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

For many individuals, the allure of indulgent foods like burgers or a refreshing pint of beer is accompanied by vivid mental imagery that drives their behavior. This connection between thought and action serves a crucial purpose – motivating us to obtain the essentials for survival. However, for some, this mechanism can become disrupted, leading to disorders such as substance abuse and overeating, ultimately resulting in obesity and alcohol dependency.

Over the years, studies have demonstrated the link between vivid mental imagery and drug abuse, with a central focus on understanding the craving-consumption relationship. This knowledge has been elusive to neuroscience for decades, until the introduction of a novel class of weight loss drugs, including Ozempic and Wegovy, which may hold the key to unraveling this mystery.

These drugs, known as GLP-1 agonists, function by mimicking the GLP-1 hormone, stimulating insulin release, slowing digestion, and increasing feelings of fullness. They were initially developed to treat type 2 diabetes as they effectively control blood sugar, but they also result in significant weight loss, sometimes equivalent to bariatric surgery.

Beyond weight loss, recent human studies have shown that GLP-1 agonists reduce alcohol consumption, while preclinical animal studies suggest they can also decrease the use of cocaine, amphetamines, opiates, and nicotine. This has prompted a reevaluation of the brain's reward system and the potential for new treatment options for obesity, alcohol dependence, and other addictive substances.

Understanding the brain's "reward circuitry" primarily involves regions that generate dopamine, such as the ventral tegmental area (VTA) and nucleus accumbens (NAc). These areas have been the focus of research on reward mechanisms for decades. However, these regions have a low density of GLP-1 receptors and are unlikely to be the direct mechanism for GLP-1 drugs' anti-consumption effect.

An alternative region to investigate is the lateral septum, a brain structure that has long been associated with emotional regulation. In 1953, researchers Joseph Brady and Walle Nauta identified the lateral septum as the origin of "septal rage," where damage to the region led to increased aggression, while stimulation reduced it.

More recent research has revealed that the lateral septum is part of a complex neural connectivity network, connecting various brain regions with diverse functions. The lateral septum receives most of its primary input from the hippocampus, known for memory formation and spatial awareness. Researchers have discovered that the lateral septum also contains place cells, which respond to rewards, effectively adding "what is good in this place" to the "where and when am I" information from the hippocampus.

Crucially, the lateral septum links with dopamine-producing regions, suggesting that it plays a role in our conscious perception and evaluation of rewards, communicating with the brain's reward system that produces dopamine, resulting in a sense of pleasure. Moreover, the lateral septum has a high concentration of GLP-1 receptors, which may explain the anti-consumption effect of GLP-1 agonists.

Recent studies have demonstrated that activating GLP-1 directly in the lateral septum can reduce food consumption in mice and alcohol consumption in humans. My laboratory has also observed that GLP-1 drugs decrease specific activity in the lateral septum, potentially preventing effective communication with other brain regions. These findings have shifted our understanding of how the brain processes rewards and have brought the lateral septum to the forefront as the potential site of cravings.