We are pleased to announce an upcoming seminar by Dr. Zanos, the Director of the Translational Neuropharmacology Lab at the Center for Applied Neuroscience & Department of Psychology of the University of Cyprus.

In this seminar, Dr. Zanos will discuss how unlike traditional monoamine-based antidepressants that require weeks to exert effects, ketamine alleviates depression within hours, though its clinical use is limited by side effects. While ketamine was initially thought to work primarily through NMDA receptor (NMDAR) inhibition, his research reveals a more complex mechanism. Dr. Zanos will demonstrate that NMDAR inhibition alone cannot explain ketamine’s sustained antidepressant effects, as other NMDAR antagonists like MK-801 lack similar efficacy.

Instead, the (2R,6R)-hydroxynorketamine (HNK) metabolite appears critical, exhibiting antidepressant effects without ketamine’s side effects. Paradoxically, his findings suggest an inverted U-shaped dose-response relationship where excessive NMDAR inhibition may actually impede antidepressant efficacy, while some level of NMDAR activation is necessary. The antidepressant actions of ketamine and (2R,6R)-HNK require AMPA receptor activation, leading to synaptic potentiation and upregulation of AMPA receptor subunits GluA1 and GluA2. Furthermore, NMDAR subunit GluN2A appears necessary and possibly sufficient for these effects.

This research establishes NMDAR-GluN2A activation as a common downstream effector for rapid-acting antidepressants, regardless of their initial targets, offering promising directions for developing next-generation antidepressants with improved efficacy and reduced side effects.

Learn more about our work on the lab’s Instagram page (@neuropharmlab).