How does cocaine rewire the brain?

A study in mouse models demonstrates how cocaine alters hippocampal function, driving relapse, and identifies a possible therapeutic target.

Researchers at Michigan State University (MI, USA), led by senior author A.J. Robison, have investigated how cocaine rewires the brain, illuminating why the drug is so addictive and why it’s proven difficult to treat. Mouse models of the substance use disorder reveal more about how the brain is altered by cocaine addiction, offering greater insight into possible treatment options.

Between 2015 and 2020, cocaine overdose deaths tripled, yet there is still no FDA-approved treatment for cocaine addiction. Although cocaine withdrawal has no physical symptoms, that doesn’t make the drug easier to quit, and for those who do successfully give it up, their chance of relapsing is significant; approximately 24% of people revert to weekly use and another 18% return to a treatment program within a year.

Previous research has implicated the connection between the ventral hippocampus (vHPC), the brain’s memory center, and the nucleus accumbens (NAc), the reward center, in the mediation of cocaine seeking and reward, producing plasticity in the vHPC synapses that innervate NAc medium spiny neurons. However, until now, it has been unclear whether cocaine exposure alters the intrinsic membrane excitability of vHPC-NAc neurons to drive subsequent cocaine use. Furthermore, although cocaine is known to induce the activity of transcription factor ΔFosB throughout the brain, its role within the vHPC-NAc is not understood.

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Using mouse models and specialized CRISPR technology, the researchers identified ΔFosB’s role within the vHPC-NAc circuit when mice were exposed to cocaine. They demonstrated that ΔFosB acts as a switch, capable of turning genes on and off between the memory and reward centers of the brain. The amount of this protein accumulating within the brain increased the longer the mice were exposed to cocaine, changing how vHPC neurons functioned and, ultimately, decreasing vHPC-NAc excitability.

“This protein isn’t just associated with these changes, it is necessary for them,” explained Andrew Eagle, lead author of the study. “Without it, cocaine does not produce the same changes in brain activity or the same strong drive to seek out the drug.”

Using circuit-specific translating ribosome affinity purification, the researchers assessed cocaine-induced, ΔFosB-dependent changes in gene expression in the vHPC-NAc circuit, finding an increase in the expression of calreticulin, a calcium-buffering protein present in the endoplasmic reticulum. Calreticulin expression was identified as essential for communicating cocaine reward.

The study shows that relapse is a biological result of the brain’s rewiring, demonstrating the need for effective treatments for the substance use disorder and illuminating a possible target in the form of the ΔFosB protein. Now, with a grant from the National Institute on Drug Abuse (MD, USA), the researchers are partnering with the University of Texas Medical Branch (TX, USA) to create compounds that target ΔFosB.

In addition to creating therapeutics for cocaine addiction, Robison’s lab is interested in investigating the biological differences in addiction risk between men and women, examining how hormones impact these brain circuits.

If you have been affected by any of the issues discussed in this article, or know someone who has, you can visit Rehab 4 Addiction, a helpline and a directory of treatment centers throughout the UK, for resources and information about addiction and mental health.