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 2+ -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.
Gupta et al. (Wed,) studied this question.