Picture this: It's Friday night, and you're getting ready to go out with your friends, and your favorite going-out or go-to karaoke song starts playing. Suddenly you're thinking about the last time you heard that song, maybe who you were with, and even the drinks you had. But what if those memories were doing more than just making you nostalgic? For millions of people across the U.S that struggle with Alcohol Use Disorder (AUD), it is. The human brain is constantly strengthening and weakening connections between neurons as you experience and repeat sensory information. This process is called neuroplasticity and is the reason someone may associate winter with snow, or a scent with a specific person. Regarding Alcohol Use Disorder, this plasticity looks like repeatedly drinking alcohol in a certain environment, and their brain making associations between alcohol and music, people, places etc.
I was recently able to sit in on a presentation given by Dr. Jessica Hoffman from Loyola University Chicago's Stritch School of Medicine, who focused on alcohol and brain vulnerability. In the presentation, Dr. Jessica Hoffman explained the volume of Americans that Alcohol Use Disorder effects and how it directly impacts the reward system in our brain. More specifically, glutamate which is a main driver of reinforcement, reward, and addiction circuits in the brain. Glutamate activates receptors called AMPA receptors which help neurons communicate and are important for synaptic plasticity. Dr. Hoffman's research and experiment is focusing on TARP y-8 which is a regulatory protein that determines where the AMPA receptors function and are located. Through various experiments involving mice, Dr. Hoffman found that changing TARP y-8 signaling impacted how motivated mice were to seek alcohol. Reducing TARP y-8 signaling decreased motivation to seek alcohol and increasing signaling had an inverse effect. While this research suggests a possible way to weaken prior learned alcohol associations, it also suggests that alcohol related behaviors are connected to the same pathways that help us learn and make memories. Given the brain can make associations between alcohol and rewarding experiences, is it possible to change those associations after they have already formed?
When recalling a memory, it can become temporarily vulnerable and open to modulation before being stored again. This is called memory reconsolidation, and many researchers have explored whether disruption of alcohol associated memories could reduce cravings and alcohol seeking behaviors. In a study done in 2019 at University College London, Dr. Ravi Das and other researchers investigated if alcohol related memories and associations could be weakened by the administration of Ketamine and memory reactivation. Dr. Das focused on NMDA receptors which are also glutamate receptors that are involved in learning and memory. In this experiment, researchers used 90 human participants with "hazardous" drinking tendencies and divided them into 3 groups; Participants who recalled alcohol related memories and then received ketamine, participants who received ketamine without recalling alcohol related memories, and participants who recalled alcohol related memories and then received a placebo. The research found that participants who recalled alcohol related memories before receiving ketamine experienced a reduction in alcohol reward responses and drinking. This experiment suggests there is a possibility of modulation of alcohol related memories, highlighting that "MRM retrieval + ketamine produces a rapid reduction in the reinforcing and motivational properties of alcohol and substantial, lasting reductions in drinking levels compared to retrieval or ketamine alone" (Das et al., 2019).
The research done by Dr. Jessica Hoffman and Dr. Ravi Das both emphasize the role of learning and memory in alcohol related behaviors and associations. While Dr. Hoffman's modulation of TARP y-8 receptors demonstrates how glutamate related signaling helps strengthen alcohol seeking behaviors in mice, and memory reconsolidation research suggests a possibility of memory modulation, both findings are preclinical and yet establish an effective treatment for AUD, specifically in humans. However both approaches to understanding addiction raise the possibilities of future addiction treatments' ability to target rewarding effects of alcohol use as well as the memories that maintain alcohol seeking behaviors. Incremental research like Dr. Hoffman and Dr. Das's work helps establish a relationship between alcohol, reward, learning and memory that is important for future scientific and medical advancements.
Work Cited
Das, R.K., Gale, G., Walsh, K. et al. Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nat Commun 10, 5187 (2019). https://doi.org/10.1038/s41467-019-13162-w
Hoffman, Jessica L., et al. “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, vol. 45, no. 7, July 2021, pp. 1424–35, https://doi.org/10.1111/acer.14639.
Nader K. (2015). Reconsolidation and the Dynamic Nature of Memory. Cold Spring Harbor perspectives in biology, 7(10), a021782. https://doi.org/10.1101/cshperspect.a021782
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