The G protein-coupled estrogen receptor in the nucleus accumbens mediates the estrogen-induced increase in cataplexy-like behavior.

Estrogen functions not only as a female reproductive hormone but also as a psychological agent in the brains of both sexes. Here, we examined the potential effect of estrogen on cataplexy attacks, which are triggered by positive emotions in narcoleptic humans and animals. In orexin neuron-ablated mice, an animal model of narcolepsy, the number of cataplexy-like behaviors increased with estrogen administration and decreased with tamoxifen, an estrogen receptor (ER) modulator, in both sexes. The increase in cataplexy-like behaviors caused by estrogen in ovariectomized female mice indicated its action outside reproductive organs. In female mice, the estrous cycle influenced the frequency of cataplexy-like behaviors, with the highest count during estrus, when blood estrogen levels peak. In a pharmacological study with male mice, a G protein-coupled estrogen receptor (GPER) antagonist reduced the frequency of cataplexy-like behaviors, while a GPER agonist increased it. Conversely, neither an ER alpha agonist nor an ER beta agonist showed any effect. The GPER agonist activated neurons in the nucleus accumbens (NAc). Finally, microinjection of a GPER agonist into the NAc increased the occurrence of cataplexy-like behaviors. Together, these results demonstrate that GPER in the NAc mediates the psychological effects of estrogen on cataplexy.