Repeated administration of estradiol promotes mechanisms of sexual excitation and inhibition: Glutamate signaling in the ventromedial hypothalamus attenuates excitation

• Repeated estradiol treatments sensitize sexual behaviors in ovariectomized rats.
• Copulation and vaginocervical stimulation attenuate the sensitization.
• We show that AMPA receptor activation in the vlVMH also attenuates sensitization.
• Estrous termination is accelerated by repeated estradiol in the absence of copulation.
• Estradiol promotes the activation and inhibition of female sexual behavior.

Repeated administration of 10 μg of estradiol benzoate (EB) every 4 days to the ovariectomized (OVX) rat induces a behavioral sensitization of sexual behaviors. Repeated copulation or the receipt of vaginocervical stimulation (VCS) attenuates the sensitization of appetitive sexual behaviors, suggesting that VCS acts in opposition to the mechanisms that induce the sensitization. It is known that VCS accelerates the onset of estrous termination (characterized by a decrease in appetitive sexual behaviors, and an increase in defensive behaviors prior to the decline in lordosis), and glutamate transmission in the ventromedial hypothalamus (VMH), particularly via AMPA receptor signaling, is an important regulator of this effect. Thus, the current studies examined whether mechanisms of estrous termination are involved in the attenuated sensitization to EB that occurs with repeated copulation. In the first study, OVX rats received infusions of AMPA to the VMH on tests 2–4, and sexual behavior was measured on tests 1 and 5. Appetitive sexual behaviors were lower in females that received AMPA infusions in place of copulation compared to saline, suggesting that AMPA receptor activation by VCS may be playing a role in the attenuation of sensitization. In the second study, females that were not given the opportunity to copulate on tests 2–4 fell out of behavioral estrus faster than those that did, suggesting that both excitatory and inhibitory mechanisms of sexual behavior become sensitized with repeated administration of EB. Together these findings extend our hypothesis that repeated episodes of heat sensitize the activation of sexual behaviors to increase the probability of eventual fertilization.