Abstract

Clinical research shows that serotonergic psychedelics (i.e. psychoactive agonists at 5-HT2A receptors) are efficacious as rapid and long-lasting treatments of various psychiatric disorders such as major depressive disorder and anxiety. Despite this, the mechanisms underlying this therapeutic benefit remain unknown. These drugs are also evidenced to increase various measures of structural and functional plasticity in vitro. These pro-neuroplastic effects likely play a role in the therapeutic action of these drugs, but it is unclear whether psychedelics acutely induce plasticity, or whether they do so post-acutely. Further, it is unclear whether enduring behavioral change is due to short term changes in plasticity or longer-term changes to metaplasticity and if these can be observed in vivo.

Using both ex vivo and in vivo electrophysiology in mice, I explored the effects of psychedelic administration on synaptic excitability and plasticity in the hippocampus (HPC) and along the ventral hippocampus (vHPC) – medial prefrontal cortex (mPFC) pathway, areas which are highly dysregulated in psychiatric illness and are also reliably dysregulated in stress induced phenotypes in rodent models. Ex vivo experiments were conducted on male C57BL/6J mice (3-5 mo) in which a recording and stimulating electrode was placed in the schaffer collaterals of the HPC. Recordings of stimulus evoked responses were obtained 24 hours after administration of either saline, ketamine (1 mg/kg) or serotonergic psychedelics DOI (1 mg/kg). In the in vivo experiments bipolar stimulating electrode was placed in CA1 of ventral hippocampus (vCA1), and a recording electrode was placed in ipsilateral mPFC.

Recordings of passive and evoked responses were obtained at baseline, 4 hr, 1, 3, and 7d after IP injection of either the serotonergic psychedelic psilocybin (3 mg/kg), 4-AcO-DMT (1 mg/kg), non-hallucinogenic serotonergic DMT analogue 6-FDET (1 mg/kg), or saline (5 mg/ml). I observed evidence for metaplasticity in the hippocampus, and increased excitability but not metaplasticity in mPFC synapses during an acute window after psychedelic administration. This increase in excitability in limbic regions may underlie the observed therapeutic benefit shown in clinical trials, though more investigation into the neural mechanistic basis for therapeutic change is necessary.