Available online at www.sciencedirect.com Behavioural Brain Research 189 (2008) 180–190 Research report The role of the read through variant of acetylcholinesterase in anxiogenic effects of predator stress in mice Robert Adamec a,∗ , David Head a , Hermona Soreq b , Jacqueline Blundell c a Department of Psychology, Memorial University, 232 Elizabeth Avenue, St. John’s, NF, A1B 3X9 Canada b The Hebrew University of Jerusalem, Jerusalem, Israel c UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Boulevard Dallas, TX 75390-9023, USA Received 31 October 2007; received in revised form 19 December 2007; accepted 27 December 2007 Available online 5 January 2008 Abstract This study examined the role of the read through variant of acetylcholinesterase (AChE-R) in lasting changes in murine affective behavior produced by a brief predator stress. AChE-R is elevated by stress in limbic cholinergic circuits implicated in anxiogenic effects of predator stress. The expression of AChE-R was blocked with a systemically administered central acting antisense oligonucleotide for AChE-R (EN101). EN101 was injected at multiple points prior to and after a predator stress in male C57 mice. Seven days after the last injection, behavior was tested. Predator stress caused a significant increase in startle amplitude, which EN101 blocked. This effect was specific to EN101, as the negative control inactive form of EN101, INVEN101 was without effect on stress effects on startle. Neither EN101 nor INVEN101 altered the anxiogenic effects of predator stress on behavior in the elevated plus maze, and both drugs partially reduced stress suppression of time active in the hole board. In the light dark box test, INVEN101 exhibited a weak block of stress effects on behavior for reasons which are unclear. Taken together, findings support the view that multiple neural systems are responsible for the different changes in behavior produced by predator stress. Present findings also suggest a role for AChE-R in specific anxiogenic (hyperarousal) effects following predator stress. Since AChE-R manipulations took place starting 23 h prior to predator stress and continued 48 h after predator stress, further research is necessary to determine the role of AChE-R in initiation and/or consolidation of hyperarousal effects of predator stress. © 2008 Elsevier B.V. All rights reserved. Keywords: Acetylcholinesterase; Anxiety; Cat exposure; Elevated plus maze; Hole board; Lasting effects; Light dark box; Mice; Predator stress; PTSD; Startle 1. Introduction Severe stress may precipitate affective disorder [41,42,58,75] lasting up to a life time after traumatic stress [86]. Stress and affective disorder are serious problems given that 50–60% of North Americans experience traumatic stress in their lifetimes, and of those 6.8–15% may develop posttraumatic stress disorder (PTSD) [43,44]. Moreover, affective psychopathology follows terrorist attacks, such as the one that took place in New York on 11 September 2001 [37,46,73]. World terrorism makes more urgent the need to understand mechanisms of stressor induced changes in brain function underlying affective psychopathol- ogy and their reversal. Preclinical animal models are a valuable resource in this effort. ∗ Corresponding author. Tel.: +1 709 737 7671; fax: +1 709 737 2430. E-mail address: radamec@mun.ca (R. Adamec). There is no ideal animal model of mechanisms of stress induced affective disorder. However, several are promising, reflecting different aspects of stress effects on affect. Promi- nent among these is fear conditioning. Work in this area has advanced our understanding of mechanisms of neural plasticity underlying acquisition and extinction of enhanced fear response to simple and complex sensory stimuli (contextual condition- ing) [22,50,66,72]. Neural plasticity and long term potentiation (LTP) in amygdala circuitry likely plays a central role in both conditioning and extinction of fear [18,22,54,55,70–72]. More- over, there is clinical interest in fear conditioning findings as a guide to post-stressor prophylactic intervention in humans [36,59] and to improvement of therapeutic outcome of exposure therapies [54]. Studies of lasting changes in affect of exposure to species- relevant, life threatening situations provide models of stressor induced affective psychopathology with ecological validity. Exposure of rodents to predator stimuli is fear provoking and 0166-4328/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2007.12.023