Abstract

Opioid misuse remains rampant as potent synthetic opioids such as fentanyl flood the market. Large-scale genetic tools like the GWAS identify previously unrecognized targets and biomarkers in opioid misuse with the hopes of combating the opioid epidemic and opioid use disorder (OUD). One such target is the AMPA receptor (AMPAR) auxiliary protein Cornichon Homolog-3 (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 a 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. Next, we use Western Blotting to determine AMPAR subunit activation and expression in key opioid-related brain regions: the medial prefrontal cortex (mPFC), hippocampus (HPC), and nucleus accumbens (NAc), in naïve and IVSA-trained male and female CNIH3 KO and WT mice to assess CNIH3-driven regulation of glutamatergic transmission in the context of opioid learning. Preliminary data suggest no basal differences, but sex-specific activation of GluA1 in the mPFC after IVSA. These findings highlight an important role of CNIH3 in opioid use through learning and memory processes and AMPAR-mediated plasticity that differ between males and females.

Committee Chair

Jose Moron-Concepcion

Committee Members

Anne Murphy; Arpana Agrawal; Hugo Tejeda; Ream Al-Hasani

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

12-31-2025

Language

English (en)

Author's ORCID

0000-0002-6849-7979

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