5-HT function in rodent models of anxiety
This thesis attempts to determine the role of 5-hydroxytryptamine (5-HT) in rodent models of anxiety. Using the elevated X-maze it was possible to detect dose-dependent anxiolytic effects of diazepam and dose-dependent anxiogenic effects of FG 7142 (a β-carboline derivative) and idazoxan. The fear-potentiated acoustic startle paradigm also detected the effects of these compounds but the results were neither dose-dependent nor very reproducible. Using the X-maze the 5-HT1A receptor partial agonist ipsapirone had no effect after either acute or chronic treatment, while both the 5-HT2 receptor antagonist, ritanserin, and the 5-HT3 receptor antagonist, ondansetron, had anxiolytic activity after chronic treatment. Using in vivo mirodialysis it was demonstrated that extracellular levels of 5-HT in the ventral hippocampus increase when the animal is on the X-maze, and both diazepam and F 2692 (1-(3'-trifluoro-methylphenyl) 1.4- dihydro 3-amino 4-oxo 6-methyl pyrldazine) reduced the increased 5-HT levels and produced an anxiolytic behavioural profile in the same animal. Thus the inhibition of increased 5-HT release may be important for anxiolytic activity. However, ipsapirone also reduced the increased 5-HT but did not produce an anxiolytic profile. The lack of an anxiolytic effect may be the result of postsynaptic 5-HT1A receptor stimulation. Rats reared in isolation immediately post-weaning (21 days of age) displayed enhanced locomotor activity and an anxiogenic profile on the X-maze. This anxiogenic profile was neither reversed by resocialisation of the isolation-reared rats nor produced by isolation of adult socially housed animals, indicating a permanent developmental change. Isolation-reared rats had reduced stimulated release of 5-HT measured in the frontal cortex, indicating reduced presynaptic function and enhanced responsiveness to agonists acting at postsynaptic 5-HT1A and 5-HT2 receptors, suggesting supersensitivity at these sites. Overall, 5-HT appears to be involved in anxiety with 'anxious' behaviour either on the X-maze or by isolation-rearing causing changes in 5-HT function. Thus one of the mechanisms of action of established and putative anxiolytic and anxiogenic compounds may be via modulation of the ascending dorsal raphe serotonergic neuronal pathways. All work in this thesis was undertaken under Home Office Personal Licence PIL 70/02103 and Project Licences PPL 40/0380 (Nottingham University) and PPL 70/00349 (SmithKline Beecham).