To understand the mechanism behind ketamine’s ability to alter memory recall, it is first important to understand how long-term memories are processed and stored. Our current and most widely accepted model of memory splits memory into two main categories: working memory and long-term memory. Working memory lasts less than 30 seconds and allows us to temporarily store and process information. Working memory can become a long-term memory if it is reconsolidated. By reconsolidating a memory, we strengthen connections in our brain (yay, plasticity!), and store these memories away in different brain areas, including, but not limited to the hippocampus (“Types of Memory”, 2019). Every time we recall a long-term memory it gets altered, reconsolidated and restored.
So, what exactly is happening with addiction? Addictive substances hijack reward pathways in the brain as well as memory reconsolidation pathways. Very simply, memories have emotional links and are incredibly plastic. Addictive substances strengthen the emotional link to memories of substance use. Long-term memories stick around and are difficult to get rid of, unfortunately for individuals with alcoholism, this means that long-term memories of alcohol use stick around. In a recovering alcoholic, a random stimulus can trigger an association to a long-term memory of alcohol use, and because that memory is so powerful and emotionally linked, relapses occur at an alarming rate of 40-60%. Thus, to recover fully recover from alcoholism, it would help to alter the relapse-inducing long-term memories that are associated with alcohol use.
This is where ketamine enters the picture. Ketamine is a non-competitive NMDA receptor antagonist. Since NMDA receptors are involved in neuronal plasticity and LTP, it is not surprising that they play an integral role in memory reconsolidation. If we block NMDA receptors in reconsolidation pathways we interfere with the brain’s ability to restore the memory. Additionally, Every time a memory is recalled it is vulnerable to alteration before getting reconsolidated and restored (Torregrossa & Taylor, 2013). With this in mind, researchers gave ketamine to participants with alcoholism and asked them to recall a long-term memory of alcohol use. In theory, recalling the memory will destabilize it and ketamine will inhibit the brain’s ability to restore the memory, so overtime the memory will be broken down and fade away. Excitingly, researchers found that individuals on ketamine reported decreased anticipatory enjoyment, urge to drink, enjoyment of alcohol and urge to drink more when compared to the control group (Das et al., 2019).
This is a huge finding when considering the prevalence of alcoholism in America. Even with the promising results of this study, I hesitate to jump on board too quick because I can only imagine how huge the adverse side effects of the disruption of memory consolidation are. If ketamine is powerful enough to degrade a memory of alcohol use, then what are its effects on other long-term memories? Despite my caution, the implications of this study should not be downplayed. Understanding alcohol addiction helps us understand other types of addiction and can greatly improve the quality of life of millions of individuals and families that are suffering.
References:
National Institute on Drug Abuse. (n.d.). Treatment and Recovery. Retrieved from https://www.drugabuse.gov/publications/drugs-brains-behavior-science-addiction/treatment-recovery.
Das, R. K., Gale, G., Walsh, K., Hennessy, V. E., Iskandar, G., Mordecai, L. A., … Kamboj, S. K. (2019). Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nature Communications, 10(1). doi: 10.1038/s41467-019-13162-w
Torregrossa, M. M. & Taylor, J. R. (2013). Learning to forget: manipulating extinction and reconsolidation processes to treat addiction. Psychopharmacol. (Berl.). 226, 659–672
Types of memory. (2019, November 20). Retrieved from https://qbi.uq.edu.au/brain-basics/memory/types-memory.
I honestly had no idea prior to this blog post what ketamine was used for in medical circumstances. I only had the stereotypical understanding of it as a hallucinogen that generally makes people, "go crazy." So I looked into other reasons for its use. There were some obvious connections to this blog. Ketamine is commonly given through IV to depressive patients in the hospital. It is effective but does not last particularly long. Research is being conducted in order to have more oral esketamine available for patients with major depressive disorder (Smith-Apeldoorn, S.Y., et al., 2019). Results thus far seem promising.
ReplyDeleteAddiction and depression are commonly co-occurring issues. People with depression may attempt to treat their symptoms with addictive substances. And addiction may negatively impact someone's life enough to become depressed. Either way, using one medication to be able to help these patients (given they turn out to be effective) would be likely better than mixing multiple other pharmaceuticals. Hopefully the long term memory removal can be limited, as you pointed out.
References:
Juergens, J. (2019, September 17). Depression and Substance Abuse - Addiction Center. Retrieved from https://www.addictioncenter.com/addiction/depression-and-addiction/.
Smith-Apeldoorn, S.Y., Veraart, J.K.E., Kamphuis, J. et al. Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial. BMC Psychiatry 19, 375 (2019) doi:10.1186/s12888-019-2359-1