Cornichon Homolog-3 (Cnih3) deletion impairs spatial memory, reward-cue association, and fentanyl self-administration behavior.

Opioid misuse remains rampant as new synthetic opioids reach the market. Large-scale genetic tools like the GWAS identify previously unrecognized targets and biomarkers in opioid misuse with hopes of combating the opioid epidemic. One such target is the AMPAR auxiliary protein Cornichon Homolog-3 (human analog: CNIH3, mouse analog: Cnih3), which determines AMPAR subunit composition and kinetics. Though CNIH3 was identified as a gene of interest in OUD, its role in opioid use and accompanying risk factors has not been studied. Using mice with Cnih3 deletion, we assess the role of CNIH3 in risk factors for opioid use, cognition, and opioid use itself. We find that Cnih3 deletion moderately impairs spatial memory, reward-cue association, and reversal learning. Cnih3 deletion also impairs fentanyl-cue association and blunts fentanyl intake during IVSA. We use principal component analysis to pinpoint the dimensions in which Cnih3 deletion impacts behavior in an unbiased manner. Additionally, we identify in previously published human data that single-nucleotide polymorphisms are more protective against progression to daily opioid use in women than in men, suggesting a potential sex-specific role of CNIH3. These findings highlight an important role of CNIH3 in opioid use through learning and memory processes that may differ between males and females.