A new study in mice suggests that -suppressing nociceptin neurons in the brain's reward-and- center (called the ventral tegmental area) become very active just before a mouse reaches a breakpoint when it gives up on exerting effort to receive a sugary treat. According to the authors, nociceptin is "a complex molecule that suppresses dopamine, a chemical largely associated with motivation." This paper, "A Paranigral VTA Nociceptin Circuit That Constrains Motivation for Reward," was published July 25 in the journal Cell.

Source: Pexels

We all know the deflated feeling of realizing that a dream or goal you've been working toward is out of reach and unattainable. Usually, giving up is accompanied by a little voice in your head that says, "I can't do this anymore; I have to quit. I give up." Even if you've been persevering and struggling toward achieving a particular goal—like a rock climber trying to reach the summit of a mountain—within a millisecond, it can feel like the urge to give up becomes so overwhelming that it stops you dead in your tracks and forces you to throw in the towel.

As an ultra-endurance , I know from experience that the sudden urge to give up often seems to come out of nowhere. To avoid allowing this phenomenon to prevent me from reaching the finish line—and having a DNF ("Did Not Finish") next to my name on the results board—I came up with some road-tested methods for overriding the potentially paralyzing urge to give up during a race. But, until now, surprisingly little has been known about the neural circuits that seem to block the brain's motivation to seek rewards and the of giving up.

The recent discovery of a possible link between dopamine-suppressing neurons and giving up came to light via lab experiments in which mice had to poke their snouts against a dispenser to get a "hit" of sucrose.

At first, one nose poke dispensed some sucrose, then it took two nose pokes, then five, and so on. The researchers purposely increased the amount of nose poking required for a mouse to get the sucrose reward. Using state-of-the-art techniques, the researchers were able to identify that just before a mouse reached the breakpoint of giving up, dopamine-suppressing nociceptin neurons linked to the VTA became very active.

The artistic representation (below) of this study by Max Huffman brings this research to life in a playful and whimsical way that makes it easy to visualize what it feels like when nociceptin suppresses free-flowing dopamine supplies, constrains motivation, and increases the odds of giving up. (In my mind's eye, the Huffman illustration depicts dopamine as red rock climbing bodies that are scaling a mountain, while the green tentacles of dopamine-suppressing nocipeptin neurons are grabbing hold of their bodies in an attempt to push them to the breakpoint of giving up their summit attempt.)

Source: Max Huffman

"We are taking an entirely new angle on an area of the brain known as VTA [ventral tegmental area]," co-lead author Christian Pedersen, a fourth-year Ph.D. student in bioengineering at the University of Washington School of Medicine and the UW College of Engineering, said in a statement.

For this study, Pedersen and colleagues spent four years examining the role nociceptin plays in regulating reward-driven motivation and giving up. As mentioned, one significant highlight of their research is that nociceptin neurons project locally onto VTA dopamine neurons and become extremely active when mice become demotivated to seek rewards.

What Are the Real-World Applications of Identifying the Power of Nociceptin to Suppress Dopamine and Constrain Motivation?

During pleasurable and rewarding activities or pursuits, specific neurons in the VTA release dopamine. Previous research on motivation and reward has focused primarily on the activation of dopamine neurons, but overlooked the dopamine-suppressing role of the nociception modulatory system.

According to the UW researchers, their latest nociceptin-related discoveries could lead to interventions that boost motivation in clinically depressed patients experiencing crippling "demotivation." Targeting nociceptin neurons in different ways could also be used to curb the motivation to seek drugs or in those with substance use disorders.

"We might think of different scenarios where people aren't motivated like and block these neurons and receptors to help them feel better," senior author Michael Bruchas said in a statement. "That's what's powerful about discovering these cells. Neuropsychiatric diseases that impact motivation could be improved. Looking to the future, these neurons could perhaps be modified in people seeking drugs or those that have other addictions."

Bruchas is a professor of anesthesiology, pain medicine and pharmacology at the University of Washington School of Medicine. He's also a principal faculty member at the UW Center of Excellence in Neurobiology of Addiction, Pain, and Emotion (NAPE).

From an evolutionary perspective, the researchers speculate that neural circuits linked to motivation and reward in mammals are designed to preserve energy when resources are scarce. Therefore, nociceptin neurons may be a biological mechanism designed to force humans and animals to cut losses as opposed to continuing fruitless attempts to go after a reward due to sunk costs. "Persistence in seeking uncertain rewards can be disadvantageous due to risky exposure to predators or from energy expenditure," the researchers noted in a press release.

The researchers are that someday their findings on nociceptin activation and giving up could be used to boost motivation in healthy ways and as an intervention to curtail reward-seeking behaviors associated with .