Ozempic may have revealed the brain’s hidden “craving center”

For many individuals, envisioning a delectable burger or a refreshing pint of beer triggers a vivid mental image and compels actions. This connection between thoughts and behavior serves a clear purpose – to motivate us to secure life's essentials. However, for certain individuals, this process can become dysfunctional. An excessive focus on rewarding stimuli may lead to substance abuse disorders, such as overeating resulting in obesity or alcohol addiction.

Research dating back to the 1970s has established a correlation between vivid mental imagery and drug addiction. Grasping the relationship between craving and consuming is crucial to comprehending addiction. This enigma has perplexed neuroscience for decades until the emergence of a novel class of weight loss medications may have provided the key to unravel it.

These newly developed drugs, including Ozempic and Wegovy, function by mimicking the GLP-1 hormone, which stimulates insulin release, slows digestion, and enhances feelings of satiety. Initially developed to treat type 2 diabetes by controlling blood sugar, these drugs have demonstrated significant weight loss effects, sometimes comparable to or even surpassing bariatric surgery results.

Nevertheless, an additional, less widely recognized consequence has come to light. Human studies indicate that GLP-1 agonists decrease alcohol intake. Preclinical animal studies further suggest that these drugs also diminish the consumption of cocaine, amphetamines, opiates, and nicotine. The weight loss medications are transforming our understanding of the brain's reward system and may present new treatment avenues for obesity, alcohol dependence, and the consumption of other addictive substances.

The brain's "reward circuitry," primarily associated with the neurotransmitter dopamine, is reasonably well-understood. The ventral tegmental area (VTA) and nucleus accumbens (NAc) have been the primary focus of reward research for decades. These brain regions are considered the most plausible candidates for investigating the mechanism of GLP-1 action in the brain.

However, these regions exhibit limited GLP-1 receptor density, making them unlikely to be the direct mechanism. Therefore, exploring other brain areas to comprehend the anti-consumption effect of GLP-1 drugs becomes necessary. One region, the lateral septum, is a compelling candidate, having been historically linked to emotional regulation.

In 1953, US behavioral researchers Joseph Brady and Walle Nauta identified the lateral septum as the origin of "septal rage" when animals with damage in the area exhibited increased aggression, while direct stimulation of this region reduced aggression. Recent research has positioned the lateral septum at the heart of a neural connectivity network, altering our perception of its function.

The lateral septum receives substantial input from the hippocampus, which is renowned for creating long-term episodic memories and housing "place cells" that encode thoughts about spatial position and time. These "where and when am I" signals are transmitted to the lateral septum.

Surprisingly, the lateral septum also harbors place cells that strongly respond to rewards. These cells synthesize "what is good in this place" with "where and when am I" information from the hippocampus. Crucially, the lateral septum communicates with the dopamine-producible regions typically linked to reward. Neuroscientists now consider the lateral septum as the brain region responsible for conscious reward perception and relaying this information to the dopamine-producing machinery in the brain's reward system.

A final piece of evidence supporting the lateral septum as the mechanism behind the anti-consumption effect of GLP-1 agonists is its extensive GLP-1 receptor presence. Recent research demonstrates that GLP-1 activation directly in the lateral septum reduces food consumption in mice and alcohol consumption in humans. My laboratory's findings, published this year, suggest that GLP-1 drugs may suppress specific lateral septum activity, thus preventing effective communication with other brain regions.

These groundbreaking discoveries are revolutionizing our comprehension of the brain's reward processing and have put the spotlight squarely on the lateral septum as the epicenter of cravings.