CO 2 Reactivity but Not CO 2 ‐Induced Orexin/c‐Fos Colocalization Differentially Predicts Alcohol‐Seeking Behaviour After Extinction and Retrieval‐Extinction in Rats

ABSTRACT Cues associated with alcohol consumption can trigger cravings, seeking behaviour and relapse after abstinence in individuals with alcohol use disorder (AUD). These conditioned responses can be attenuated through extinction learning, a core component of cue exposure therapy (CET). CET is effective in some individuals with AUD but not all, so it is necessary to develop strategies to identify and intervene with individuals unlikely to benefit from CET. Another method for attenuating conditioned responding is retrieval‐extinction, which renders the original associative memory labile via distinct neural mechanisms. We recently demonstrated that CO 2 reactivity predicts extinction memory for both fear and food cues, and fear memory after retrieval‐extinction, and CO 2 ‐induced orexin/c‐Fos colocalization predicts fear extinction memory. The purpose of the current study was to examine whether the predictive power of CO 2 reactivity might extend to alcohol‐seeking behaviour after extinction or retrieval‐extinction in male and female rats. We also examined the relationship between CO 2 reactivity, return of alcohol‐seeking behaviour and CO 2 ‐induced orexin/c‐Fos colocalization. Male and female rats first underwent alcohol drinking induction in the homecage followed by dependence via exposure to chronic intermittent ethanol vapour or control air and homecage drinking. All rats then underwent Pavlovian alcohol conditioning followed by either standard extinction or retrieval‐extinction. They then received a long‐term memory (LTM) test and CO 2 challenge followed by euthanasia for brain harvesting. CO 2 reactivity differentially predicted LTM after extinction and retrieval‐extinction. There were no relationships between orexin/c‐Fos colocalization and CO 2 reactivity or LTM. The predictive power of CO 2 reactivity extends to alcohol‐seeking behaviour after extinction and retrieval‐extinction in alcohol dependent and nondependent male and female rats, while its relationship with orexin/c‐Fos colocalization does not. CO 2 reactivity could be used as a screening tool to determine whether an individual may be a good candidate for CET or a retrieval‐extinction–based approach.