Carbonic anhydrase 4 disruption and pharmacological inhibition reduce synaptic and behavioral adaptations following oxycodone withdrawal

Subhash C Gupta; Rebecca J. Taugher-Hebl; Ali Ghobbeh; Marshal T. Jahnke; Rong Fan; Ryan T. LaLumiere; John A. Wemmie

doi:10.1101/2025.01.23.634619

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Carbonic anhydrase 4 disruption and pharmacological inhibition reduce synaptic and behavioral adaptations following oxycodone withdrawal

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Carbonic anhydrase 4 disruption and pharmacological inhibition reduce synaptic and behavioral adaptations following oxycodone withdrawal

Subhash C Gupta, Rebecca J. Taugher-Hebl, Ali Ghobbeh, Marshal T. Jahnke, Rong Fan, Ryan T. LaLumiere and John A. Wemmie

bioRxiv

Cold Spring Harbor Laboratory, 1.1

01/25/2025

DOI: 10.1101/2025.01.23.634619

PMCID: PMC11785184

PMID: 39896547

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https://doi.org/10.1101/2025.01.23.634619View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

The ongoing opioid crisis underscores the need for innovative treatments targeting neurobiological mechanisms underlying opioid-seeking behaviors and relapse. Here we explored the role of carbonic anhydrase 4 (CA4) in modulating synaptic adaptations to oxycodone withdrawal in mice. We disrupted CA4 genetically and inhibited it pharmacologically with acetazolamide (AZD), a carbonic anhydrase inhibitor used clinically. We found that oxycodone withdrawal increased AMPAR/NMDAR ratio and synaptic recruitment of calcium-permeable AMPARs in nucleus accumbens core (NAcC) medium spiny neurons (MSNs). Synaptic changes required an extended period of abstinence, generalized across opioids including morphine and heroin, were specific to D1 dopamine receptor-expressing MSNs, and were prevented by CA4 disruption. AZD administration in vitro and in vivo reversed the synaptic alterations, and effects of AZD depended on CA4 and acid sensing ion channel 1A (ASIC1A). Interestingly, abstinence from oxycodone did not affect dendritic spine density in NAcC MSNs, in contrast to previously observed effects of abstinence from cocaine. Finally, in an oxycodone self-administration paradigm, CA4 disruption and AZD reduced drug-seeking behaviors following 30 days of forced abstinence. Together, these findings identify a critical role for CA4 in synaptic adaptations in opioid withdrawn mice and drug-seeking behavior. Moreover, they suggest pharmacological inhibitors of CA4 may hold therapeutic potential for reducing opioid-seeking and relapse in opioid use disorder.

Neuroscience

Details

Title: Subtitle: Carbonic anhydrase 4 disruption and pharmacological inhibition reduce synaptic and behavioral adaptations following oxycodone withdrawal
Creators: Subhash C Gupta - University of Iowa
Rebecca J. Taugher-Hebl - University of Iowa
Ali Ghobbeh - University of Iowa
Marshal T. Jahnke - University of Iowa
Rong Fan - University of Iowa
Ryan T. LaLumiere - University of Iowa
John A. Wemmie - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
Edition: 1.1
DOI: 10.1101/2025.01.23.634619
PMID: 39896547
PMCID: PMC11785184
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory
Number of pages: 49
Language: English
Date posted: 01/25/2025
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neurosurgery
Record Identifier: 9984786449102771

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