The role of orexin and serotonin 1A receptor in the expression or modulation of the cardiovascular and behavioural components of psychological and physical stress

This thesis attempted to identify the site(s) of action of orexin and 5HT1A receptor agonists in the central network thatmediate/modulate the cardiovascular and behavioural changes evoked by psychological and physical stress.Central blockade of orexin receptors with Almorexant in the lateral ventricle significantly reduced the locomotor response toNovelty stress but did not significantly reduce the associated cardiovascular response. Comparison of the effect of orexin-A inthe lateral ventricle, fourth ventricle and thoracic cord showed that orexin injections in the upper thoracic cord could evokesubstantial cardiovascular effects, comparable to those evoked from the fourth and lateral ventricle, suggesting that orexin couldact at spinal level to mediate the cardiovascular effects of stress. This was confirmed by showing high levels of Fos expression inorexin neurons retrogradely labelled from the upper thoracic cord after Fear, Novelty and Exercise. Finally, orexin-A in themedullary raphe evoked clear cardiovascular effects, indicating that the medullary raphe could also be an important supraspinalsite of action of orexin in the cardiovascular response to stress.The 5HT1A receptor agonist 8-OH-DPAT evoked greater reduction in the cardiovascular response to Novelty, Restraint, Fear andCold after injection in the fourth ventricle than after injections in the lateral ventricle. This indicates that the lower brainstem islikely the main site of action of 8-OH-DPAT for the cardiovascular component of these stressors, suggesting a directsympathoinhibitory effect. However, the reduction of the freezing response evoked by Fear was greater after lateral ventricle thanfourth ventricle injections, suggesting an anxiolytic effect in the forebrain and/or midbrain region.Thus, this thesis has identified the most probable site(s) of action of orexin and 5HT1A agonists for the cardiovascular responseto stress. Orexin is likely to have a direct action in the upper thoracic cord toget