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

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 depressivelike 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 burstsuppression (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.

Rethinking data treatment: The sucrose preference threshold for anhedonia in stress-induced rat models of depression

“…Only one study presented a clear definition of what was considered abnormal 7 . Three studies separated their animals based on a within-subject decrease in sucrose consumption 16,17 or preference (the proportion of the total liquid intake that was made up of the sucrose solution) 19 . How much rats had to change their sweet intake from their initial values to be considered stress-susceptible varied from 25% to 50%.…”

“…In some instances, these stressed animals -considered non-anhedonic -were excluded from further analysis, focusing the study only on animals considered "susceptible" to the stress protocol [7][8][9][10][11][12][13][14] . In other studies, the non-anhedonic animals formed a new cohort and were considered "resilient" to the effects of stress on reward sensitivity [15][16][17][18][19][20][21][22][23][24] . The concept of susceptibility and resilience to stress is not new.…”

Pimavanserin treatment increases plasma brain-derived neurotrophic factor levels in rats

“…Therefore, the effects of isoflurane on BDNF levels cannot be ruled out. However, a number of studies have reported inconsistent data on the influence of isoflurane on BDNF levels in rodents suggesting the need for additional studies to determine the dose and time-dependent effects of isoflurane on BDNF levels ( Zhang et al, 2014 ; Antila et al, 2017 ; Zhang et al, 2019 ; Theilmann et al, 2020 ). It is important to note that we found significant changes in plasma, but not serum BDNF levels following chronic treatment with Fluoxetine or Pimavanserin.…”

Isoflurane Rescue Schizophrenia-related Deficits through Parvalbumin-positive Neurons in the Dentate Gyrus

“…Antipsychotic medications can cure positive symptoms like hallucinations and delusions, but they are nearly never effective for treating cognitive problems [3]. Volatile anesthetics, such as nitrous oxide (N2O), isoflurane and sevoflurane, have recently drawn keen attention for their therapeutic effects on mental illnesses due to their easy administration, safety, and rapid onset of action [4][5][6]. Recent research suggests that inhaling sevoflurane at low concentration for several days can attenuate the symptoms of schizophrenia patients and schizophrenia-like phenotypes in mice, such as hyper-locomotion and social interaction deficit [7].…”