a suppressive effect on testosterone-inducible infanticide in adulthood. With respect to three major testosterone-dependent behavioral systems reflecting masculiniza-tion, these findings demonstrate three different types of effects due to ER␣ gene disruption. I T IS WELL known that testosterone regulates various be-havioral and neuroendocrine functions in male mice. In the brain, as in many peripheral tissues, testosterone not only acts through androgen receptors (AR) in its original form or as the 5␣-reduced form (dihydrotestosterone), but also partly through estrogen receptors (ER), after being aromatized to estrogen. The relative importance of these two mechanisms in specific reproductive behaviors, e.g. sexual, aggressive, and …