S136. Is Ketamine Metabolism to Norketamine and (2R,6R)-HNK Necessary for its Sustained Antidepressant-Like Activity and Cortical Neurotransmitter Release in Mice?

Abstract

Ketamine exhibits a rapid and persistent antidepressant (AD) activity, at sub-anesthetic doses in treatment-resistant depressed (TRD) patients and in preclinical studies in rodents. Recent reports suggested that the metabolism of ketamine is essential for antidepressant-like activity. We recently showed that a systemic or intra-cortical administration of (2R,6R)-hydroxynorketamine, (2R,6R)-HNK displays a sustained AD-like effect and activates glutamate and GABA release by pyramidal neurons and interneurons, respectively in the medial prefrontal cortex (mPFC) (Pham et al., 2018). This metabolite is formed in the liver following a systemic ketamine administration. Here, acting on hepatic cytochrome P450 (CYP) enzymes, we assessed whether metabolism to norketamine - (2R,6R)-HNK is necessary or sufficient to induce behavioral and neurochemical changes.