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

Abstract

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 [35 S ]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 dependenceinduced 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.

Dynorphin / kappa-opioid receptor regulation of excitation-inhibition balance toggles afferent control of prefrontal cortical circuits in a pathway-specific manner

“…Dysregulated expression of PFC Dyn / KOR and/or KOR availability has been observed in patients who have experienced childhood trauma, as well as chronic exposure to alcohol, opioids, and/or life-long cannabis [ 16 , 18 , 63 – 66 ]. This has been implicated in mediating cognitive deficits during alcohol and opioid withdrawal.…”

Dynorphin / kappa-opioid receptor regulation of excitation-inhibition balance toggles afferent control of prefrontal cortical circuits in a pathway-specific manner

“…Thus, Dyn release during motivationallycharged behaviors may influence mPFC processing by KORs expressed selectively within mPFC circuits and afferent inputs. Dysregulated PFC Dyn / KOR expression and/or binding is observed with low social status, with childhood trauma, chronic exposure to alcohol, opioids, and/or life-long cannabis exposure, and has been implicated in mediating cognitive deficits during alcohol and opioid withdrawal (Wei et al, 2022;Abraham et al, 2021;Bazov et al, 2013;Bazov et al, 2018;Peckys and Hurd, 2001;Lutz et al, 2018). Furthermore, KOR agonists produce psychotomimetic effects in humans and animal models.…”

“…Opioid peptides and receptors, including kappa-opioid receptors (KORs) and their endogenous ligand dynorphin (Dyn), are expressed in mPFC circuits (Brockway and Crowley, 2020; Casello et al ., 2022; Zhong et al ., 2022; Sohn et al, 2014). Dyn in the mPFC has been implicated in promoting negative affect and anxiety-like behavior, alcohol and morphine dependence-induced cognitive deficits, and stress-induced increases in cardiovascular function (Tejeda et al, 2013; Tejeda et al, 2015; Abraham et al, 2021; Fassini et al, 2015; Wei et al, 2022; Wall and Messier, 2002). Further, KOR phosphorylation (an index of recent KOR activation) is observed in the mPFC after various stressors (Abraham et al ., 2021).…”

Consequences of adolescent drug use

“…Recent studies have reported deficits in recall of an extinguished fear response [54], deficits in reversal learning [43], and impaired working memory [55,56] following AAE. Unsurprisingly, alcohol's effect on the medial prefrontal cortex (mPFC) is an important factor in producing these cognitive deficits [57]. Indeed, AAE has been reported to cause a myriad of effects in the mPFC, including greater PL spine density [54], decreased infralimbic cortex (IL) spine density [58], altered PL pyramidal neuron excitability [55,59], activation of microglia and pro-inflammatory factors [60], decreases in resting state connectivity between PFC subregions [61], and decreases in myelinated fiber density (in males but not females) [62].…”