Stress can be an important factor precipitating and exacerbating in mental illness. Stressful stimuli activate catecholaminergic systems (the sympathetic nervous system, the adrenal medulla, and cerebral catecholamines), and the hypothalamo-pituitary-adrenocortical (HPA) axis. These systems are regarded as complementary, but the relationships between them are poorly understood. There is substantial evidence for abnormalities of the HPA axis in major depression and anxiety, but current treatments emphasize the use of drugs active on noradrenergic, serotonergic and GABAergic systems. We and others have demonstrated that intracerebral injections of corticotropin-releasing factor (CRF) can mimic many of the endocrine, autonomic, neurochemical and anxiety-like behavioral responses observed in stress. That cerebral CRF may be a mediator of some of these responses is suggested by the ability of intracerebral application of CRF antagonists to prevent or attenuate them. Our previous studies have implicated both CRF and noradrenergic activity in the stress-related behavioral changes in different behavioral paradigms: the multicompartment chamber in mice, and defensive withdrawal and freezing behavior in rats. Pharmacological analyses of these stress-related changes suggests that they may be mediated by activation of noradrenergic neurons which in turn activate CRF-containing cells via alpha1-receptors. However, independent neurochemical and electrophysiological evidence indicates that CRF administration can activate noradrenergic neurons. Thus, the relationships between CRF and noradrenergic systems in the brain may be considerably more complex. The proposed experiments will examine the relationships between CRF- containing and noradrenergic neurons. Our working hypothesis is that extrahypothalamic CRF affects anxiety-like behavior by modulating NE activity a the level of the locus coeruleus. Specific objectives include the identification of the brain sites in which CRF can elicit behavioral responses resembling those observed in stress. We will then study the effects of CRF injected into these sites on norepinephrine release assessed by in vivo microdialysis and in vivo voltammetry. CRF antagonists will be tested in the same sites for their ability to antagonize the behavioral and neurochemical responses observed in response to restraint and CRF. The focus will be on the locus coeruleus (LC) because this structure has been implicated in stress and anxiety responses. The central amygdala that receives input from the LC and plays a role in acquiring and expression of fear and anxiety will be the second center of attention. If substantial CRF-NE interactions are established, selective lesions of cerebral noradrenergic systems will be used to identify neuronal circuits involved in the behavioral responses to restraint and CRF. These experiments should help us to understand the functional relationships between CRF and noradrenergic neurons involved in the behavioral responses observed during stress. Such an understanding may have implications for the treatment of depression and anxiety disorders.
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