Lack of antidepressant effects of burst-suppressing isoflurane anesthesia in adult male Wistar outbred rats subjected to chronic mild stress

PLoS One. 2020 Jun 24;15(6):e0235046. doi: 10.1371/journal.pone.0235046. eCollection 2020.

Abstract

Post-ictal emergence of slow wave EEG (electroencephalogram) activity and burst-suppression has been associated with the therapeutic effects of the electroconvulsive therapy (ECT), indicating that mere "cerebral silence" may elicit antidepressant actions. Indeed, brief exposures to burst-suppressing anesthesia has been reported to elicit antidepressant effects in a subset of patients, and produce behavioral and molecular alterations, such as increased expression of brain-derived neurotrophic factor (BDNF), connected with antidepressant responses in rodents. Here, we have further tested the cerebral silence hypothesis by determining whether repeated exposures to isoflurane anesthesia reduce depressive-like symptoms or influence BDNF expression in male Wistar outbred rats (Crl:WI(Han)) subjected to chronic mild stress (CMS), a model which is responsive to repeated electroconvulsive shocks (ECS, a model of ECT). Stress-susceptible, stress-resilient, and unstressed rats were exposed to 5 doses of isoflurane over a 15-day time period, with administrations occurring every third day. Isoflurane dosing is known to reliably produce rapid EEG burst-suppression (4% induction, 2% maintenance; 15 min). Antidepressant and anxiolytic effects of isoflurane were assessed after the first, third, and fifth drug exposure by measuring sucrose consumption, as well as performance on the open field and the elevated plus maze tasks. Tissue samples from the medial prefrontal cortex and hippocampus were collected, and levels of BDNF (brain-derived neurotrophic factor) protein were assessed. We find that isoflurane anesthesia had no impact on the behavior of stress-resilient or anhedonic rats in selected tests; findings which were consistent-perhaps inherently related-with unchanged levels of BDNF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, Inhalation
  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Depressive Disorder / etiology
  • Depressive Disorder / physiopathology
  • Depressive Disorder / prevention & control*
  • Disease Models, Animal
  • Electroconvulsive Therapy / methods
  • Electroencephalography
  • Electroshock / adverse effects
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Humans
  • Isoflurane / administration & dosage
  • Isoflurane / pharmacology*
  • Male
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiopathology
  • Rats, Wistar
  • Stress, Psychological / etiology
  • Stress, Psychological / physiopathology
  • Stress, Psychological / prevention & control*

Substances

  • Anesthetics, Inhalation
  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • BDNF protein, human
  • Isoflurane

Grants and funding

This work has been supported by the Academy of Finland (T.R.) [www.aka.fi; grants 276333, 305195, 312664], the Finnish Cultural Foundation (M.R.) [www.skr.fi] and the Finnish Pharmaceutical Society (M.R.) [www.pro.tsv.fi/finpharmsociety]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.