For many people, the thought of a tasty burger or a cold pint of beer evokes a vivid mental image and drives behavior.
This link between thinking and doing fulfills a clear function: it motivates us to satisfy the needs of life.
But for some, this process may not work correctly. Preoccupation with these rewarding stimuli can lead to substance abuse disorders, including overeating to the point of obesity and alcohol abuse.
Studies dating back to the 1970s have linked alive mental images with drug abuse.
Understanding this link between desire and consumption is essential to understanding addiction. This has eluded neuroscience for decades, but the introduction of a new class of weight-loss drugs may have given us the leverage we need to understand it.
These new medications, including Ozempic and Wegovy, mimic the hormone GLP-1 to stimulate the release of insulin, slow digestion, and increase feelings of satiety. They are known as GLP-1 agonists and were originally used to treat type 2 diabetes because help control blood sugar.
As a side effect, people using these medications also lost a lot of weight, in some cases almost as much as could be expected from bariatric surgery.
But there is another less publicized effect. Human studies show that GLP-1 agonists reduce alcohol consumption. Preclinical animal studies suggest that these medications also reduce the use of cocaine, amphetamines, opiates and nicotine.
These drugs are changing the way we think about the brain’s reward system. They may also open up new treatment options for obesity, alcohol dependence and the use of other addictive substances.
How the brain regulates reward stimuli
We have a reasonable understanding of the brain’s “reward circuitry” associated with regions that produce the neurotransmitter dopamine.
These parts of the brain, the ventral tegmental area (VTA) and nucleus accumbens (NAc) – have been the subject of reward research for decades. They are obvious candidate regions to search for a mechanism of GLP-1 action in the brain. but they lack significant density of GLP-1 receptors and are unlikely to be the direct mechanism.
Therefore, we must consider other brain regions to understand the anticonsumption effect of GLP-1 drugs.
A jump “upstream” from the dopamine-producing parts of the brain is a region called the lateral septum. This brain structure has historically been involved in emotional regulation.
In 1953, pioneering American behavioral researchers Joseph Brady and Walle Nauta coined the term “septal rage” when animals with damage to the lateral septum showed increased aggressionwhile direct stimulation of this brain region reduced aggression.
Much more recent work has placed the lateral septum at the center of a network of neural connectivity. This has reframed the way we think about its function.
While a link between the lateral septum and another region called the hypothalamus is probably responsible for septal anger, the lateral septum links with many other regions with various functions.
The brain’s reward control center
The lateral septum inherits much of its primary information from a region of the brain called the hippocampus.
“This region is well known as the place that allows us to train ourselves in the long term”episodic memories.” A famous case of hippocampal damage, Henry Molaison (patient HM), was unable to form new memories after his epilepsy surgery. He lived effectively without a past, in permanent present tense.
The hippocampus also contains the remarkable “place cells”: neurons that fire in response to a person’s thoughts about their position in space and how recent research time has shown.
This “where and when I am” information is sent to the side partition. Key research has recently shown that the lateral septum also contains place cells, but these cells respond strongly to rewards. They effectively add “what’s good about this place” to the “where and when I am” information from the hippocampus.
Crucially, the lateral septum shares this information with the dopamine-producing regions that we would normally associate with reward.
Neuroscientists now think that the lateral septum is the region of the brain that allows us to “think” about rewards (our conscious perception of them) and communicates with the brain’s reward system machinery that produces dopamine to make us feel good about them.
There is one final reason to suspect that the lateral septum is the mechanism behind the anticonsumption effect of GLP-1 agonists. it is absolutely loaded with GLP-1 receptors.
Emerging research indicates that this is the mechanism. It has recently been shown that activation of GLP-1 directly in the lateral septum reduce food consumption in mice. Earlier this year, another study showed the same thing for alcohol consumption.
My own lab has shown this year that GLP-1 drugs reduce a type of activity in the lateral septum that may prevent it from communicating as effectively with other brain regions.
These findings are reshaping our understanding of how the brain processes rewards and have put the spotlight firmly on the lateral septum as the home of cravings.