Kappa opioid receptor antagonism protects working memory performance from mild stress exposure in Rhesus macaques

Extensive preclinical and emerging clinical evidence point to an involvement of the kappa opioid receptor (KOR) in brain networks that promotes neurobehavioral stability. KOR expression in mesolimbic and mesocortical pathways has been the basis for characterizing the role of this receptor system in regulating motivation and emotion; however, the involvement of the KOR system in higher-order executive processes such as working memory (WM) is not well-understood. WM is readily impaired with uncontrollable stress exposure and is dys-regulated in many neurobehavioral disorders. To empirically evaluate the role of the KOR system on WM per-formance, we administered a selective KOR antagonist, NMRA-140 (0, 0.1, 0.3, 1.0 mg/kg, intramuscular) to monkeys under both stress and non-stress conditions. In this study, NMRA-140 was co-administered with FG7142, a benzodiazepine inverse agonist, known to produce a mild stress response and to impair WM function in monkeys. NMRA-140 protected WM performance from the detrimental effects of FG7142-induced stress and exhibited no significant effect under non-stress conditions. Collectively, these data highlight the functional in-fluence of the KOR system in mediating stress-induced dysfunction of executive processes and suggest that modulating KOR activity could offer therapeutic benefit in stress-related neurobehavioral disorders.

Automated summary

This study demonstrates the protective role of KOR on working memory function and its crucial regulatory function under stress conditions. These findings provide important insights for the development of therapeutic strategies for stress-related neurobehavioral disorders.