Divergent Effects of Ketamine and the Serotoninergic Psychedelic 2,5-Dimethoxy-4-Iodoamphetamine on Hippocampal Plasticity and Metaplasticity.
Zarmeen Zahid, Ziyad W. Sultan, Bryan M Krause, Cody J. Wenthur, Robert A Pearce, Matthew I Banks
Psychedelic Medicine September 1, 2024 DOI: 10.1089/psymed.2023.0061 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | C57BL/6J mice |
| Interventions | Ketamine 2 5-Dimethoxy-4-iodoamphetamine (DOI) |
| Duration | 24 hours after treatment |
| Topics | Esketamine Ketamine Serotonin |
| Keywords | Psychedelic-therapy Brain-plasticity Mental-health Pharmacology |
| Citations | 5 |
| Key findings | 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. |
Abstract
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. 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 stratum radiatum of CA1 in response to stimulation of Schaffer collateral fibers before and after induction of short-term and long-term potentiation (STP, LTP). Before LTP induction, responses differed across treatment groups (F1,2 = 5.407, p = 0.00665), with fEPSPs enhanced in slices from DOI-treated animals (p = 0.0182), but not ketamine-treated animals (p = 0.9786), compared to saline. There were no treatment effects on LT (F1,2 = 0.6, p = 0.516), but there were on STP (F1,2 =, p = 0.0167), with enhanced STP in DOI-treated (p = 0.0352) but not ketamine-treated (p = 0.9999) animals compared to saline. A presynaptic component to the mechanism for the DOI effects was suggested by (1) significantly enhanced FV amplitudes (F1,2 = 3.17, p = 0.049) in DOI-treated (p = 0.0457) but not ketamine-treated animals compared to saline (p = 0.8677); and (2) enhanced paired pulse ratios (F1,2 = 3.581, p = 0.0339) in slices from DOI-treated (p= 0.0257) but not ketamine-treated animals (p = 0.4845) compared to saline. 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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 5
- Psychedelic medicine: mechanisms, evidence, and translation to practice BMJ February 23, 2026
- The emotional architecture of the psychedelic brain Trends in Cognitive Sciences August 18, 2025
- Lysergic acid diethylamide pretreatment prolongs brain-stimulation induced neural activity changes. Brain Stimulation May 21, 2026
- Psychedelics and Autism Therapy: A Review of Current Research and Future Directions Current Issues in Molecular Biology April 18, 2026
- Lysergic acid diethylamide pretreatment prolongs brain-stimulation induced neural activity changes bioRxiv (Cold Spring Harbor Laboratory) December 19, 2025
Cites 63
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- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
and 58 more in the library