Scientists explain why nothing feels quite like the first time by tracking dopamine during fly sex

A new study in Nature Neuroscience identifies a biological mechanism that explains why repeated experiences become less motivating over time, revealing a direct link between natural behavioral fatigue and the brain changes seen in drug addiction. By examining the neural circuits of fruit flies, researchers found that the receptors responsible for receiving dopamine signals become less sensitive after repeated use, a finding that offers insight into how the brain naturally regulates motivation.

Dopamine functions as a chemical messenger in the brain that reinforces behaviors by signaling reward and establishing motivation. It operates by binding to specific receptors on the surface of neurons, a process that creates an internal record of pleasurable or significant experiences. One specific receptor, known as the D2 receptor, has been studied extensively in the context of substance abuse.

In cases of addiction, these receptors tend to become less sensitive after chronic overstimulation, which leads to a need for increasing amounts of a drug to achieve the same effect. This biological desensitization is generally viewed as a pathological breakdown of the system. However, the mechanism resembles the natural decline in interest that occurs after repeating any rewarding activity, prompting the question of whether this receptor change is actually a standard tool the brain uses to regulate behavior.

The researchers initiated this investigation to understand the precise cellular mechanisms that cause motivation to fade over time. While it is well documented that animals and humans eventually tire of repeated experiences, the specific changes within neural circuits that dictate this decision remain unclear.

“My lab is interested in obtaining a deep, mechanistic understanding of decisions that are under motivational control. In my opinion, this key to understanding complex life remains shockingly mysterious. To find a meaningful answer, we study a decision made by one sex of a relatively simple animal, the fruit fly, Drosophila melanogaster, so we can focus in on small groups of neurons and their molecular properties,” explained Michael Crickmore from the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, the corresponding author of the study.

Fruit flies provide a useful model because its brain circuits are relatively simple and can be manipulated with high precision. The researchers were particularly interested in the decision-making process of the male fly when he faces a threat during copulation. This scenario forces the fly to weigh the motivation to complete the mating against the urgent need to survive a potential danger.

The researchers began by observing the natural behavior of male flies. They placed a male and a female in a small chamber and allowed them to mate. During the mating session, the scientists introduced threats, such as heat or simulated predator attacks.

“Should he end the mating to flee or stick it out to complete the process? It’s pretty interesting: at the beginning of mating the male will sacrifice both his and his partner’s life for the chance to continue, as the mating progresses he becomes more and more inclined to truncate it and escape the threats.”

The research team then exposed the males to a “satiety assay” to induce behavioral fatigue. They placed a single male in a vial with approximately 15 female partners for two and a half hours, allowing him to mate multiple times. Following this period of repeated activity, the researchers tested the males again. They found that these sexually satiated males behaved very differently from the naive ones. When presented with the same threats, the experienced males were much more likely to abandon the mating and flee.

This behavioral shift allowed the scientists to probe the neural mechanism behind the change. They examined a specific group of neurons known as copulation decision neurons. These nerve cells act as a brake on mating behavior. When they are active, they signal the fly to stop copulating. The researchers found that dopamine normally prevents these neurons from firing. Dopamine acts as a motivator by inhibiting the “stop” signal, effectively telling the fly to persevere.

The researchers found that this dopamine signal is received by a specific receptor on the copulation decision neurons called the D2-like receptor. When the male mates for the first time, dopamine binds to these receptors effectively. This binding suppresses the decision neurons and maintains the fly’s focus on the task. The system ensures that the first experience is prioritized and protected against interruptions.

However, the researchers discovered that the system changes with repetition. Every time the male mates, dopamine is released. This repeated exposure triggers a protein called beta-arrestin to interact with the D2 receptors. Beta-arrestin dampens the sensitivity of the receptors, a process known as desensitization. As the receptors become desensitized, they lose their ability to detect the dopamine signal.

Without a functional dopamine signal to inhibit them, the copulation decision neurons become more active. They become more responsive to threats and negative stimuli. Consequently, the fly decides to stop mating much sooner when challenged.

The researchers used advanced imaging techniques to monitor calcium levels in these neurons. The imaging confirmed that in satiated flies, the neurons simply stopped responding to dopamine, even when the chemical was present in high amounts.

To confirm that this desensitization was the cause of the behavioral fatigue, the research team conducted genetic manipulations. They created mutant flies that lacked the beta-arrestin protein in their copulation decision neurons. These flies could not desensitize their dopamine receptors. The results showed that these flies never developed behavioral fatigue.

“If we prevent the dopamine receptors on decision-making neurons from desensitizing, the male treats every mating as if it were his first,” Crickmore told PsyPost. “So the effect is very strong.”

On the other hand, when the researchers artificially reduced the number of D2 receptors in the decision neurons, the flies acted as if they were already bored or tired. Even on their very first mating, these flies were quick to give up in the face of danger.

This provided evidence that the sensitivity of these specific receptors dictates the level of motivation. The finding implies that the “fatigue” is not due to running out of dopamine or physical exhaustion. Instead, it is a local resistance to the motivating chemical.

The researchers noted that this mechanism is highly specific. The desensitization occurred only in the circuits related to mating. It did not affect the flies’ response to heat when they were not mating, nor did it affect other behaviors. This suggests that the brain can downregulate interest in one specific activity while remaining motivated for others.

This mechanism has significant parallels to drug addiction. In addiction, drugs of abuse flood the brain with dopamine. This overwhelming surge causes dopamine receptors throughout the brain to desensitize. The result is a broad loss of interest in natural rewards, as the brain can no longer sense pleasure effectively. The new study suggests that the brain naturally uses this same mechanism, but in a targeted way, to manage motivation for specific tasks.

“In this paper we asked: do the rules change if the male has recently mated?” Crickmore explained. “Would mating become devalued in the way that our behaviors become devalued with repetition and goal achievement? Over the years, we’d found that the fly uses dopamine signaling to bias his responses, more dopamine means he’s more likely to endure the threat.”

“We found that the dopamine that motivates the male to stick with matings not only makes the decision-making dopamine-receiving neurons more likely to ignore threats, but it also causes a long-term inactivation of the dopamine receptors. So the next time around, the same dopamine doesn’t have the same motivating effect.”

“We know that this happens in humans who are addicted to drugs, where high levels of dopamine lead to long-term inactivation of dopamine receptors,” Crickmore continued. “That’s one reason why you need more drug the deeper in you are, and why naturally motivating and rewarding experiences lose their value in addiction. We argue that this is happening in microcosm every time you do anything that uses dopamine. That’s why it’s so hard to recapture that first-time feeling with just about anything.”

The study has some limitations that frame directions for future research. While fruit flies share many genetic and neural similarities with mammals, human brains are far more complex. It remains to be seen if this precise circuit mechanism governs behavioral fatigue in humans in the exact same manner.

“I’m sure many readers will be skeptical that insights from insects will have much to do with complex the decisions humans make,” Crickmore said. “But I see little fundamental difference. The neurons, genes, neurochemistry, and behavioral phenomena are all remarkably similar.”

“I think if we were able to scale up flies to the size of dogs, without changing the number of neurons or anything about the biology, people would be more inclined to think they hold the answers. But why would different size mean different mechanisms? The history of biology, and the many Nobel Prizes won using Drosophila, argue that it doesn’t–it just makes them easier to study!”

“These insights were generated almost entirely by the hard work and creativity of my former PhD student Lauren Miner, now a postdoc at MIT,” Crickmore added.

The study, “Behavioral devaluation by local resistance to dopamine,” was authored by Lauren E. Miner, Aditya K. Gautham, and Michael A. Crickmore.