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

• Published in: Addiction biology Vol. 27; no. 2; pp. e13138 - n/a
• Main Authors: Wei, Gengze, Sirohi, Sunil, Walker, Brendan M.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2022
• Subjects: Agonists; Alcohol; alcohol dependence; Alcoholism - complications; Alcoholism - drug therapy; Animals; Drug dependence; Dynorphin; Ethanol; Executive function; intermittent ethanol vapor; kappa opioid receptor; Male; medial prefrontal cortex; Memory Disorders; Memory, Short-Term; Mental task performance; Narcotics; Opioid receptors (type kappa); Prefrontal cortex; Prefrontal Cortex - metabolism; Rats; Rats, Wistar; Receptors, Opioid, kappa; Rodents; Short term memory; Therapeutic targets; withdrawal; working memory; intermittent ethanol vapor; medial prefrontal cortex; withdrawal; kappa opioid receptor; alcohol dependence; working memory
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.13138

Impaired working memory is one symptom contributing to compromised executive function in alcohol use disorder (AUD). Dysregulation of cortical dynorphin (DYN) and κ‐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‐naïve rats was compared with that of alcohol‐dependent and nondependent rats using a DYN A‐stimulated [35S]GTPγS 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‐naïve 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. A role for medial prefrontal cortex (mPFC) kappa opioid receptors (KORs) in working memory deficits induced by chronic intermittent vapor exposure during spontaneous withdrawal was investigated. mPFC KORs showed increased function in alcohol‐dependent rats, and site‐specific KOR activation in the mPFC produced working memory deficits. KOR antagonism in the mPFC ameliorated alcohol dependence‐induced working memory deficits and identifies a novel therapeutic target to treat alcohol use disorder.