Glutamate Afferents From the Medial Prefrontal Cortex Mediate Nucleus Accumbens Activation by Female Sexual Behavior

Abstract

Low levels of desire and arousal are the primary sexual dysfunctions in women, necessitating neurobiological studies of sexual motivation in female animal models. As the mesocorticolimbic system is a primary neural circuit underlying sexual motivation, the goal of this study was to test the hypothesis that medial prefrontal cortex (mPFC) glutamate mediates sexual behavior activation of the nucleus accumbens. Glutamatergic neurons in the mPFC were activated by sex behavior, and these sex-activated cells shown to project to the nucleus accumbens. During sexual interactions with the male, glutamate transients recorded in the nucleus accumbens of female hamsters were specifically associated with the receipt of intromissions from the male. Further, inhibition of the mPFC during sex significantly decreased nucleus accumbens activation. Glutamatergic medial prefrontal cortical input to the nucleus accumbens mediates the activity in the nucleus accumbens during female sexual behavior. These results offer novel insights into the neurobiology of the motivational control of female sexual behavior and provide attractive avenues for pursuing target-specific and clinically-relevant therapies for sexual dysfunction in women.

Effect of Aggressive Experience in Female Syrian Hamsters on Glutamate Receptor Expression in the Nucleus Accumbens

“…Regarding comparisons with other natural reward, we have published a series of studies with sexual experience in female Syrian hamsters suggesting a casual link for synaptic plasticity and morphology in the NAc in the rewarding properties of sex behavior (Hedges et al, 2009;Been et al, 2013;Staffend et al, 2014;Moore et al, 2019). Coolen's group has published similar findings for male sex behavior in rats (Pitchers et al, 2010(Pitchers et al, , 2013.…”

Glutamate in Male and Female Sexual Behavior: Receptors, Transporters, and Steroid Independence

“…During vaginocervical stimulation, FOS-positive glutamatergic neurons increased, and glutamate is released in the VMH of Long-Evans rats (Georgescu et al, 2009(Georgescu et al, , 2014. A more recent study demonstrated that in Syrian hamsters, glutamatergic neurons (CaMKIIa+) in the mPFC that projected to the NAc also became FOS-positive during sexual testing (Moore et al, 2019). Furthermore, they used biosensors to find glutamate release in NAc, and the release both preceded and occurred during intromission (Moore et al, 2019).…”

“…A more recent study demonstrated that in Syrian hamsters, glutamatergic neurons (CaMKIIa+) in the mPFC that projected to the NAc also became FOS-positive during sexual testing (Moore et al, 2019). Furthermore, they used biosensors to find glutamate release in NAc, and the release both preceded and occurred during intromission (Moore et al, 2019). Additional work to build upon these studies could study glutamate release in other brain regions pertinent to female sexual behavior, in conjunction with how glutamate release synchronizes with different phases of sexual motivation.…”

Altered Sexual Behavior in Dopamine Transporter (DAT) Knockout Male Rats: A Behavioral, Neurochemical and Intracerebral Microdialysis Study

“…Among these, one shows that the acquisition of sexual experience causes long-term alterations in glutamate receptor expression and function (i.e., a decrease in AMPA/NMDA receptors ratio) and that changes in the NMDA (NR1 subunit) and AMPA (GluA1 and GluA2 subunits) receptors are differentially associated to experience acquisition, reward and abstinence, pointing out to a complex fine-tuning (i.e., changes in receptor subunits trafficking) at the synaptic level of the neuroplastic processes occurring during the acquisition of sexual experience in male rats (Pitchers et al, 2012). Another one shows that in female Syrian hamsters a glutamatergic projection from the medial PFC to the Acb is activated during sexual behavior and that silencing these mPFC glutamatergic afferents (with DREADD techniques) to the Acb prevents C-Fos expression in the Acb due to sexual interaction, although this silencing did not affect female sexual behavior expression, thus excluding a role in sexual performance and pointing out on a possible role in the motivational (i.e., anticipatory and rewarding) aspects of sexual activity (Moore et al, 2019). The other available studies support a facilitatory role of glutamic acid in sexual behavior in brain areas such as the PVN and the medial preoptic area of male rats.…”

“…However, it is also possible that ∆-FosB expression in DAT KO rats is lower because these rats are also those that show the lowest levels of glutamic acid release in the Acb shell during sexual activity and this could have interfered with its dopamineinduced activation (Beloate and Coolen, 2017). Interestingly, in this regard, inhibition of the mPFC glutamatergic input to the Acb has been found to prevent C-Fos expression in this area during sexual activity in the female hamster (Moore et al, 2019). The above hypotheses may also be not mutually exclusive.…”