Dysregulated kappa-opioid receptors in the medial prefrontal cortex contribute to working memory deficits in alcohol dependence

Impaired working memory is one symptom contributing to compromised executive function in alcohol use disorder (AUD). Dysregulation of cortical dynorphin (DYN) and kappa-opioid receptors (KORs) has been implicated in alcohol dependence-induced impairment in executive function. The present experiments test the hypothesis that dysregulated medial prefrontal cortex (mPFC) KORs contribute to impaired working memory in alcohol dependence. Alcohol dependence was induced in male Wistar rats via 4 months of intermittent ethanol vapor exposure prior to training/testing in an mPFC-dependent working memory task (delayed nonmatching-to-sample task; DNMST). mPFC KOR function in alcohol-naive rats was compared with that of alcohol-dependent and nondependent rats using a DYN A-stimulated [35(S)]GTP gamma S coupling assay. A functional role for mPFC KORs in the regulation of working memory was assessed via intra-mPFC infusions of a KOR agonist prior to assessment in the DNMST, and the contribution of mPFC KORs to compromised working memory in dependence was assessed via mPFC infusions of the KOR antagonist norbinaltorphimine (nor-BNI). In alcohol-dependent rats, impaired performance in the DNMST confirmed compromised working memory. Furthermore, DYN A-stimulated mPFC KOR function was pathologically increased in alcohol-dependent rats compared with nondependent and alcohol-naive rats. Additionally, mPFC KOR involvement in working memory was functionally confirmed by intra-mPFC KOR agonist-induced deficits in DNMST performance. Importantly, alcohol dependence-induced impairment in the DNMST was ameliorated by intra-mPFC KOR antagonism. Regulation of working memory by mPFC KORs and alcohol dependence-induced dysregulation of mPFC KOR function identify a novel therapeutic target to treat AUD-related symptoms of working memory impairment.