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Adrenaline andNoradrenaline:

IntroductionS Clare Stanford, University College London, London, UK

Adrenaline and noradrenaline belong to a family of mol-ecules known as ‘catecholamines’. They are both released

fromtheadrenalglandandneuronsinthecentralnervous

system. Noradrenaline is also released from the majority

of postganglionic, sympathetic neurons in the peripheral

(autonomic) nervous system. Conversion of the amino

acid,tyrosine,to l -3,4-dihydroxyphenylalanine is the rate-

limiting step in the pathway for synthesis of both of these

catecholamines. This biosynthetic pathway is regulated

by several hormones and neurotransmitters, which act

through intracellular messengers and help to ensure that

the rate of catecholamine synthesis matches the rate of

their release. Adrenaline and noradrenaline have

important roles in mediating peripheral autonomic

function and the maintenance of a stable internal body

state(‘homoeostasis’). In the brain,their distribution and

functional interactions underlie their strong influence on

arousal state (attention/vigilance/alarm) and its inte-

gration with the autonomic system.

Introduction

Adrenaline and noradrenaline (named epinephrine andnorepinephrine in the USA) are members of a class of molecules known as catecholamines (Figure 1). They areboth secreted from the core (medulla) of the adrenal gland

and act as neurotransmitters in the brain. Noradrenaline isalso released from the majority of postganglionic sympa-thetic neurons in the periphery.

This article first outlines the distribution of adrenaline-and noradrenaline-releasing neurons in the brain. Thebiosynthesis of these neurotransmitters is described next,including the regulation of this process, which enablesneurons to adapt to continually changing demands on theirneurotransmitter stores. Finally, recent ideas on the func-tion(s) of these catecholamines in the brain and peripherywill be discussed.

Details of all the physiological responses in variousperipheral organs that follow release of adrenaline andnoradrenaline from the adrenal gland and postganglionic

sympathetic neurons are beyond the scope of this article.These responses are described elsewhere. See also: Adrena-line and Noradrenaline; Autonomic Nervous System;

Dopamine; Endocrine System in Vertebrates

Noradrenaline and Adrenaline in thePeriphery

Noradrenaline is found in most, but not all, postganglionicneurons of the sympathetic nervous system. These neuronsproject from autonomic ganglia in the sympathetic chain,on either side of the spinal column, to their target organs(e.g. theheart, spleen, salivary glandsand smoothmuscle in

the vasculature and gastrointestinal tract). Chromaffincells in the core (medulla) of the adrenal gland also secretenoradrenaline and adrenaline into the circulation and sothese two compounds have a hormonal function thatcomplements their role as neurotransmitters. Both neur-onal and hormonal release of these catecholamines arestimulated by preganglionic cholinergic neurons.

A key feature of postganglionic sympathetic neurons isthe absence of specialised synaptic contacts with their tar-

get cells. It is presumed that this indicates a lack of targetedrelease of noradrenaline in these tissues. Instead, nor-adrenaline is thought to diffuse through the extracellular

fluid before it reaches its target receptors. This process isknown as ‘volume’ (or ‘nonsynaptic’ or ‘extrasynaptic’)

Introductory article

Article Contents

. Introduction

. Noradrenaline and Adrenaline in the Periphery

.

Noradrenaline and Adrenaline in Specific BrainPathways

. Noradrenaline and Adrenaline: Storage and Synthesis

. Biosynthesis of Noradrenaline

. Biosynthesis of Adrenaline

. Influence of Noradrenaline on Behaviour

. Regulation of Autonomic Function by Noradrenaline

and Adrenaline

. Summary

Online posting date: 15th April 2013

eLS subject area: Neuroscience

How to cite:

Stanford, S Clare (April 2013) Adrenaline and Noradrenaline:

Introduction. In: eLS. John Wiley & Sons, Ltd: Chichester.

DOI: 10.1002/9780470015902.a0000271.pub3

eLS & 2013, John Wiley & Sons, Ltd. www.els.net 1

http://dx.doi.org/10.1002/9780470015902.a0001401.pub2


http://dx.doi.org/10.1038/npg.els.0000081










transmission. See also: Autonomic Nervous System;Dopamine; Endocrine System in Vertebrates

Noradrenaline and Adrenaline inSpecific Brain Pathways

The distribution of neurons that release noradrenaline andadrenaline was first mapped in the 1960s using fluorescence

microscopy of the rat brain. This technique involves incu-bating freeze-dried tissues with hot formaldehyde vapour,which reacts with catecholamines to produce compoundsthat fluoresce in ultraviolet light (‘fluorophores’). Amicroscope, equipped with an ultraviolet light source, isused to visualise the fluorophores which serve as markersfor noradrenaline- and adrenaline-releasing neurons. Thecell bodies of these neurons are all confined within thepons/medulla region in the brainstem (Figure 2), but theiraxons project to other regions throughout the brain andspinal cord. As far as it is known, the topographical dis-tribution of these neurons in the brainstem and other brain

regions is similar in all mammalian species, includinghumans, but many species (e.g. the mouse) have not yetbeen studied systematically.

Noradrenaline

The cell bodies of noradrenaline-releasing (noradrenergic)neurons in the brainstem are found within seven distinct,bilateral clusters (‘nuclei’). These groups of cell bodies(known as nuclei A1–A7) are subdivided into the ‘locus

coeruleus complex’ and the ‘lateral tegmental system’.See also: Brainstem

The locus coeruleus complex comprises the A6 (the

nucleus locus coeruleus, proper) and the A4 (locus sub-coeruleus) nuclei. The latter is a group of cells that lies

ventral to A6.Of all noradrenergic nuclei, theA6 nucleus in

the pons, has received the most attention because it is thesource of more than 40% of all noradrenaline-releasingneurons in the brain. In fact, neurons from this nucleus

innervate almost every region of the central nervous sys-tem. These neuronal projections are distributed to different

forebrain regions via three major ascending pathways of which the most important is the noradrenergic dorsalbundle (Figure 2). Neuronal fibres projecting to the cere-bellum and the spinal cord form two further pathways.See also: Cerebellum: Anatomy and Organisation; SensorySystem Organization

Thelateral tegmentalsystem includes theA1, A3,A5 andA7 nuclei. Neurons project from these nuclei, via the cen-tral tegmental tract, and innervate the telencephalon(particularly the septum and amygdala), diencephalon (thethalamus and all areas of the hypothalamus) and brain-stem, where they innervate primarily motor and visceral(i.e. nonsensory) nuclei. There are also descending (bul-bospinal) neurons that pass down the spinal cord. Most of these noradrenaline-releasing neurons in the spinal cordderive from the A5 nucleus. The dorsomedial medullarynoradrenaline-containing neurons in the A2 nucleus aresometimes included in the lateral tegmental group but are

often regarded as a separate system within the nucleustractus solitarius. See also: Motor System Organization

There is extensive overlap in the innervation of different

brain areas by neurons that project from the locus coer-uleus complex and lateral tegmental nuclei, but there are afew exceptions (Figure 3). For instance, neurons projectingfrom the locus coeruleus are the sole source of noradren-

aline that is released in thefrontalcortex andhippocampus.Conversely, most subregions of the hypothalamus areinnervated by neurons that derive from the lateral teg-mental nuclei, but certain regions of the hypothalamus (e.g.the paraventricular nucleus and, possibly, the suprachias-matic nucleus) are innervated by neurons from both thelocus coeruleus and the lateral tegmental nuclei. See also:Hippocampus; Hypothalamus

Locus coeruleus: principal collection of noradrenaline-containing neurons in the

brainDespite being the source of the majority of noradrenaline-releasing nerve terminals in the brain, the locus coeruleus isremarkably small. Even in humans, there are onlyapproximately 14 000–20 000 cell bodies in this nucleus, oneach side of the brain. In most species, it is a compact, dis-tinct nucleus, but, in humans and cats, it is relatively diffuseand the noradrenergic cell bodies are scattered amongstother types of neurons. The noradrenaline-containing

neurons are multipolar and have dendrites that project intopericoerulear regions (the ‘locus coeruleus shell’).

The axons of noradrenaline-releasing neurons that

project from the locus coeruleus form an extensive,branching network that penetrates nearly every region of

(a)

CH CH2 NH2HO

HO

OH

(b)

HO

HO

CH CH2 NH

OH

CH2

Catechol nucleus

Figure 1 The chemical structure of (a) noradrenaline and (b) adrenaline.

Adrenaline and Noradrenaline: Introduction

eLS & 2013, John Wiley & Sons, Ltd. www.els.net2























the central nervous system. Each neuron is thought to yieldapproximately 100 000 terminals. Because of this diffuse

network of terminals, it is still widelybelievedthat thebrainnoradrenergic system lacks either temporal or spatial spe-cificity. This was apparently supported by early reportsthat these neurons did not make specialised synaptic con-tacts with their target cells.

In fact, neither of these claims is correct (Foote et al.,

1983). First, the majority (more than 90%) of neuronsprojecting from the locus coeruleus to the cerebral cortexform specialised synaptic contacts with somatodendriticregions of their target neurons, although this might not bethe case throughout the brain.

Second, there is topographical organisation of neuronal

projection from the locus coeruleus. For example, most(if not all) noradrenaline-containing terminals in regions of

the cerebral cortex that are concerned with the special sensesderive from cell bodies located in the dorsal rostrocaudalzone of the locus coeruleus. Neurons in the ventral zone of

this nucleus project to the spinal cord. Cytochemical studies,using retrograde labelling techniques, have revealed thatsingle neurons often project to more than one brain region,

even those as remotely spaced as the neocortex and thespinal cord. In general, it is the neurons in the core of the

locus coeruleus that branch the most.Further functional specificity could arise from the many

different neuroactive molecules that have been identifiedwithin the locus coeruleus. These include b-endorphin,neurophysin, neurotensin, angiotensin II, acetylcholine(muscarinic), corticotropin-releasing factor (CRF) andsubstance P. Some of these agents are presumed to act ascotransmitters (i.e. to undergo impulse-evoked releasefrom neurons that also release noradrenaline), but there isno firm evidence for this.

Studies that have used retrograde labelling techniqueshave revealed many different sources of neuronal input tothe locus coeruleus. These include: glutamatergic and

GABAergic projections from the prefrontal cortex (Jodoet al ., 1998) and a prominent input from areas of the brainthat have an important role in arousal (Lee et al ., 2005).Other neuronal inputs include: serotonergic neurons from

the raphe ´ nuclei; glycinergic inputs from the periaque-ductal grey; and hypocretin neurons from the lateralhypothalamus. See also: Neurotransmitters; PeptideNeurotransmitters and Hormones

Adrenaline

The most important source of adrenaline is the chromaffin

tissue in the adrenal medulla. These chromaffin cells areinnervated by preganglionic, cholinergic neurons and so

Neocortex Hippocampus Thalamus Cerebellum

Septum

Amygdala

Median forebrain bundle

Hypothalamus

Dorsal longitudinal fasciculus

Dorsal bundle

Pituitary

Central tegmental tract

Spinal cord

A2

A1C1C2C3

A7 A5

A6

Ventral bundl

Figure 2 A schematic representation of the distribution of noradrenaline-releasing neurons in the rat brain. The brainstem nuclei that contain neurones the

release for neurons that release noradrenaline or adrenaline (C1-C3) are indicated, also. The main projections from the locus coeruleus (A6) are the

(noradrenergic) dorsal bundle, dorsal longitudinal fasciculus and central tegmental tract. Some fibres of the dorsal bundle innervate the thalamus directly,

whereas others, together with the central tegmental tract, join the medial forebrain bundle at the level of the caudal hypothalamus. This pathway then

projects to many brain areas, including the amygdala nuclei, anterior thalamus, septum, olfactory areas and the neocortex. Fibres from the dorsal

longitudinal fasciculus innervate the paraventricular nucleus and, possibly, the supraoptic nucleus in the hypothalamus. The medullary bundle, in whichneurons from the locus coeruleus branch from the central tegmental tract, projects to the caudal medulla (not illustrated). Fibres from the central tegmental

tract also descend to the spinal cord.

Locuscoeruleus

A4, A6,subcoeruleus

Brainstem nuclei(sensory)

HippocampusCerebral cortex

Spinal cordCerebellumThalamusHypothalamus(paraventricular nucleus)

AmygdalaSeptum

Brainstem nuclei(motor)

Hypothalamus(all nuclei)

Ventral tegmentalnuclei

A1, A3, A5, A7 (A2)

Figure 3 The distribution of neuronal projections from the locus coeruleus

and lateral tegmental (noradrenaline) systems in the brain.











they are functionally equivalent to postganglionic sympa-

thetic neurons. In fact, mature adrenal medullary tissueand postganglionic sympathetic neurons derive from thesame embryonic cells. This explains why most of the pro-

cesses that govern the synthesis storage and release of noradrenaline were first characterised in the adrenal

medulla and later found in noradrenergic neurons in theperipheral and the central nervous systems as well. Anyadrenaline found in other peripheral tissues probablyderives from uptake from the circulation. See also:Endocrine System in Vertebrates

There are also some adrenergic neurons in the brain(Ziegler et al ., 2002). Many adrenergic neuron terminals inthe brain are close to capillaries and glial cells, suggestingthat they have a metabolic role, or possibly interact withneuroactive cytokines (e.g. interleukin-1b).

Fluorescence microscopy and cytochemical studies,using labelled antibodies for the enzyme phenylethanola-mine N -methyl transferase (PNMT), have identified threemain clusters of these adrenergic neurons. These areknownas nuclei C1–C3 and are found in the rostral medulla of the

brainstem, where they overlap with the A1–A3 nora-drenergic nuclei (Figure 2). It is striking that the brain areasin which these cell bodies are clustered are densely

innervated by neurons projecting from the thorax andabdomen.

The C1 group is found within the nucleus para-

gigantocellularis (PGi). These adrenergic neurons innerv-ate brain areas that are strongly linked with anxiety andtheresponse to stress (e.g. the periaqueductal grey and hypo-thalamus). The C1 group of neurons also provides the

major adrenergic input to the locus coeruleus.C2 neurons are located in the nucleus tractus solitarius

and dorsal motor nucleus of the vagus. They innervateneither the locus coeruleus nor the periaqueductal grey.However, C2 neurons are the source of most of theadrenaline-releasing neurons that innervate the amygdala,another brain area with a key role in anxiety.

The C3 group of adrenergic neurons is located within theregion of the nucleus prepositus hypoglossi. Like the C1cell cluster, these neurons project rostrally to innervate thelocus coeruleus.

Neurons from these three nuclei project to other brain-stem regions, including forebrain areas. They also pass

down the spinal cord where they modulate the function of preganglionic sympathetic neurons. It is interesting thatthe innervation of the amygdala by the adrenergic neurons

in the C1 and C3 nuclei is mirrored by neurons that projectfrom the central nucleus of the amygdala, which innervatethe C2 nucleus but not the C1 or C3 nucleus.

The arrangement of these inputs and their connectionswith the spinal cord suggests that adrenaline-releasingneurons have a key role in the regulation of autonomicfunction, especially of blood pressure. Their connectionswith brain areas, such as the serotonergic raphe ´ nuclei,locus coeruleus and limbic system, also point to their

involvement in synchronising emotional and autonomicresponses to external and internal (‘interoceptive’) stimuli.

See also: Autonomic Control; Brainstem; Limbic System;Mood Disorders; Oculomotor System; Sensors of ExternalConditions in Vertebrates; Somatosensory Systems

Noradrenaline and Adrenaline:Storage and Synthesis

The concentration of noradrenaline is the greatest in theneuronal terminals, where it is stored in membrane-boundvesicles of approximately 50–90 nm diameter. These ves-icles are the site of the final step in noradrenaline synthesis(see below). They are assembled in the neuronal cell bodyand transported down the axons to the terminals.

The degree to which the terminal vesicles in post-ganglionic sympathetic neurons are filled with noradren-aline varies from organ to organ. In general, the vesicularstore is less full in sympathetic neurons that are continually

(‘tonically’) active, such as those innervating the cardio-vascular system, than in those which undergo short burstsof (‘phasic’) activity, such as salivary glands and vas def-erens. Nevertheless, the steady state concentration of noradrenaline in the neuronal storage vesicles is remark-ably constant for each individual peripheral organ or brainregion. This is possible because, under normal conditions,the rate of synthesis of noradrenaline balances the rate atwhich it is released and metabolised. The mechanisms thatcouple these two processes have been characterised and aredescribed below.

Biosynthesis of Noradrenaline

The primary substrate for synthesis of noradrenaline istyrosine. This amino acid is converted into l -3,4-dihy-droxyphenylalanine (l -DOPA) by the enzyme tyrosinehydroxylase. This process is the rate-limiting step of thepathway. Synthesis of noradrenaline can be increased bygiving l -DOPA, which bypasses this rate-limiting step(tyrosine hydroxylation). Because l-DOPA penetrates theblood–brain barrier, this increase in synthesis even occursin the brain and is exploited in treatment of Parkinson’sdisease. The amino acid, phenylalanine, can also be con-

verted to tyrosine by the enzyme phenylalanine hydro-xylase, but this is thought not to happen unless the dietarysupply of tyrosine is compromised, which is exceptional.

The activity of tyrosine hydroxylase is increased byphosphorylation of the enzyme by protein kinases, whichare activated by intraneuronal second-messengers (e.g.cAMP) (Dunkley et al., 2004). This phosphorylationincreases the affinity (i.e., reduces the K D) of tyrosinehydroxylase for its substrate and/or increases its maximal

activity (V max). The concentration of these intracellularmessengers is increased by neuronal activation, whichprovides a mechanism that couples acceleration of the rate

of synthesis of noradrenaline with an increase in its rate of release.























The activity of tyrosine hydroxylase is inhibited by high

concentrations of noradrenaline. This end-product inhib-ition was thought to operate a negative feedback pathwaythat regulated noradrenaline synthesis and stabilised the

size of the transmitter store. It is now known that thishappens only under exceptional circumstances: for

example, when the metabolism of noradrenaline is pre-vented by drugs that block monoamine oxidase, which isone of the two enzymes that metabolise noradrenaline. It isthis action which makes monoamine oxidase inhibitorseffective in treatments for depression.

l -DOPA is converted into dopamine by the enzyme, l -aromatic amino acid decarboxylase (also called ‘DOPAdecarboxylase’, in this context). Dopamine is anothercatecholamine and neurotransmitter that is found inneurons in the brain with cell bodies clustered in nuclei(A8–A12), within the midbrain and hypothalamus. Allcatecholaminergic neurons express tyrosine hydroxylaseand DOPA decarboxylase and so the two-stage conversionof tyrosine to dopamine takes place in all catecholamine-releasing neurons. Because these are both soluble enzymes,

synthesis of dopamine takes place only in the cell cyto-plasm. See also: Amine Neurotransmitters; Dopamine;Enzyme Activity: Control

The synthesis of noradrenaline from dopamine is thenext step in the pathway and involves b-hydroxylation of dopamine by the enzyme dopamine-b-hydroxylase (DbH)

(Figure 4). This is a Cu2+-containing glycoprotein, whichneeds O2 and ascorbic acid for its catalytic activity. DbH isfound in vesicles (‘granules’) within chromaffin cells of the

adrenal medulla and in the transmitter storage vesicles in

the terminals of neurons that release noradrenaline oradrenaline. Most, but not all, of the enzymes are bound tothe membranes of these vesicles. The remainder is soluble

enzyme confined within these organelles. There is no DbHin the neuronal cytoplasm or chromaffin cells and so the

synthesis of noradrenaline follows uptake of dopamineinto the storage vesicles. Because only those neurons thatexpress this enzyme are capable of synthesising noradren-aline and adrenaline, its expression is used to distinguishnoradrenergic and adrenergic from dopaminergic neur-ones in immunocytochemical studies. See also: AmineNeurotransmitters; Enzymes: General Properties

The high affinity of DbH for dopamine and its high V max(maximum velocity of conversion of substrate into prod-uct) ensure that this step in the pathway is normally notrate-limiting in the biosynthesis of noradrenaline. How-ever, like allproteins, DbH is assembledin theneuronalcellbody and is delivered to the terminals by rapid axoplasmictransport. This can take several hours or days, dependingon the length of the axon. If the supply of viable vesicles iscompromised (such as after bursts of intense neuronalactivity), their capacity to take up dopamine from thecytoplasm for conversion into noradrenaline is diminished.

Under these conditions, DbH activity can become ratelimiting and, as a consequence, dopamine accumulates inthe neuronal cytosol. See also: Binding and Catalysis;

Enzyme Activity: Control; Substrate Binding to EnzymesThe activity of DbH is strongly dependent on pH (with a

maximum at pH 6.0) and is increased by anions, such asCl – , which are present inside storage vesicles and chro-

maffin granules. However, stress, or drug treatments thatstimulate noradrenaline release (e.g. d -amphetamine),triggers increased synthesis of DbH enzyme. Such stimulicould recruit any of a wide range of endogenous com-pounds that influence DbH gene transcription. Theseinclude glucocorticoids, oestrogens, nerve growth factor,bradykinin, cyclic adenosine monophosphate (cAMP) andgene transcription factors such as activating protein-2(AP-2) and cAMP response element-binding protein(CREB). See also: Axonal Transport and the NeuronalCytoskeleton

Biosynthesis of AdrenalineAdrenaline is the methylated derivative of noradrenaline.Conversion of noradrenaline into adrenaline depends onthe enzyme PNMT and so the expression of PNMT is thecriterion for distinguishing the adrenaline-releasing neur-onal phenotype. The richest source of PNMT is the chro-maffin tissue of the adrenal medulla, but it is alsoprominent in the brain, retina and heart. It is even found in

astrocytes, which are one type of specialised non-neuronalcells in the brain, known as glia. Adrenaline can also beformed from noradrenaline by a less specific enzyme,

N -methyltransferase. This enzyme is prevalent in thebronchi, liver and kidney, but whether neurons in these

Dopamine

DOPA

DOPA decarboxylase

T yrosine hydroxylase

Tyrosine

Adrenaline

PNMT

NA

DβH

Figure 4 The synthetic pathway for noradrenaline (NA) and adrenaline in

neuron terminals and chromaffin cells. Tyrosine, derived from the diet, is

taken up into catecholamine-secreting neurons, where it is converted into

l -DOPA in the neuronal cytoplasm. After conversion of l -DOPA into

dopamine, the latter is taken up into the storage vesicles, where it is

converted into NA by the enzyme DbH. NA that leaks out of the vesicles is

converted into adrenaline in the cytoplasm of neurons that contain PNMT.

Vesicle stores of NA and adrenaline are maintained by active uptake via a

protein transporter in the vesicle membrane.



























tissues actually synthesise and release adrenaline under

normal conditions is not known.PNMT is a cytoplasmic enzyme that requires the methyl

donor, S -adenosylmethionine (SAM), as a cofactor. Nor-

adrenaline is the preferred endogenous substrate forPNMT, but high concentrations of noradrenaline inhibit

PNMT activity. The continuous leakage of noradrenalinefrom the storage vesicles into the cytoplasm, down itsconcentration gradient, gives PNMT access to its substrateand enables the synthesis of adrenaline. However, bothadrenaline and noradrenaline are substrates for the vesiclemembrane-associated transporters. These are protonantiporters that return these transmitters from the cyto-plasm to the storage vesicles. See also: Binding Constants:Measurement and Biological Range; NeurotransmitterTransporters

Experiments carried out by Julius Axelrod, in the 1960s,showed that removal of the pituitary gland (hypophy-sectomy) reduced the activity of PNMT in the adrenalmedulla. This finding strongly suggested that PNMTactivity in the adrenal gland was increased by glucocorti-

coid hormones (e.g. corticosterone or cortisol), which aresecreted from the adrenal cortex (shell) in response to thepituitary hormone, adrenocorticotropin. The efficiency of

the stimulation of PNMT activity by glucocorticoids isoptimised by an intra-adrenal portal vascular system whichdelivers hormones secreted from the adrenal cortex directly

to the adrenal medulla. It is now known that PNMT genetranscription is augmented by a brief exposure to gluco-corticoids, equivalent to a dose of hormone that would beexperienced during a bout of stress. Under normal con-

ditions, activation of PNMTsynthesis by glucocorticoids isprobably already maximal because it is not increased inpatients suffering from hypercortisolaemia (as in Cushingdisease). However, glucocorticoids also prevent degrad-ation of PNMT: this process depends on the methyl donor,SAM. It is thought that SAM induces a conformationalchange in the PNMT protein molecule that renders it lessvulnerable to proteolysis. See also: Adrenal Disease;Axelrod, Julius

Other processes that increase PNMT synthesis in theadrenal medulla include activation of nicotinic and mus-carinic receptors. These cholinergic receptors recruit dif-ferent second messenger systems and stimulate PNMT

gene expression in different ways. The actions of muscari-nic receptors involve an intermediate early gene product,Egr-1. The mechanism underlying the stimulation of PNMT gene expression by nicotinic receptorsis not certainbut could involve mobilisation of intracellular Ca2+ storesor activation of the PNMT gene promotor by a novel

regulatory process (nicotine-responsive element) (Evingeret al., 2005). Several hormones, such as progesterone andoestradiol, also modify the expression of gene transcriptionfactors (Egr-1, AP-2, Sp1 and MAZ0) that influence thesynthesis of PNMT. See also: Calcium Signalling andRegulation of Cell Function; Muscarinic Acetylcholine

Receptors; Nicotinic Acetylcholine Receptors; Transcrip-tional Gene Regulation in Eukaryotes

Little is known about the regulation of PNMT activity/

gene expression in the brain. However, adrenaline-releasing neurons are richly endowed with glucocorticoidreceptors and, drawing parallels with the noradrenaline

system, the regulation of adrenaline synthesis in neuronsis likely to resemble that in the adrenal medulla.

Influence of Noradrenaline onBehaviour

A good deal of research of the role of noradrenaline in thebrain hasconcentrated on thelocuscoeruleus,whichhas anundisputed role in modulating arousal (Berridge et al.,2012). The spontaneous firing rate of noradrenergic neu-rons projecting from this nucleus increases with arousalstate and is greater during quiet waking (1–2 spikes persecond) than during slow-wave sleep (0.2–0.5 spikes persecond) and is increased still further when animals changefrom vegetative or consummatory behaviours (e.g.grooming or feeding) to periods of vigilance. Because theincrease in the firing rate anticipates changes in arousal,neurons in thelocuscoeruleus arethought to be responsiblefor thalamocortical desynchronisation and the ensuingbehavioural changes. Destruction of the locus coeruleusincreases slow-wave sleep and some cells (‘rapid eye-movement (REM)-off’ cells) stop firing altogether duringREM (paradoxical) sleep. Yet, it is unlikely that nor-

adrenaline release is needed for the waking state because

animals with more than a 90% lesion of noradrenaline-releasing neurons in the brain are still capable of (quiet)waking periods. See also: Sleep

There is less agreement about the role of central nora-drenergic neurons during waking itself (Sara, 2009).Certainly, their activityis increased by sensory stimuli andshows a characteristic brief (phasic) burst of activity fol-lowed by a quiescent period of poststimulus inhibition.Stimuli that activate these neurons include not onlynoxious and internal (‘interoceptive’) stimuli but alsonon-noxious environmental stimuli (e.g. tones and lightflashes), especially those that provoke attention to specificstimuli (e.g. approach of the experimenter). However, not

all arousing stimuli activate these neurons. For instance,thesight of rats, which have been confined within a distantcage, has no effect on firing rate of neurons in the cat’slocus coeruleus. Yet, this is evidently an arousing stimu-lus. Moreover, the neuronal response, along with behav-

ioural arousal, declines on successive presentations of astimulus, suggesting rapid habituation. On the basis of such findings, it was proposed that noradrenergic neuronsin the locus coeruleus serve as an alarm system that helpsto integrate adaptive responses to environmental chal-lenges. See also: Sensory Systems in Vertebrates: GeneralOverview

More recently, studies using the technique in vivomicrodialysis, which enables the measurement of changes





































in the concentration of extracellular noradrenaline (an

index of neurotransmission), have confirmed that this isincreased by a wide range of noxious and non-noxiousstimuli. In the frontal cortex, the concentration of extra-

cellular noradrenaline is even increased when rats areexposed to a conditioned (formerly neutral) cue (a tone)

that signals imminent exposure to a brightly lit novelenvironment, which rats find mildly aversive (McQuadeand Stanford, 2000). This response echoes early electro-physiological evidence for an increase in the firing rate of neurons in the locus coeruleus when rats are exposed to aconditioned cue for footshock. Such findings have led tothe suggestion that the salience of the stimulus is the keyfactor. Others have argued that noradrenergic neuronsrespond to a change in the salience of a stimulus.

More recent research has led to the ‘attentional shift’hypothesis, whereby an increase in the firing rate of nor-adrenaline-releasing neurons is thought to influence cog-nitive performance but does not affect the learning processdirectly. It is proposed that the tonic activity of theseneurons determines arousal, whereas phasic responses

determine attentiveness (Aston-Jones et al., 2000). More-over, the phasic response seems to depend on the under-lying tonic firing rate, and the relationship between the two

is described by a bell-shaped curve. As a consequence, anoptimal phasic response is evident only at intermediatelevels of tonic arousal. This proposal is consistent with the

relationship between noradrenergic transmission in thebrain and behavioural resistance to stress (Stanford, 1993).This is also thought to be described by a bell-shaped curve,such that an increase in noradrenaline transmission would

augment behavioural resistance to a mild stress butdiminish behavioural resistance to a severe stress. See also:Learning and Memory; Neuronal Firing PatternModulation

Few studies have investigated the role of neurons origi-nating in the lateral tegmental area on behaviour. It is clearthat these neurons respond to concurrent (unconditioned)environmental stimuli. They are also capable of adaptivechanges on repeated exposure to the stimulus; these chan-ges possibly contribute to behavioural habituation. How-ever, unlike the cortex, they do not develop a response toconditioned (formerly neutral) environmental stimuli(McQuade and Stanford, 2000).

These regional differences in the noradrenergic responsecould reflect the different sources of noradrenergic neuronsthat project to these two brain areas. Thus, it seems that

neurons in the locus coeruleus that innervate the frontalcortex can respond to conditioned cues, whereas neurons inthe lateral tegmental system, which innervate the hypo-thalamus, do not. Furthermore, it is likely that nora-drenergic inputs to higher brain circuits encode contextualaspects of aversive stimuli, whereas those innervating lowerbrain circuits are more concerned with the flight/fightresponse to unconditioned aversive stimuli. This proposalresembles a scheme already proposed to explain the role of

different groups of serotonergic neurons in the response tostress and anxiety.

Regulation of Autonomic Function byNoradrenaline and Adrenaline

Each of the catecholamine nuclei in the brainstem hasnumerous connections with, and receives reciprocal

innervation from, other brainstem nuclei as well as higherbrain centres. The overall influence of noradrenaline andadrenaline on autonomic function will depend on the neteffect of all these neuronal links. Although different clustersof catecholaminergic neurons in the brainstem probably

have different roles in the regulation of autonomic func-tion, there is still no clear picture of the effects of thiscomplex network on neuronal circuits on higher brain

centres or the periphery. Reasons for this include:

. Experiments investigating the regulation of autonomicfunction usually require anaesthesia, which disruptsautonomic control. The development of in vivo telemetry

is helping to resolve this problem.. Neuronal lesions or electrical stimulation can easily

disrupt the function of other neurons whose axons passthrough the brain region being tested.

. The coexistence, and possible corelease, of neuropep-tides (e.g. galanin, neuropeptide Y and substance P)makes it extremely difficult to tease out the specific rolesof catecholamines.

. Central actions of noradrenaline and adrenaline can beeither excitatory or inhibitory, depending on which of the many receptors for these transmitters are activated.

. Release of endogenous neurotransmitters and adminis-tration of exogenous drugs are likely to activate different

populations of receptors (i.e. synaptic versus extra-synaptic transmission).

Despite these difficulties, there is strong evidence thatnoradrenaline-releasing neurons in the A1 and A2 nucleiinnervate preganglionic sympathetic neurons in the spinalcord and modulate blood pressure. The A1-noradrenergic-derived neurons are thought to operate indirectly byinhibiting C1 (adrenaline releasing) neurons. A2-derivedneurons possibly act indirectly. Neurons in the A2 nucleusare thought to have an important role in autonomic regu-lation and project to several medullary centres including

the cell bodies of neurons that slow down heart rate.Neurons in the A5 and A7 nuclei mainly innervate the

spinal cord and they seem to regulate the activity of preg-anglionic, sympathetic neurons. Stimulation of the neu-rons in the A5 nucleus generally reduces blood pressure,but there are marked regional differences in the response.

The A6 nucleus has a pivotal role in regulating auto-nomic activity and synchronising peripheral autonomicfunction with arousal. The firing rate of neurons in thisnucleus closely parallels the activation of sympatheticneurons and inhibition of parasympathetic neurons in theperiphery. This is achieved through its projections to thespinal cord and also via brain regions that maintainhomoeostasis (e.g. the hypothalamus).











The integration of these responses could well be the role

of the PGi, which is one of the major inputs to the locuscoeruleus (see above). This nucleus is thought to act as arelay between environmental stimuli and autonomic acti-

vation. Such coordination of the activity of noradrenalineneurons in the locus coeruleus and peripheral sympathetic

neurons could help to synchronise cognitive and auto-nomic responses (Samuels and Szabadi, 2008a, b).

Even less is known about the role of central adrenaline-releasing neurons in regulation of the autonomic system.The C1 cell group of neurons is a major source of projectionsto the spinal cord, but it is not certain that they make directconnections with preganglionic sympathetic neurons.Nevertheless, the firing rate of neurons in the C1 area issynchronised with the cardiac rhythm and these neurons arethought to have a key role in autonomic control.

Most ascending pathways, particularly those from thelocus coeruleus, help to regulate complex behaviours andthere are parallel, indirect changes in autonomic activity.Both noradrenaline- and adrenaline-releasing neurons inthe brainstem innervate the hypothalamus. The hypo-

thalamus, in turn, has reciprocal connections with cat-echolamine-releasing nuclei in the medulla and helps tocoordinate autonomic function. Release of noradrenaline

and adrenaline in the hypothalamus influences hormonesecretion and this will cause further, secondary, changes inautonomic activity. In these ways, medullary catechola-

minergic nuclei could modulate activation of the locuscoeruleus and higher centres, as well as influence theactivity of sympathetic neurons. Obviously, higher centres,such as the amygdala, will influence this process and are

doubtless involved in the modulation of autonomic func-tion by emotionally arousing stimuli. See also: Adrenalineand Noradrenaline; Hypothalamus

Summary

The distribution of noradrenaline and adrenaline in thebrain and periphery suggests that these catecholamines

have pivotal roles in the regulation and synchronisation of arousal and the activity of the autonomic nervous system.The neurochemical plasticity of these neurons, evidenced

by the adaptive changes in the enzymic machinery for

manufacturing their neurotransmitters, confirms that theseneurons are capable of responding to changing demands on

their functional output. The extent to whichnoradrenaline-and adrenaline-releasing neurons are capable of functionalor temporal specificity, in terms of either the stimuli thatactivate them or the signals they transmit to higher centres,is as yet unclear but has probably been underestimated.

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Further Reading

BradingA (1999) The AutonomicNervous System and its Effectors.

Oxford: Blackwell Science.

Fillenz M (1990) Noradrenergic Neurons. Cambridge, UK:

Cambridge University Press.

Iversen L, Iversen S, Bloom Fe et al . (2009) Introduction to Neu-

ropsychopharmacology . Oxford: Oxford University Press.

ISBN-10: 0195380533 | ISBN-13: 978-0195380538.

Steckler T, Klain NH and Reul JMHM (2005) Handbookof Stress

and the Brain. Amsterdam: Elsevier. ISBN: 0-444-51822-3.

Trendlenburg U and Weiner N (eds) (2012) Catecholamines II

(Handbook of Experimental Pharmacology) Vol. 90/II, ISBN-

10: 3642735533 | ISBN-13: 978-3642735530. Heidleberg:

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