Abstract
This thesis attempted to identify the site(s) of action of orexin and 5HT1A receptor agonists in the central network that
mediate/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 to
Novelty stress but did not significantly reduce the associated cardiovascular response. Comparison of the effect of orexin-A in
the lateral ventricle, fourth ventricle and thoracic cord showed that orexin injections in the upper thoracic cord could evoke
substantial cardiovascular effects, comparable to those evoked from the fourth and lateral ventricle, suggesting that orexin could
act at spinal level to mediate the cardiovascular effects of stress. This was confirmed by showing high levels of Fos expression in
orexin neurons retrogradely labelled from the upper thoracic cord after Fear, Novelty and Exercise. Finally, orexin-A in the
medullary raphe evoked clear cardiovascular effects, indicating that the medullary raphe could also be an important supraspinal
site 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 and
Cold after injection in the fourth ventricle than after injections in the lateral ventricle. This indicates that the lower brainstem is
likely the main site of action of 8-OH-DPAT for the cardiovascular component of these stressors, suggesting a direct
sympathoinhibitory effect. However, the reduction of the freezing response evoked by Fear was greater after lateral ventricle than
fourth 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 response
to stress. Orexin is likely to have a direct action in the upper thoracic cord together with an indirect action in the lower brainstem,
most probably in the medullary raphe. 5HT1A agonists appear to act preferentially in the lower brainstem, most probably in the
medullary raphe also. In contrast, both systems preferentially act on forebrain/midbrain regions to mediate/modulate the
behavioural response to stress.