The role of the read through variant of acetylcholinesterase in anxiogenic effects of predator stress in mice

Head, David Martin (2008) The role of the read through variant of acetylcholinesterase in anxiogenic effects of predator stress in mice. Masters thesis, Memorial University of Newfoundland.

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Abstract

The goal of this study was to examine the role of the read-through variant of acetylcholinesterase (AChE-R) in the changes in affective behaviour using the predator stress model of PTSD. This read through variant has been shown to exist at higher levels in the brain following stress (Pick, Flores-Flores, & Soreq, 2004, Meshorer et al., 2002). -- The role of acetylcholinesterase in predator stress was examined in mice using a novel drug EN 101, a systematically administered central acting antisense mRNA for AChE-R. Research by Pollak at el. (2005) demonstrated that cholinergic enhancement using EN 101 produces central and peripheral anti-inflammatory effects. EN101 acts to disrupt the stress precipitated induction of the transcription of the read-through variant of AChE by selectively targeting the mRNA sequence for AChE-R. It is AChE-R in limbic cholinergic circuitry that contributes to anxiogenic effects of traumatic stress (Talma et al., 2003). We administered multiple injections of the drug to the same animals at specific time points prior to and after a predator stress exposure in male C57 mice. This was done to ascertain whether the specific action of EN 101 on AChE-R expression had any effect on stress induced lasting changes in multiple tests of murine affective behaviour. -- Predator stress caused a significant increase in startle amplitude, which EN 101 blocked. This effect was specific to EN 101, as the control inverse drug INVEN101 was without effect on stress effects on startle amplitude. INVEN101 is the inverse of the EN 101 drug consisting of the same mRNA base pairs only in a different order than EN 101. This evidence suggests that EN101 is acting to lower the levels of the read-through variant of acetylcholinesterase in brain regions responsible for startle amplitude (hyperarousal) in rodents. Neither drug affected the impact of predator stress on behaviour in the plus maze, and both drugs partially reduced stress suppression of time active in the hole board. In the light dark box test INVEN101 appeared to exhibit a weak effect partially inhibiting the effects of predator stress on light dark box behaviour. This behavioural change would require replication in order to accept. Together the data reinforce the supposition that multiple neural systems are responsible for the different changes in behaviour produced by predator stress. -- This study provides evidence for a role of AChE-R in specific changes in anxiety-like behaviour following stress. Further research is necessary to pinpoint the exact time window for administration of the drug in order to prevent or inhibit changes in affective behaviour following predator stress. Work is also needed to determine whether other systemic effects of the drug might occur.

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