Journal article
Acetazolamide inhibition of carbonic anhydrase 4 reverses opioid-induced synaptic rearrangements in nucleus accumbens and reduces drug-seeking behavior
Neuropsychopharmacology (New York, N.Y.), PMID 8904907
01/21/2026
DOI: 10.1038/s41386-025-02319-5
PMID: 41565998
Abstract
Persistent vulnerability to drug-seeking is driven by enduring synaptic adaptations, yet current μ-opioid receptor-targeting pharmacotherapies provide limited efficacy against these neuroadaptations. Thus, there is a critical need for mechanistically distinct, non-opioid interventions. We recently found that carbonic anhydrase 4 (CA4) disruption reduces cocaine-induced synaptic adaptations and drug-seeking. Building on this foundation, we sought to determine whether deleting CA4 or pharmacological inhibition with acetazolamide (AZD), a clinically employed carbonic anhydrase inhibitor-could mitigate opioid withdrawal-associated plasticity and thus might reduce relapse vulnerability. We studied synaptic and behavioral adaptations to withdrawal from oxycodone in mice and found that prolonged withdrawal from oxycodone increased the AMPAR/NMDAR ratio and promoted synaptic incorporation of Ca
-permeable AMPARs in nucleus accumbens core (NAcC) medium spiny neurons (MSNs). We found synaptic changes after protracted withdrawal from multiple opioids, which were most pronounced in D1-expressing MSNs, and were prevented by CA4 disruption. Moreover, AZD reversed withdrawal-induced synaptic alterations both in vitro and in vivo, in a CA4- and acid-sensing ion channel 1A (ASIC1A)-dependent manner. Unlike withdrawal from cocaine, withdrawal from oxycodone did not alter dendritic spine density in NAcC MSNs, suggesting a distinct mode of plasticity. Finally, following oxycodone self-administration, both CA4 deletion and a single systemic AZD dose reduced drug-seeking after prolonged abstinence. Together, these findings identify CA4 as a regulator of opioid-induced synaptic adaptations and suggest AZD as a promising, readily translatable pharmacological intervention. By targeting a pathway independent of classical opioid receptor signaling, CA4 inhibition represents a mechanistically distinct strategy that may reduce relapse vulnerability in OUD.
Details
- Title: Subtitle
- Acetazolamide inhibition of carbonic anhydrase 4 reverses opioid-induced synaptic rearrangements in nucleus accumbens and reduces drug-seeking behavior
- Creators
- Subhash C Gupta - University of IowaRebecca J Taugher-Hebl - University of IowaAli Ghobbeh - University of IowaMarshal T Jahnke - University of IowaRong Fan - University of IowaRyan T LaLumiere - University of IowaJohn A Wemmie - Veterans Health Administration
- Resource Type
- Journal article
- Publication Details
- Neuropsychopharmacology (New York, N.Y.), PMID 8904907
- DOI
- 10.1038/s41386-025-02319-5
- PMID
- 41565998
- NLM abbreviation
- Neuropsychopharmacology
- ISSN
- 1740-634X
- eISSN
- 1740-634X
- Publisher
- Nature
- Grant note
- 5R01DA037216 / U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) Roy J. Carver Charitable Trust / University of Iowa (UI) DA049139 / U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) Merit Award, IO1BX004440 / U.S. Department of Veterans Affairs (Department of Veterans Affairs) R01DA052953 / U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) DA048055 / U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)
- Language
- English
- Electronic publication date
- 01/21/2026
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neurosurgery
- Record Identifier
- 9985130237802771
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