Introduction: Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction. Methods: Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h). Results: Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine's subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration. Conclusion: Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.
