We have probably all experienced how seeing something can suddenly make us want it. You can be completely fine and then see someone eating your favorite food and immediately start craving it. Obviously, alcohol addiction is much more complicated than wanting a snack, but after hearing Jessica Hoffman speak about her research, I started thinking about how powerful these learned associations can become when alcohol is involved. What interested me most was the idea that alcohol does not only affect the brain while someone is drinking. Over time, the brain can learn to associate certain behaviors, environments, and cues with the rewarding effects of alcohol.
Hoffman et al. (2021) studies some of the neuroscience behind why alcohol can become such a strong reinforcer. Their research focused on the AMPA receptors, which respond to the neurotransmitter glutamate and are involved in synaptic plasticity. More specifically, they studied AMPA receptors associated with a regulatory protein called TARP y-8. TARP y-8 is highly expressed in areas including the hippocampus, prefrontal cortex and basolateral amygdala, which are brain regions that are also involved in alcohol-related behaviors.
One aspect of the Hoffman et al. study that caught my attention is the way the researchers were able to measure the behavior of seeking out alcohol. Mice learned to push a lever to obtain a mixture of sweetened alcohol or sucrose alone (Hoffman et al., 2021). I found this to be very interesting because the researchers were not only trying to figure out whether or not the mice would consume the alcohol if it was there. The mice had to learn that by doing a particular action, they could get alcohol.
The researchers next investigated the effects of a drug known as JNJ-55511118 on selective AMPA receptor inhibition connected to TARP y-8. Treatment of male mice with this drug led to a reduction in alcohol-reinforced responding and alcohol intake. Intriguingly, no such effect was seen in female mice (Hoffman et al., 2021). There was also no reduction in the response for sucrose, indicating that the drug was not just making the mice less motivated to respond for a reward.
This led me to consider how these learned associations with alcohol might work in humans outside of an animal model. I found research conducted by Kirsch et al. in 2024, which examined the responses of individuals with AUD when presented with pictures of various alcoholic beverages. In contrast to the specific receptor studied by Hoffman et al., the 2024 study of Kirsch et al. utilized fMRI to record brain activity when viewing alcohol-related stimuli. The study consisted of 70 individuals with active AUD, and their preferences for certain types of alcoholic drinks were based on recent alcohol consumption behaviors.
What was intriguing about their results was that it depended on what type of alcohol they looked at. Out of the 70 individuals in their study, 54 had a preference for alcoholic beverages. They showed increased cravings for their preferred alcoholic drink, as opposed to non-preferred alcoholic beverages. There was also a difference in how their brain responded. Their preferred alcohol cues led to increased activation in the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC). Their increased activation may be related to the value that their preferred alcohol acquired(Kirsch et al., 2024).
I think this makes the connection to Hoffman’s research especially interesting. Both studies show that addiction is not only about physically consuming a substance. Learning, reinforcement, and the value that the brain gives to alcohol- related experiences also matter. In Hoffman’s research, the mice learned that pressing a particular lever would result in alcohol. In the human study, people’s own drinking patterns were related to how strongly they craved and neurologically responded to different alcohol cues.
It has also altered my perspective on the challenges of avoiding alcohol among individuals with AUD. Externally, it could appear that avoiding alcohol would merely require the individual to choose not to drink. However, the individual would be surrounded by stimuli that their brain has been conditioned to respond with alcohol. These stimuli could be particular alcoholic beverages, a particular setting, a set of individuals, or even the sight of an actual bottle. According to Kirsch et al. (2024), even viewing an image of an alcoholic beverage that one prefers was linked to craving and neurophysiological differences. To me, this illustrates the concept that a stimulus that may be mundane to one individual can have far greater significance to another.
At the same time, I believe it would be wrong to claim that the two articles uncovered precisely the same mechanisms. Hoffman et al. (2021) used the manipulative design to influence the particular mechanism in the glutamate pathway in the mice’s brain, while Kirsch et al. (2024) conducted a study on human subjects by means of fMRI analysis of their brain activity. It should be noted that the second article did not find any evidence that the AMPA receptors were responsible for the participants’ response to alcohol- related stimuli. In my opinion, the two studies offer two parts of the same bigger picture.
The most important lesson that I learned through making this connection was the fact that addiction indeed involves learning but only with much greater stakes involved. Our brains are constantly learning what predicts rewarding experiences and what behavioral adjustments to make accordingly. As a result of repeated drinking, some of the associations might become extremely strong and eventually it might not be necessary for the substance to induce any kind of response. It would suffice for the associated cue to have a special significance by itself.
The connection made after listening to Hoffman’s lecture helped me understand the biological aspect of the issue better. In addition to wondering about the reasons why the person continues their drinking behavior despite all the negative outcomes it brings, we can ask another question, which neuroscientific approach enables us to answer: What exactly happens in the brain that causes this behavior to persist? I think knowing that along with knowing the cues responsible for cravings might help us devise better addiction treatment strategies in the future.
References
Hoffman, J. L., Faccidomo, S., Saunders, B. L., Taylor, S. M., Kim, M., & Hodge, C. W. (2021). Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ-8 with JNJ-55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self-administration. Alcoholism: Clinical and Experimental Research, 45(7), 1424–1435. https://doi.org/10.1111/acer.14639
Kirsch, D. E., Ray, L. A., Wassum, K. M., & Grodin, E. N. (2024). Anterior cingulate and medial prefrontal cortex alcohol cue reactivity varies as a function of drink preference in alcohol use disorder. Drug and Alcohol Dependence, 256, 111123. https://doi.org/10.1016/j.drugalcdep.2024.111123
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