Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition

Abstract

Following repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component of this response may be mediated by the endogenous dynorphin/kappa opioid system in neocortex. In mice, we find that acute morphine withdrawal evokes dynorphin release in the medial prefrontal cortex (PFC) and disrupts cognitive function by activation of local kappa opioid receptors (KORs). Immunohistochemical analyses using a phospho-KOR antibody confirmed that both withdrawal-induced and optically evoked dynorphin release activated KOR in PFC. Using a genetically encoded sensor based on inert KOR (kLight1.2a), we revealed the in vivo dynamics of endogenous dynorphin release in the PFC. Local activation of KOR in PFC produced multi-phasic disruptions of memory processing in an operant delayed alternation behavioral task, which manifest as reductions in response number and accuracy during early and late phases of an operant session. Local pretreatment in PFC with the selective KOR antagonist norbinaltorphimine (norBNI) blocked the disruptive effect of systemic KOR activation during both early and late phases of the session. The early, but not late phase disruption was blocked by viral excision of PFC KORs, suggesting an anatomically dissociable contribution of pre- and postsynaptic KORs. Naloxone-precipitated withdrawal in morphine-dependent mice or optical stimulation of pdynCre neurons using Channelrhodopsin-2 (ChR2) disrupted delayed alternation performance, and the dynorphin-induced effect was blocked by local norBNI. Our findings describe a mechanism for control of cortical function during opioid dependence and suggest that KOR antagonism could promote abstinence.

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

“…aCSF = artificial cerebrospinal fluid; DNMST = delayed nonmatchingto-sample task; IEV = intermittent ethanol vapor; KOR = kappaopioid receptor; mPFC = medial prefrontal cortex; nor-BNI = norbinaltorphimine (Figure3B) and indicative of a canonical mPFC KOR agonist-mediated reduction in working memory performance. These results correspond well with data suggesting that mPFC KOR presynaptic and postsynaptic mechanisms contribute to development of KOR agonist-mediated conditioned place aversions14 and deficits in a delayed alternation task,50 although both of these previous studies utilized systemic KOR agonist injections in conjunction with mPFC nor-BNI infusions whereas the current experiment utilized site-specific mPFC infusions of both the KOR agonist and antagonist. The present results demonstrate mPFC KOR-mediated regulation of working memory and support the hypothesis that alcohol dependence-induced dysregulation of mPFC KOR function could contribute to working memory impairment.…”

“…The present experiment evaluated working memory performance in the DNMST following long‐term IEV during spontaneous withdrawal when BECs had dropped to negligible levels (see Figure 1A) following the daily ethanol vapor exposure. Recent data evaluating DYN/KOR contributions to a mPFC‐dependent delayed alternation task 50 showed that naloxone‐precipitated morphine withdrawal induced deficits that appeared to be blunted by local nor‐BNI administration. However, the presence of naloxone to induce a withdrawal response in conjunction with nor‐BNI could complicate the interpretation of those results, as could the short morphine regimen utilized (i.e., 4 days) to induce deficits compared with the long‐term IEV exposure of the current experiment (i.e., 4 months).…”

Three Mutations Convert the Selectivity of a Protein Sensor from Nicotinic Agonists to S-methadone for Use in Cells, Organelles, and Biofluids

“…Along with other sensors of opioid signaling 11,32 , this study establishes the first genetically encoded fluorescent protein biosensor for an opioid drug, enabling real-time quantification. Furthermore, the enantioselectivity encourages biosensor development to investigate “chiral switching” of other drugs where a single enantiomer substitutes a clinically used racemate 33 .…”

Cocaine self-administration augments kappa opioid receptor system-mediated inhibition of dopamine activity in the mesolimbic dopamine system

“…The Kennedy laboratory is making headway in analytical techniques to allow rapid measurements of dynorphin using microdialysis and liquid chromatography/mass spectrometry, but these methods are not currently widely available ( Li et al, 2009 , Zhou et al, 2013 , Al-Hasani et al, 2018 ). The Chavkin laboratory has recently used the sensor kLight1.2a to detect both pharmacological and endogenously released KOR ligands in mice ( Abraham et al, 2021 ), which would be useful to determine if there is upregulation of DYN after cocaine self-administration. Though several KOR antibodies have been created, they may lack specificity, as is often the case with antibodies against G-protein coupled receptors (for review, see Michel et al, 2009 ).…”