Weight-loss drug semaglutide alters reward-seeking behavior in healthy mice

A new small study in healthy mice reveals that the popular weight-loss drug semaglutide alters behavior and brain activity related to reward and stress. Researchers found that daily doses of the drug changed how animals pursued natural rewards and reacted to stressful situations, while also shifting electrical patterns in a central reward circuit. The findings were published in the journal Molecular Brain.

Semaglutide is a medication widely used to treat diabetes and obesity. The medication is frequently recognized by brand names such as Ozempic and Wegovy. It mimics a naturally occurring hormone called GLP-1, which regulates appetite and blood sugar. Recently, scientists have begun exploring whether the drug might also treat addiction by dampening the brain’s response to cravings.

Most prior research has focused on animal models with obesity or diabetes. To understand the drug’s baseline effects on a typical nervous system, researchers Alejo Mosqueira, Sanaz Ansarifar, and their colleagues at Aarhus University investigated how semaglutide impacts the behavior and brain waves of healthy mice. The research team specifically looked at the nucleus accumbens, a region deep in the brain that plays a primary role in processing motivation, pleasure, and reward.

The researchers first designed a behavioral experiment using healthy adult male mice. They divided the animals into two main treatment groups to test different dosing schedules. One group received a weekly injection of semaglutide for eight weeks, which mirrors how the drug is prescribed to human patients. The second group received daily injections to account for the faster metabolism of mice and to observe any short-term behavioral changes.

Following the injection periods, the researchers ran the mice through a battery of tests designed to measure movement, anxiety, and reward-seeking habits. They monitored the animals’ food intake, water consumption, and body weight throughout the process to track general physiological health. Both the daily and weekly groups experienced substantial weight loss, alongside noticeable reductions in eating and drinking. The researchers ran statistical analyses to confirm that the weight loss itself was not responsible for the altered behavior.

Free daily newsletter

When assessing behavior, the researchers found changes exclusively in the daily injection group. In an open field test used to measure general movement and anxiety, the daily-dosed mice displayed an increase in jumping against the walls of the testing box. The researchers interpret this as an increased attempt to escape the enclosure. In a separate marble burying test used to measure repetitive actions, the differences between the treated and untreated mice were not statistically significant.

The team also used a nestlet shredding test, providing the mice with a cotton nesting material to see how much they would tear it apart. Mice given daily semaglutide shredded far less of the material than the control group. This reduction suggests a shift in how the animals explore their environment or a potential increase in underlying anxiety.

To evaluate reward-seeking behavior without relying on food, the researchers used a scent-based test. Healthy male mice naturally seek out the smell of female mouse urine, which acts as a rewarding social cue. The semaglutide-treated mice spent much less time sniffing the female urine than the untreated mice. This drop in interest indicates a suppression of natural reward-seeking drives.

Finally, the researchers placed the mice in small containers of water for a forced swimming test, which is commonly used to measure stress coping and depressive-like states. Mice treated with daily semaglutide spent less time floating motionless and more time actively swimming compared to the control group. This behavior often suggests improved stress resilience or an antidepressant-like effect.

In a separate experiment, Mosqueira and Ansarifar’s team examined how a single dose of semaglutide affects neural activity. They anesthetized a small group of healthy mice and inserted microscopic electrodes into the nucleus accumbens. The researchers recorded the animals’ baseline brain waves for 30 minutes, injected the drug, and then recorded for another hour.

The researchers focused on local field potentials, which are the collective electrical signals generated by large groups of neurons firing together. They analyzed different speeds of brain waves, breaking the signals down into slower rhythms known as delta, theta, and alpha waves. These specific wave patterns are heavily involved in how the brain anticipates and responds to rewards, making them a useful target for understanding motivation.

Following the semaglutide injection, the rhythmic electrical activity in the nucleus accumbens shifted. The dominant frequencies of the delta, theta, and alpha waves became slightly faster. At the same time, the physical strength or amplitude of these slow waves decreased. The researchers note that a reduction in delta and theta wave strength aligns with a dampened reward anticipation system.

The study relies on a relatively small number of animals, and the behavioral changes only appeared under the daily dosing schedule. The weekly injection group lost weight but did not exhibit the same behavioral shifts. This discrepancy suggests that the frequency of the dose heavily influences the behavioral outcomes in healthy animals.

The brain wave recordings took place while the mice were under anesthesia, which fundamentally alters normal electrical activity in the brain. The behavioral tests, conversely, involved awake animals taking the drug over multiple days. Because of these differing conditions, the electrical changes cannot be directly linked to the behavioral shifts.

Future research will need to record brain activity in awake, freely moving animals over longer periods. Measuring these electrical signals while mice are actively making choices could clarify exactly how semaglutide changes motivation. Testing different dosages may also help determine whether these effects apply broadly across different treatment regimens.

The study, “Semaglutide alters behaviour and nucleus accumbens oscillatory activity in healthy mice,” was authored by Alejo Mosqueira, Sanaz Ansarifar, Sadegh Nabavi, and Andrea Moreno.