UI study identifies potential target for treating addiction and relapse

Date: Tuesday, January 17, 2023

New research from the University of Iowa finds that blocking an enzyme that lowers localized acidity in the brain reduces cocaine withdrawal symptoms and drug-seeking behavior in mice. The research led by UI professor of psychiatry John Wemmie, MD, PhD, suggests that the enzyme, carbonic anhydrase 4 (CA4), might represent a new therapeutic target for addiction and relapse.

Withdrawal symptoms fuel relapse

When people stop using drugs of abuse, they go into withdrawal and experience cravings for the drug that increase over time. These withdrawal symptoms are incredibly difficult to overcome and are a key factor that perpetuates the cycle of addiction.  

At a molecular level, research has shown that cocaine use followed by withdrawal causes structural changes in the synapses of the brain’s reward center. These synaptic rearrangements parallel the development of cravings for more drugs. 

“Critically, our study suggests that disrupting CA4 prevents these insidious synaptic changes that are likely critical for sustaining the addiction cycle,” says Wemmie, who also is a member of the Iowa Neuroscience Institute. “Although more work is needed to better understand these findings, they raise the intriguing possibility that disrupting or inhibiting CA4 in the brain may have value in treating substance use disorders.”

Acid signaling in brain’s reward center key to drug cravings

Wemmie’s lab had previously discovered that a form of neurotransmission, based on acidity and acid-sensing proteins, plays a role in these synaptic rearrangements. They also found that reducing the activity of an acid-sensing ion channel protein (ASIC) influences the long-lasting memory created by addictive drugs and the subsequent craving for these drugs of abuse.  

“We knew from that previous study that loss of ASIC activity leads to addiction-like characteristics in mice—changes to the synapses and an increase in the animal’s drug seeking behavior following withdrawal,” says Subhash Gupta, PhD, a research scientist in Wemmie’s lab and lead author of the new study. “So, we hypothesized that increasing the ASIC activity might have the opposite effect.” 

Because the CA4 enzyme removes the acidity that activates ASICs, the researchers reasoned that disrupting the CA4 enzyme might increase ASIC activation and protect against the withdrawal induced changes. 

The UI team found that disrupting CA4 in either the whole brain, or just in the brain’s reward center (the nucleus accumbens), of the mice, significantly reduced the synaptic changes that occurred after cocaine withdrawal. In addition, mice missing the CA4 enzyme showed lower levels of cocaine seeking behavior and relapse in the withdrawal phase than wildtype mice with normal CA4 enzyme levels. The findings were published in Science Advances. 

Importantly, the effects of blocking CA4—both on synaptic structure and on the mice’s behavior—were limited to the post-withdrawal time period, when the potential to prevent relapse could have a significant impact. 

“The implication from this work is that CA4 may be a good pharmacological target for treating addiction and relapse,” Wemmie says.  

While much of the biological details still need to be understood, the team plans to continue their research by investigating the effect of medications that can target CA4. 

In addition to Wemmie and Gupta, the UI team included Ali Ghobbeh, Rebecca Taugher-Hebl, Rong Fan, Jason Hardie and Ryan LaLumiere. The research was funded in part by grants from the National Institute on Drug Abuse, the U.S. Department of Veterans Affairs, and the Roy J. Carver Charitable Trust.