Noradrenergic systems function

McCormick, DA, Pape, HC and Williamson, A (1991) Actions of norepinephrine in the cerebral cortex and thalamus implications for function of the central noradrenergic system. Prog. Brain Res. 88 293-305. 

Virtually all types of drug that have been shown to be effective in major depression exert profound effects on the functioning of the serotoninergic or noradrenergic systems, or both. Although some treatments have been shown to decrease the sensitivity of certain postsynaptic 5-HT and NE receptors, it is generally believed that it is an enhancement of neurotransmission in these systems that is responsible for the improvement of the core symptoms of depression. For instance, long-term administration of tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) decreases the density of (3-adrenoceptors and cortical 5-HT2 receptors (Blier and Abbott 2003). 

There is ample support for the hypothesis of noradrenergic system dysfunction in depression however, the inconsistencies in findings rule out any simple model of increased or decreased noradrenergic activity. It is important to determine which noradrenergic system abnormalities relate specifically to the pathogenesis of mood disorders, and which are related to nonspecific effects of stress, homeostatic mechanisms, or comorbid psychopathology. More work is needed on the mood-state-depen-dence of noradrenergic function. 

Noradrenaline is the neurotransmitter most closely associated with the peripheral and central stress response (Figure 9.5). There is experimental evidence to show that drugs such as yohimbine that block the noradrenergic autoreceptors (e.g. on cell bodies and nerve terminals) and thereby enhance noradrenaline release cause fear and anxiety in both man and animals. Conversely, drugs that stimulate these autoreceptors (as exemplified by clonidine) diminish the anxiety state because they reduce the release of noradrenaline. Benzodiazepines have been shown to inhibit the fear-motivated increase in the functional activity of noradrenaline in experimental animals, but it is now widely believed that the action of the benzodiazepines on the central noradrenergic system is only short term and may contribute to the sedative effects which most conventional benzodiazepines produce, at least initially. Nevertheless, altered noradrenergic... 

There is strong evidence that function of the brain noradrenergic system is involved in mediating fear conditioning (Rasmussen et al. 1986 Charney and Deutch 1996). Neutral stimuli paired with shock (CS) produce increases in brain NE metabolism and behavioral deficits similar to those elicited by the shock alone (Cassens et al. 1981) as well as increased firing rate of cells in the LC (Rasmussen et al. 1986). An intact noradrenergic system appears... 

There is extensive clinical evidence that NE plays a role in hiunan anxiety. Well-designed psychophysiological studies have been conducted that have documented heightened autonomic or sympathetic nervous system arousal in combat veterans with chronic PTSD. Because central noradrenergic and peripheral sympathetic systems function in concert (Aston-Jones et al. 1991), the data from these psychophysiology investigations are consistent with the hypothesis that noradrenergic hyperreactivity in patients with PTSD may be associated with the conditioned or sensitized responses to specific traumatic stimuli. 

What then, is the current evidence to support a role of norepinephrine in depression, such that manipulation of noradrenergic activity bears particular relevance to the successful treatment of mood disorders Interpretation of studies depends on the continually evolving conceptualizations of the roles of brain noradrenergic systems. A potentially useful way of thinking about the function of the norepinephrine in the brain can be derived from examining the neuroanatomy of the noradrenergic system. A summary of findings [primarily from rodents and primates) is as follows. 

Lithium carbonate and lithium citrate are the most commonly used compounds. Lithium has effects on cation transport, on individual neurotransmitters (including 5-HT) and on intracellular second messenger systems. Which of these is key to its therapeutic efficacy is not entirely clear but, as for the antidepressant drugs, the net effects seem to be to enhance serotonin function and to stabilise the noradrenergic system. Once lithium treatment is established it is very important that it is not suddenly stopped as this may result in rebound hypomania. 

Certainly, such a complex system for metabolism of noradrenaline (which is shared with the other catecholamines) strongly suggests that its function extends beyond that of merely destroying transmitter sequestered from the synapse. However, as yet, little is known about the regulation of this pathway and any influence it might have on noradrenergic transmission. One crucial, additional role for MAO appears to be the... 

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