Decoding Addiction: How Cocaine Changes the Amygdala at the Single-Cell Level

Drug addiction is a complex struggle that involves powerful memories and intense emotions. While we know the brain’s reward system is involved, we are still learning how specific cells within the brain's emotional center, the amygdala, change during addiction. In our recent study with the Telese lab at UCSD, we used cutting-edge technology to look at individual cells in the amygdala to see how they differ between those who are highly vulnerable to addiction and those who are more resilient.

The Big Question

We wanted to understand why some individuals develop compulsive drug-seeking behaviors while others do not, even when exposed to the same amount of cocaine. Specifically, we investigated the gene regulatory programs—the instruction manuals inside our cells—that change in the amygdala during long-term abstinence from cocaine.

Exploring the Amygdala's Atlas

To find answers, we studied genetically diverse rats that mimic the variety seen in humans. We allowed them to self-administer cocaine and categorized them into high addiction and low addiction groups based on their behavior, such as how hard they worked for the drug and if they continued taking it despite mild negative consequences. We then used single-nucleus genomics to create a high-resolution map of over 160,000 cells in the amygdala, looking at which genes were active and how the DNA was packaged.

What We Discovered

Our findings revealed that addiction literally rewires the amygdala at a cellular level:

• A Shift in Brain Balance: We found that rats with high addiction traits had much stronger GABAergic inhibition in their amygdala. This means the brakes of the brain were working differently than in the resilient rats.

• Opposite Cellular Reactions: In rats with high addiction traits, excitatory neurons (cells that send "go" signals) showed increased DNA accessibility, while inhibitory neurons (cells that send "stop" signals) showed decreased accessibility.

• Energy Metabolism: Many of the genes that were different between the two groups are involved in how cells produce energy. This suggests that the metabolic state of these cells may directly influence addiction behaviors.

• A Potential New Treatment: We discovered that by inhibiting an enzyme called GLO1, we could reverse the high level of inhibition in the brain and reduce relapse-like behaviors in the highly addicted rats.

  
  

Why It Matters

This research provides a valuable atlas for scientists to understand the molecular drivers of cocaine use disorder. By identifying specific cell types and pathways, like the GLO1 enzyme and GABAergic signaling, we are opening the door to more targeted, personalized treatments for addiction. We believe that by understanding these deep biological differences, we can help find better ways to support long-term recovery and prevent relapse.

Reference: Zhou, J.L., de Guglielmo, G., Ho, A.J., Kallupi, M., Pokhrel, N., Li, H.-R., Chitre, A.S., Munro, D., Mohammadi, P., Carrette, L.L.G., George, O., Palmer, A.A., McVicker, G., & Telese, F. (2023). Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition. Nature Neuroscience, 26(11), 1868-1879. https://doi.org/10.1038/s41593-023-01452-y