Jones, Nicholas; (2003) Unconditioned escape behaviour in rats: Implications for pre-clinical research into pathological extreme anxiety disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Pre-clinical models of anxiety act as paradigms to facilitate investigation into the biological bases of anxiety and assess the efficacy of anxiolytic compounds. Models that measure the flight/escape component of rodents' defensive behaviours are potentially analogous to the symptoms of extreme anxiety conditions (e.g. panic disorder [PD] and post traumatic stress disorder [PTSD]) as opposed to generalised anxiety disorder (GAD). The unstable elevated exposed plus maze (UEEPM) is a novel model of extreme anxiety in rats that possesses elements of face and construct validity. The current thesis aimed to investigate the pharmacological substrates of escape in the UEEPM. As pre-clinical models are susceptible to a range of methodological variables, experiments 1 and 2 examined the effects of circadian phase, test illumination and strain of subject in the UEEPM and a battery of anxiety models. Anxiety-related behaviour on all tests was independent of circadian phase and illumination. Clear strain differences in escape behaviour were observed, suggesting the use of strains optimal for observing panicolytic and panicogenic drug effects may benefit pre-clinical research into extreme anxiety disorders. Experiments 3 and 5 assessed the predictive validity of the UEEPM by examining the behavioural profiles of compounds known to affect the symptoms of PD, PTSD and GAD. Drugs which potentiate the symptoms of PD and PTSD increased escape in the UEEPM. Treatment regimes effective for PD decreased escape, whereas those effective for GAD were without effect. Thus, the UEEPM displayed bi-directional predictive validity as a model of extreme, as opposed to generalised, anxiety disorders. Experiment 4 revealed the behavioural effects of the 5-HT2C/2B receptor agonist m- chlorphenylpiperazine (mCPP) in the UEEPM were attenuated by the 5-HT2C antagonist SB-242084. Thus, escape in the paradigm may be mediated, at least in part, by the 5-HT2C receptor and 5-HT2C antagonists may hold potential as therapeutic agents for panic-related disorders.

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