¹Eli Lilly and Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, IN, USA

Correspondence: Dr GG Nomikos, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA. Tel: +1 317 433 2541; Fax: +1 317 276 5546; E-mail: gnomikos@lilly.com

Received 24 August 2004; Revised 13 October 2004; Accepted 19 October 2004; Published online 8 December 2004.

Abstract

Anxiety disorders may result from an overexpression of aversive memories. Evidence suggests that the hippocampal cholinergic system could be the point of convergence of anxiety and memory. We propose that clinically effective anxiolytics may exert their effect by interfering with this integration mechanism. To assess anxiety and aversive memory, we used the shock-probe burying test. A reduction in anxiety in this test is indicated by decreased burying, whereas impaired cognition is reflected by an increased number of probe-contacts and/or reduced retention latency. Both an aversive stimulus and the memory of that stimulus significantly increased hippocampal acetylcholine (ACh) levels (Experiment 1). In fact, the memory of the event seemed to be more important than the event itself since the aversive memory induced a greater increase in hippocampal ACh. Injections (i.p.) of fluoxetine (Prozac®) reduced burying behavior, while not affecting probe contacts or retention latency (Experiment 2). Although injections of fluoxetine did not affect basal hippocampal ACh efflux (Experiment 3), fluoxetine abolished the increase in ACh induced by the aversive stimulus and the memory of that stimulus (Experiment 4), emphasizing the significance of aversive memories in anxiety disorders. These actions may be mediated by a decrease in the event-related enhancement in cholinergic neurotransmission through M1 cholinergic receptors (Experiment 5). Therefore, anxiety disorders may stem from an unopposed formation of aversive memories and clinically effective anxiolytics hinder the association between emotional and cognitive processing. This reduces the emotional impact of aversive memories, thereby opposing consequent anxiety.