(2R,6R)-HYDROXYNORKETAMINE TARGETING THE BASOLATERAL AMYGDALA REGULATES FEAR MEMORY

Abstract Background (2R,6R)-Hydroxynorketamine (HNK), a ketamine metabolite, is a promising next-generation antidepressant known for its rapid and long-lasting effects. Recent studies have explored its impact on memory, yet its influence on fear memory extinction remains uncharted. Objective We investigated (2R,6R)-HNK's effects on synaptic transmission and plasticity in the basolateral amygdala (BLA) and its role in auditory fear memory extinction. Method Adult male C57BL/6J mice were utilized for extracellular electrophysiological recordings and fear conditioning tests. Result (2R,6R)-HNK at 30 mg/kg increased cfos-positive cell count in the BLA and dose-dependently enhanced long-term potentiation (LTP) induction and maintenance. Moreover, (2R,6R)-HNK improved BLA synaptic transmission. Both local and systemic administration of (2R,6R)-HNK reduced recent and remote fear memory retrieval and inhibited spontaneous remote fear memory recovery. Conclusion (2R,6R)-HNK could be a potential treatment for posttraumatic stress disorder (PTSD) patients by regulating BLA synaptic function and fear memory modulation.