Abstract
The locus coeruleus (LC), the major noradrenergic nucleus of the brain, gives rise to fibres innervating most structures of the neuraxis. Recent advances in neuroscience have helped to unravel the neuronal circuitry controlling a number of physiological functions in which the LC plays a central role. Two such functions are the regulation of arousal and autonomic activity, which are inseparably linked largely via the involvement of the LC. Alterations in LC activity due to physiological or pharmacological manipulations or pathological processes can lead to distinct patterns of change in arousal and autonomic function. Physiological manipulations considered here include the presentation of noxious or anxiety-provoking stimuli and extremes in ambient temperature. The modification of LC-controlled functions by drug administration is discussed in detail, including drugs which directly modify the activity of LC neurones (e.g., via autoreceptors, storage, reuptake) or have an indirect effect through modulating excitatory or inhibitory inputs. The early vulnerability of the LC to the ageing process and to neurodegenerative disease (Parkinson’s and Alzheimer’s diseases) is of considerable clinical significance. In general, physiological manipulations and the administration of stimulant drugs, α2-adrenoceptor antagonists and noradrenaline uptake inhibitors increase LC activity and thus cause heightened arousal and activation of the sympathetic nervous system. In contrast, the administration of sedative drugs, including α2-adrenoceptor agonists, and pathological changes in LC function in neurodegenerative disorders and ageing reduce LC activity and result in sedation and activation of the parasympathetic nervous system.
Highlights
The locus coeruleus (LC), the major noradrenergic nucleus of the brain, gives rise to fibres innervating most structures of the neuraxis
It is of interest that while the influence of the LC on premotor autonomic neurones in the Paraventricular nucleus (PVN) and Caudal raphe (CR) is excitatory, it is inhibitory on neurones in the Rostroventrolateral medulla (RVLM) (see Fig. (2))
The activity of the LC can be altered through a variety of physiological manipulations such as the presentation of a noxious or anxiety-provoking stimulus or by variations in ambient temperature, through pharmacological manipulations such as the administration of drugs which act directly at the autoreceptors located on the neurones of the LC, that modify the reuptake or storage of noradrenaline, or that act indirectly to modify LC activity, through neuronal loss from the LC in aging, and through pathological changes that occur as a result of neurodegenerative disease (PD, Alzheimer’s disease (AD)) and brainstem trauma resulting in coma
Summary
Inhibition of noradrenaline uptake at the excitatory noradrenergic synapses in the cerebral cortex and in wakefulnesspromoting nuclei, together with a similar action at inhibitory noradrenergic synapses in the VLPO, is expected to lead to an increase in arousal. Uptake of dopamine, these drugs are potent inhibitors of noradrenaline reuptake [495]. These drugs produce robust increases in arousal (amphetamine [157, 171]; cocaine [492]). A number of antidepressants have been developed whose only or principal action is the inhibition of noradrenaline reuptake (e.g., reboxetine, venlafaxine, atomoxetine, duloxetine). Some of these drugs have, albeit relatively weak, alerting effects. Phentermine, an anorectic agent used in the treatment of obesity, inhibits noradrenaline and dopamine reuptake and has been shown to increase wakefulness in rats [371]
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