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

Abstract

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 h 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 stratum radiatum of CA1 in response to stimulation of Schaffer collateral fibers before and after induction of short-term potentiation (STP) and long-term potentiation (LTP).

Results: Before LTP induction, responses differed across treatment groups (F2,67 = 5.407, p = 0.00665), with fEPSPs enhanced in slices from DOI-treated animals (p = 0.0182), but not in ketamine-treated animals (p = 0.9786), compared with saline. There were no treatment effects on LTP (F2,56 = 0.6, p = 0.516), but there were on STP (F2,56 = 4.409, p = 0.0167), with enhanced STP in DOI-treated animals (p = 0.0352), but not in ketamine-treated (p = 0.9999) animals, compared with saline. A presynaptic component to the mechanism for the DOI effects was suggested by (1) significantly enhanced FV amplitudes (F2,61 = 3.17, p = 0.049) in DOI-treated animals (p = 0.0457), but not in ketamine-treated animals, compared with saline (p = 0.8677); and (2) enhanced paired pulse ratios (F2,61 = 3.581, p = 0.0339) in slices from DOI-treated animals (p = 0.0257), but not in ketamine-treated animals (p = 0.4845), compared with saline.

Conclusions: DOI, but not ketamine, induced significant neuroplastic and metaplastic effects at hippocampal CA1 synapses 24 h after treatment, likely in part via a presynaptic mechanism.