Summary: Researchers report that acetazolamide (AZD), a drug used for glaucoma, altitude sickness, and seizures, shows promise for preventing relapse in opioid use disorder (OUD). Rather than acting on opioid receptors, AZD inhibits the brain enzyme carbonic anhydrase 4 (CA4) in the reward center, reversing synaptic changes produced by long-term drug exposure.
In mouse studies, a single dose of AZD or genetic disruption of CA4 reduced drug-seeking behavior and strengthened resistance to relapse by reversing addiction-associated synaptic rearrangements in the nucleus accumbens core (NAcC), a central hub of the brain’s reward circuitry.
Key Facts
- New therapeutic pathway: Targets CA4 enzyme instead of mu-opioid receptors, offering a non-opioid mechanism for relapse prevention.
- Reverses synaptic changes: AZD reduces harmful synaptic adaptations that occur after opioid withdrawal, restoring more normal neuronal signaling in the NAcC.
- Repurposing potential: Because acetazolamide is already approved for other clinical uses and has an established safety profile, it could be evaluated for addiction treatment more rapidly than a novel compound.
Study overview
A research team led by John Wemmie, MD, PhD, at the University of Iowa investigated whether inhibiting CA4 could prevent the long-lasting brain adaptations that make people vulnerable to relapse after opioid exposure. Building on prior work showing CA4 disruption reduced cocaine-related synaptic changes, the team examined oxycodone withdrawal models in mice to see if the same pathway regulated opioid-induced plasticity and drug-seeking.
Wemmie and colleagues found that prolonged withdrawal from oxycodone increased the AMPAR/NMDAR ratio and promoted insertion of calcium-permeable AMPA receptors into medium spiny neurons (MSNs) of the NAcC, especially in D1-expressing MSNs. Those synaptic adaptations are known to enhance responsiveness to drug cues and elevate relapse risk. Genetic disruption of CA4 prevented these changes, and pharmacological inhibition with a single systemic dose of acetazolamide reversed the synaptic alterations both in vitro and in vivo.
Mechanistically, inhibiting CA4 appears to boost activity of acid-sensing ion channels (ASICs), particularly ASIC1A, which play a role in how neurons in the reward center respond to local pH shifts associated with synaptic signaling. Increased ASIC activity counteracted the drug-induced sensitivity of NAcC neurons, reducing the strengthening of drug-related synapses and lowering the drive to seek opioids after abstinence.
Why this matters for opioid relapse prevention
Current FDA-approved medications for OUD, such as methadone and buprenorphine, act primarily at mu-opioid receptors to ease withdrawal and reduce cravings. While these medications are effective for many patients, they do not directly reverse the persistent synaptic adaptations that contribute to relapse vulnerability. AZD’s CA4-centered mechanism addresses those adaptations, offering a complementary and mechanistically distinct approach that could improve long-term recovery outcomes if validated in humans.
Importantly, the findings reported by the University of Iowa team do not claim AZD is a proven clinical cure for OUD. The positive results were observed in animal models, and the authors emphasize the need for clinical trials to determine safety, dosing, and efficacy of acetazolamide for treating substance use disorders in people.
Potential broader application
The research also supports the idea that CA4 inhibition may have utility across different substance use disorders. Prior experiments showed CA4 disruption reduced cocaine-induced synaptic changes and drug-seeking, and the current study demonstrates similar protective effects after opioid withdrawal, suggesting the pathway may be relevant to multiple drugs of abuse.
Study contributors and funding
The research team included Subhash Gupta, Rebecca Taugher-Hebl, Ali Ghobbeh, Marshal Jahnke, Rong Fan, Ryan LaLumiere, and John A. Wemmie. Funding sources included grants from the National Institute on Drug Abuse, the Department of Veterans Affairs, and the Roy J. Carver Charitable Trust.
Frequently asked questions
A: Methadone and buprenorphine act on mu-opioid receptors to reduce withdrawal and cravings. Acetazolamide targets CA4, a different enzyme pathway that can reverse synaptic rewiring in the brain’s reward center, addressing the neuroplastic changes that contribute to relapse.
A: Early animal studies indicate CA4 inhibition reduced synaptic changes and drug-seeking after cocaine as well as oxycodone, suggesting potential applicability to multiple substance use disorders pending further research.
A: Acetazolamide is an approved drug for other conditions, but it requires clinical trials focused on opioid use disorder before it could be recommended or approved for relapse prevention in people with OUD.
Editorial notes
- This article was edited by an editor at Neuroscience News.
- The journal paper was reviewed in full by editorial staff.
- Additional context was provided by the reporting team.
About this research news
Author: Jennifer Brown
Source: University of Iowa
Contact: Jennifer Brown, University of Iowa
Image: Image credited to Neuroscience News
Original research: Open access. Title: “Acetazolamide inhibition of carbonic anhydrase 4 reverses opioid-induced synaptic rearrangements in nucleus accumbens and reduces drug-seeking behavior” by Subhash C. Gupta, Rebecca J. Taugher-Hebl, Ali Ghobbeh, Marshal T. Jahnke, Rong Fan, Ryan T. LaLumiere & John A. Wemmie. Journal: Neuropsychopharmacology. DOI: 10.1038/s41386-025-02319-5
Abstract (condensed)
Enduring synaptic adaptations drive persistent vulnerability to drug-seeking, and existing μ-opioid receptor–targeted therapies do not effectively reverse these neuroadaptations. Building on prior findings that CA4 disruption reduces cocaine-related synaptic and behavioral adaptations, the investigators tested whether CA4 deletion or pharmacological inhibition with acetazolamide could mitigate opioid withdrawal–associated plasticity. In mice, prolonged oxycodone withdrawal increased the AMPAR/NMDAR ratio and promoted incorporation of Ca2+-permeable AMPARs in NAcC MSNs, particularly D1-expressing cells. CA4 disruption prevented these changes, and a single systemic dose of acetazolamide reversed withdrawal-induced synaptic alterations in a CA4- and ASIC1A-dependent manner. Both CA4 deletion and one dose of AZD reduced drug-seeking after prolonged abstinence. These results identify CA4 as a regulator of opioid-induced synaptic adaptations and suggest acetazolamide as a promising, readily translatable pharmacological strategy to reduce relapse vulnerability by targeting a mechanism distinct from classical opioid receptor signaling.