At the base of the brain, inside the hypothalamus, and coursing through specialized dopamine-releasing neurons, there is a signaling pathway that regulates the sex drive, that is, the motivation to engage in mating behavior. The specialized neurons and the signaling pathway were recently identified by researchers at Beth Israel Deaconess Medical Center (BIDMC).

In experiments with mice, the researchers optogenetically stimulated dopamine-releasing neurons in different brain areas to recapitulate the priming effect that male mice experience upon exposure to female mice. The researchers found that neurons in different brain areas, such as the medial preoptic area (MPOA) and the nucleus accumbens (NAc) exhibit different kinetics of cyclic adenosine monophosphate (cAMP) clearance that enable persistent or episodic modes of neuromodulation.

In other words, the BIDMC scientists identified a molecular mechanism that can regulate mating behaviors across minutes and days. Besides suggesting a general principle about the neurobiology of motivation, the mechanism could lead to targeted therapies to offset the sexual side effects linked to antidepressants, side effects that sometimes discourage patients from treating mental illnesses.

The BIDMC scientists, who were led by Mark L. Andermann, PhD, presented their findings August 25 in Nature, in an article titled, “Hypothalamic dopamine neurons motivate mating through persistent cAMP signaling.” In this article, the scientists sought an explanation for a well-known phenomenon in mice: A male’s investigation of females will prime the male’s interest to mate for tens of minutes, whereas a single successful mating will be followed by a relatively lengthy period of satiety, one that gradually dissipates over days.

“Using optical and molecular methods for tracking and manipulating intracellular signaling, we show that the priming effect emerges from the accumulation of mating-related dopamine signals in the MPOA through the accrual of cAMP levels and protein kinase A activity,” the article’s authors wrote. “Dopamine transients in the MPOA are abolished after a successful mating, which is likely to ensure abstinence. Consistent with this idea, the inhibition of anteroventral and preoptic periventricular (AVPV/PVpo) dopamine neurons selectively demotivates mating, whereas stimulating these neurons restores the motivation to mate after sexual satiety.”

This research builds on Andermann and colleagues’ previous investigations into the brain circuitry that governs hunger and thirst. “The neurotransmitter dopamine is typically studied in reward-related brain circuits,” Andermann explained. “For decades, dopamine was also known to act on mating-related brain regions. However, the exact neuronal source of this dopamine remained unknown. Our study explains how dopamine translates a brief 30-second exposure to a female mouse into sustained changes in the male mouse’s brain.”

When male mice investigate female mice, dopamine release leads to sustained biochemical signaling in the mating circuit that underlies the persistent increase in the male’s motivation to mate. If dopamine-releasing neurons are artificially stimulated or silenced, the drive to mate can be powerfully increased or decreased.

“Our study provides a foundation for addressing important questions, such as: How do these neurons control the gradual recovery from satiety across days, and how might they control mating drive in females?” said first author Stephen X. Zhang, PhD, a postdoctoral researcher in Andermann’s lab. “Further, our findings may help explain how mating drive is altered by certain medications such as selective serotonin reuptake inhibitors (SSRIs).”

The researchers propose that elevated serotonin may act as a brake on dopamine signaling in mating-related circuits, thereby decreasing libido—a side effect that nearly 75% of patients taking SSRIs experience. The scientists suggest that future therapies could target the newly identified dopamine-releasing neurons that regulate the drive to mate to alleviate the problem, thereby eliminating a major reason patients discontinue taking antidepressant medications.