Divergent Effects of Ketamine and the Serotoninergic Psychedelic 2,5-Dimethoxy-4-Iodoamphetamine on Hippocampal Plasticity and Metaplasticity.

Introduction: Serotonergic psychedelics and ketamine produce rapid and long-lasting symptomatic relief in multiple psychiatric disorders. Evidence suggests that despite having distinct molecular targets, both drugs may exert therapeutic benefit via their pro-neuroplastic effects. Following treatment with ketamine or serotonergic psychedelics, patients are reported to be more open to behavioral change, which is leveraged for psychotherapy-assisted reframing of narratives of the self. This period of enhanced behavioral change is postulated to be supported by a post-treatment window of enhanced neural plasticity, but evidence for such 'metaplastic' effects is limited. In this study, we tested for neural plasticity and metaplasticity in murine hippocampus. Methods: Brain slices were obtained from C57BL/6J mice 24 hours after treatment (intraperitoneal injection) with saline, ketamine, or the serotonergic psychedelic 2,5-Dimethoxy-4-iodoamphetamine (DOI). Extracellular fiber volleys (FVs) and field excitatory postsynaptic potentials (fEPSPs) were recorded in Results: Before LTP induction, responses differed across treatment groups (F Conclusions: DOI, but not ketamine, induced significant neuroplastic and metaplastic effects at hippocampal CA1 synapses 24 hours after treatment, likely in part via a presynaptic mechanism.