Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part II: physiological and pharmacological manipulations and pathological alterations of locus coeruleus activity in humans - PubMed (original) (raw)
Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part II: physiological and pharmacological manipulations and pathological alterations of locus coeruleus activity in humans
E R Samuels et al. Curr Neuropharmacol. 2008 Sep.
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, alpha(2)-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 alpha(2)-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.
Keywords: Alzheimer’s disease; Locus coeruleus; Parkinson’s disease; aging.; anxiety; arousal; autonomic function; noxious stimuli.
Figures
Fig. (1)
Schematic diagram of the connections within the arousal-controlling neuronal network. Wakefulness-promoting nuclei (grey): TMN, tuberomamillary nucleus; LH/PF, lateral hypothalamic/perifornical area; Th, thalamus; LC, locus coeruleus; VTA, ventral tegmental area; PPT, pedunculopontine tegmental nucleus; R, raphe nuclei. Sleep-promoting nucleus (hatched): VLPO, ventrolateral preoptic nucleus. GABAergic interneurones, in (white). Neurotransmitters: ACh, acetylcholine; NA, noradrenaline; H, histamine; Ox, orexin; GABA, γ-aminobutyric acid; DA, dopamine; 5HT, 5-hydroxytryptamine; Glu, glutamate. Receptors: α1, excitatory α1-adrenoceptors; α2, inhibitory α2-adrenoceptors; H1, excitatory H1 histamine receptors; 5HT2A and 5HT2C, excitatory 5HT receptors. Neuronal outputs: excitatory (solid arrows) and inhibitory (broken arrows). The wakefulness-promoting nuclei exert a direct activating effect on the cerebral cortex; the VLPO promotes sleep by inhibiting the TMN and the LC. The LC promotes wakefulness by stimulating the cerebral cortex and the wakefulness-promoting neurones of the PPT, and by inhibiting the VLPO. The LC also inhibits the REM-sleep-promoting neurones of the PPT. The raphe nucleus promotes wakefulness by activating the cerebral cortex; this effect is attenuated by stimulation of GABAergic interneurones, which inhibit the LC and the VTA. The VTA exerts its wakefulness-promoting effect largely via activation of the LC, and the LH/PF largely via activation of the TMN and the LC. The connections of the LC are reviewed in detail in Part I. The GABAergic interneurones, activated by excitatory 5HT2C receptors, are located in the VTA itself [55, 140] and in the vicinity of the LC [140]. Modified with permission from Szabadi, 2006.
Fig. (2)
The central role of the locus coeruleus (LC) in the regulation of autonomic functions. Nuclei: PVN, paraventricular nucleus; Pre ggl Para, preganglionic parasympathetic neurones; EW, Edinger-Westphal nucleus; Saliv, salivatory nucleus; Pre ggl Symp, preganglionic sympathetic neurones; Symp ggl, sympathetic ganglion; Para ggl, parasympathetic ganglion. Neurotransmitters: NA, noradrenaline; ACh, acetylcholine. Receptors: α1 and α2, adrenoceptor subtypes. Symbols: +, excitatory, -, inhibitory. Organs comprising of smooth muscle (e.g., blood vessels, iris), or glandular tissue (e.g., sweat glands, salivary glands) receive autonomic (sympathetic and parasympathetic) innervations. Both innervations consist of a chain of two neurones (preganglionic and postganglionic) joined in a synapse located in the autonomic ganglion. Preganglionic sympathetic neurones are located in the intermediolateral cell column (IML) of the spinal cord whereas the preganglionic parasympathetic neurones are located in brainstem nuclei. Blood vessels (arterioles) and sweat glands receive sympathetic and salivary glands parasympathetic inputs whereas the smooth muscles in the iris are controlled by opposing sympathetic and parasympathetic inputs. The preganglionic neurones are always cholinergic, the postganglionic sympathetic neurones are noradrenergic, with the exception of those innervating the sweat glands which are cholinergic, whereas the postganglionic parasympathetic neurones are always cholinergic. The preganglionic neurones are influenced by premotor autonomic nuclei of which three are shown (PVN, vasomotor neurones located in the rostroventrolateral medulla, and the LC). The LC plays a pivotal role in autonomic regulation, influencing the activities of preganglionic neurones both directly and indirectly via the PVN and vasomotor neurones. The outputs from the LC can activate either excitatory α1-adrenoceptors or inhibitory α2-adrenoceptors. The output from the LC to the PVN is largely to its parvicellular subdivision; this connection plays a relatively minor role. The LC exerts an excitatory effect on preganglionic sympathetic neurones and an inhibitory effect on vasomotor premotor neurones and on preganglionic parasympathetic neurones. The activity of the preganglionic neurones is under the influence of the cerebral cortex. The light reflex is a parasympathetically-mediated reflex consisting of the constriction of the pupil in response to a light stimulus reaching the retina. The neuronal chain in the reflex includes the pretectal nucleus, the EW, and the ciliary ganglion. The connections of the LC shown in this figure are discussed in detail in Part I.
Fig. (3)
A: Relationship between pupil diameter and the firing rate of an LC neurone in a monkey. The two recordings were taken simultaneously. There was a clear parallelism between fluctuations in pupil diameter and firing rate. Reproduced with permission from Aston-Jones and Cohen (2005). B: An example recording from the pupillographic sleepiness test (PST) demonstrating fluctuations in resting pupil diameter (top) and the power spectrum (bottom) over an 11-minute recording period. The data for the total time period are divided into eight equal bins for further analysis. The fluctuations in resting pupil diameter are used in the analysis of the pupillary unrest index (PUI), the distance for which the margin of the pupil travels in one minute. The mean value of PUI obtained for the whole recording period is shown on the right of the figure. Vertical axis: pupil diameter (mm), horizontal axis: time (min). The mean pupil diameter for each bin is displayed above the horizontal axis, with the average diameter over the total recording period shown on the right of the figure. The mean PUI for each bin is displayed above the recording. The power spectrum is used in a Fast Fourier Transform analysis to derive a measure of total power (arbitrary units), shown on the right of the figure. Power (arbitrary units) is displayed along the vertical axis and frequency (Hz) is displayed along the horizontal axis for each time-bin individually. The total power for each bin is displayed above the power spectrum.
Fig. (4)
The central sites of action of α2-adrenoceptor agonists (e.g., clonidine, dexmedetomidine). Nuclei: TMN, tuberomamillary nucleus; VLPO, ventrolateral preoptic area; LC, locus coeruleus; PT, pretectal nucleus; SN, salivatory nucleus; EWN, Edinger-Westphal nucleus; RVLM, rostroventrolateral medulla; IML, intermediolateral cell column; SaG, salivary ganglion; SG, sympathetic ganglion; SCG, superior cervical ganglion; CG, ciliary ganglion. Neurotransmitters: NA, noradrenaline; GABA, γ-aminobutyric acid; Glu, glutamate; ACh, acetylcholine. Receptors: α1 and α2, adrenoceptor subtypes. Neuronal connections are indicated by arrows: solid lines, excitatory; dotted lines, inhibitory. The sites at which the LC exerts an inhibitory influence are indicated by numbers: 1. autoreceptors on LC neurones, 2. VLPO, 3. EWN, 4. RVLM, 5. SN. For the effects of the consequences of alterations of LC activity on arousal and autonomic function, see text.
Fig. (5)
Magnetic resonance image showing a cross-section of the upper pons displaying the loci coerulei (LC). A picture was taken in a healthy human subject with the modification of the method of Sasaki et al., 2006, on a 3-tesla scanner to obtain neuromelanin signal to identify LC. The loci coerulei are shown by the small white areas in the bottom corners of the fourth cerebral ventricle, indicated by black arrows. By courtesy of Professor D. Auer, Queen’s Medical Centre, Nottingham.
Fig. (6)
Schematic diagram to illustrate the hypothesis of two populations of locus coeruleus (LC) neurones. Sympathetic premotor neurones (shown as blank area) are preferentially activated by noxious stimuli from collaterals of ascending pain pathways and the dopaminergic neurones of the ventral tegmental area (VTA) (meso-coerulear pathway), whereas parasympathetic premotor neurones (shown as shaded area) are preferentially activated by anxiety via an output to the LC from the amygdala (Amyg). The sympathetic premotor neurones have a stimulatory effect on sympathetic activity (Symp Activity) and level of arousal whereas the parasympathetic premotor neurones exert an inhibitory influence on parasympathetic activity (Para Activity) (see text for details).
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