Further investigation of the rapid control of male sexual behavior by neuroestrogens in mice

Neuroestrogens play a key role in the activation of male sexual behavior by testosterone through their nuclear- and membrane-initiated actions. Studies conducted in birds suggested that membrane vs. nuclear actions of neuroestrogens differentially control sexual motivation and performance. In mice, estrogen receptor alpha (ERα) plays a major role in the control of male sexual behavior. However, whether the translocation ERα and its activation at the membrane rapidly affect male sexual behavior remains unclear. Recently, a mouse model (C451A-ERα) carrying a mutated ERα unable to traffic to and signal from the membrane was generated. Moreover, the natural estrogen estetrol (E4) has been described to act as an agonist of nuclear estrogen receptors but as an antagonist on their membrane-associated fraction. Here, we used the complementary properties of estetrol and C451A-ERα mice to investigate the role of membrane ERα (mERα) on male sexual motivation and performance. Regardless of the genotype, systemic aromatase blockade decreased within 10 min sexual performance and motivation, measured by the time spent close to an estrous female. E4 rapidly decreased sexual performance only in wild-type males and had no effect on sexual motivation. Together, these data confirmed the key role of aromatization in the rapid control of male sexual performance and extended this conclusion to sexual motivation. Moreover, E4, likely acting on mERα rapidly inhibits sexual performance, but not sexual motivation. Finally, the inhibitory effect of aromatase blockade in C451A-ERα mice suggests that another estrogen receptor than mERα also regulates both aspects of male sexual behavior.