Noradrenergic systems

Ethanol also reduces the activity of the noradrenergic system in the locus coeruleus, and alterations in norepinephrine activity may account for some aspects of intoxication and the abstinence syndrome. The 0.2 antagonist clon-idine and the P-receptor antagonist propranolol reduce some symptoms of alcohol withdrawal (Bailly et al. 1992 Carlsson and Fasth 1976 Dobrydnjov et al. 2004 Kahkonen 2003 Petty et al. 1997 Wong et al. 2003). 

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. 

McMiller and Commissaris 1999). This suggests that the eentral noradrenergic system is actually needed to express the anti-anxiety effects of some drugs, but not others. 

Berridge, CW (1998) Modulation of forebrain electroencephalographic action and behavioral state by locus coeruleus-noradrenergic system involvement of the medial septal area. Adv. in... 

Rapid eye movement sleep regulation by modulation of the noradrenergic system... 

Horvath, T. L., Peyron, C., Diano, S. et at (1999). Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J. Comp. Neurol 415, 145-59. 

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). 

Hypocretin neurons also send excitatory projections to regions of the brain that synthesize DA and NE, both of which also play a role in arousal (Kaslin et al. 2004). The central noradrenergic system is involved in the control of arousal (Mallick et al. 2002). LC neurons fire fastest during wakefulness, slow down during non-REM sleep, and stop firing almost completely during REM sleep (Aston-Jones et al. 1991). 

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. 

HT/NE link hypothesis. This theory suggests that there is a link between 5-HT and NE activity, and that both the serotonergic and noradrenergic systems are involved in the antidepressant response. 

Brunello N, Racagni G, Clostre F, Drieu K, Braquet P. (1985). Effects of an extract of Ginkgo biloba on noradrenergic systems of rat cerebral cortex. Pharmacol Res Common. 17(11) 1063-72. 

Liang KC, Juler RG, McGaugh JL. 1986. Modulating effects of posttraining epinephrine on memory involvement of the amygdala noradrenergic system. Brain Res 368(1) 125-133. 

In contrast to the widespread interest in 5-HT in depression research and in the development of antidepressants, there would appear to be little interest in developing antidepressants that selectively modulate the noradrenergic system. At the present time, there do not appear to be any drugs of this type in development. 

Figure 8.2. Diagrammatic representation of noradrenergic system in mania. All main noradrenergic pathways thought to be overactive in mania.

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