There is extensive evidence that brain neurons containing norepinephrine (NE) and corticotropin-releasing factor (CRF) are activated during stress, that activations of these two neurotransmitters are related to stress-related behavioral responses, and that both may be involved in anxiety and depression. Interactions between neurons containing NE and CRF are extensive. Noradrenergic neurons are among those that can stimulate CRF-containing neurons initiating the activation of the hypothalamo-pituitary-adrenal (HPA) axis, critical in the stress response, while other CRF-neurons in the brain may also be affected. Intracerebral administration of CRF activates NE neurons, especially those with cell bodies in the locus coeruleus (LC). Thus it has been proposed that depression may result from a sensitization of these interactions, creating a """"""""feed forward"""""""" mechanism in which each system activates the other. The brain circuits involved may include the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the lateral septum, in addition to the hypothalamic paraventricular nucleus and the LC. The research proposed aims to focus our previous work on CRF and NE interactions to elucidate details of the adaptations to chronic stress that may provide insight into the mechanisms involved in anxiety disorders and depression.
The specific aim of this proposal is to determine whether or not such a feed-forward hypothesis is reasonable, by examining the adaptation in the behavioral, noradrenergic and HPA responses to acute stress and CRF in chronically stressed animals. ? This will be done by assessing the behavioral responses and NE release and plasma corticosterone in response to acute stress, and comparing these to the responses to intracerebral injection of CRF.
The specific aims will be to determine the neurochemical (NE) and behavioral responses of chronically stressed rats to acute footshock and to CRF injected locally into the LC. Two different chronic stressor paradigms will be used: footshock and exposure to the odor of a predator (fox urine). The NE responses will be determined initially by measuring NE metabolites, but this will be followed by studies using in vivo chronoamperometry and microdialysis in rats. We will determine and compare the subtype(s) of CRF receptor involved in the responses to footshock and to CRF administration. The results should establish a model and indicate the nature of the cerebral structures involved, so that we can subsequently test the feed-forward hypothesis ? ?
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