The Brainstem Noradrenergic Systems in Stress, Anxiety and Depression

The locus coeruleus (LC) is regarded as a part of the central ‘stress circuitry’ because robust activation of the LC has been reported after stressful stimuli in experimental animals. A considerable amount of clinical evidence also suggests the relationship between the central noradrenergic (NAergic) system and fear/anxiety states or depression. However, previous animal studies have not been able to demonstrate unequivocally the involvement of the NAergic system in mediating fear or anxiety. The forebrain structures, including the hypothalamus, receive massive inputs from the medullary NAergic nuclei via the ventral NAergic bundle (VNAB). The VNAB has been implicated in the neuroendocrine stress axis mainly through its action on the corticotrophin-releasing factor neurones in the paraventricular nucleus of the hypothalamus. Novel tools were introduced that are capable of disrupting the NAergic system more selectively and/or thoroughly than the neurotoxins employed in previous studies: the anti-dopamine-β hydroxylase (DBH)-saporin is an immunotoxin that is taken up from nerve endings and disrupt the NAergic neurones in a retrograde manner. The genetically DBH-depleted mice were also introduced, which lack endogenous noradrenaline. Owing to the rapid development of functional imaging technique, visualisation of the emotional phenomena has become possible in human subjects. Along with the advent of these technologies, endeavors have been continued to unravel the functional relevance of the central NAergic system to stress, anxiety and depression.