Amine Neurotransmitters Introductory article

Sandra M Pearl, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Article Contents

Michael J Zigmond, University of Pittsburgh, Pittsburgh, Pennsylvania, USA . Amines: Neurotransmitters at Different Sites in the
Nervous System
. Biosynthesis of Amine Neurotransmitters in Nerve
Biogenic amines can serve as neurotransmitters, released from one nerve to act on Terminals
another. Amine neurotransmitters, such as dopamine, serotonin, norepinephrine and . Amino Acid Hydroxylases: Rate-limiting Steps in the
epinephrine are important in many physiological functions including sleep, arousal, Synthesis of Amine Neurotransmitters

reinforcement and regulation of heart rate and blood pressure. . Storage and Release of Amines
. Amine Catabolism by Monoamine Oxidase
. Inactivation of Amine Neurotransmitters by High-
Amines: Neurotransmitters at Different affinity Uptake

Sites in the Nervous System . Postsynaptic Actions of Biogenic Amines

. Regulation of Aminergic Function

Amines (also called biogenic amines) serve as chemical . Summary

transmitters, allowing one cell to influence the activity of

another. Most of the cells that manufacture and release
these substances are neurons, and such neurons are Amines were first identified in the central nervous system
referred to as aminergic neurons. The amines were the by Ulf Von Euler (1946), Marthe Vogt (1954) and Bengt
first compounds to be described as neurotransmitters, Falk (1962) using newly developed biochemical and
having been proposed as transmitters by Thomas Elliott in histochemical procedures. Most aminergic neurons have
1904. They are found throughout the phylogenetic scale their cell bodies located in the midbrain and send their
and have been implicated in a wide variety of processes, axons into higher brain regions (Figures 3 and 4). Dopami-
including the regulation of heart rate and blood pressure, nergic pathways originate in the substantia nigra and
digestion, movement, emotions, arousal, sleep and re- ventral tegmental area and terminate in striatal, limbic and
inforcement. Dysfunctions of aminergic neurons also cortical areas of the brain. Noradrenergic pathways
appear to be involved in the aetiology of many neurological originate in two principal brainstem nuclei, the locus
and psychiatric diseases. These include some forms of ceruleus and the lateral tegmental nuclei. These noradre-
hypertension, phenylketonuria, Parkinson disease, schizo- nergic neurons send broad, profuse projections through-
phrenia and depression. Most of the drugs that are used to out the brain. Most serotonergic pathways originate in the
treat these conditions act in some way on aminergic raphe nuclei of the midbrain and terminate in many
systems or their receptors. forebrain regions, including the cortex, hippocampus,
Amines have a two-carbon side-chain ending in an striatum and limbic regions. Dopamine, noradrenaline and
amino group (R–C–C–NH3) and can be divided into two serotonin pathways also project to the spinal cord.
major categories. The largest of these categories are the Although each of these neurotransmitter systems is
catecholamines, which include dopamine, noradrenaline found in separate and discrete brain regions, their
(norepinephrine) and adrenaline (epinephrine). In each of synthesis, release, storage, regulation and metabolism
these compounds, the amine side-chain is attached to a share many commonalities. These are the topics on which
catechol ring (Figure 1). The second category consists of a this article will focus. Several other topics will not be
single compound, 5-hydroxytryptamine (serotonin, 5-HT) discussed due to space limitations but can be explored
in which the amine side-chain is attached to an indole ring using the references provided.
(Figure 2). There are additional biogenic amines, including
histamine and the polyamines, but these will not be
discussed further.
Biogenic amines play key roles in the peripheral nervous Biosynthesis of Amine
systems, as shown by the pioneering studies of Otto Loewi, Neurotransmitters in Nerve Terminals
Walter Cannon and others in the 1920s and 1930s.
Noradrenaline is the transmitter used by the sympathetic Much is known about the synthesis of amines from their
nervous system to regulate the contraction of smooth and amino acid precursors, tyrosine and tryptophan. In
cardiac muscle, functions reinforced by adrenaline and catecholaminergic neurons (Figure 1), the amino acid
noradrenaline released as hormones from the adrenal tyrosine is actively taken up from the bloodstream and
medulla. Serotonin, on the other hand, serves as a extracellular fluid into the cytoplasm, where it is converted
transmitter in the enteric nervous system and helps to to dihydroxyphenylalanine (DOPA) by the specific enzyme
regulate gastrointestinal function. tyrosine hydroxylase, the rate-limiting step in this path-

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 Amine Neurotransmitters

NH2 NH2
HO CH2C COOH CH2 C COOH
H
H
N
L-Tyrosine Tryptophan

Tyrosine hydroxylase Tryptophan

(tetrahydrobiopterin, O2) hydroxylase

NH2
HO
HO CH2 C COOH
NH2 H
HO CH2C COOH N
H 5-Hydroxytryptophan

L-DOPA
Aromatic
amino acid decarboxylase
DOPA decarboxylase
(pyridoxal phosphate)
HO CH2 CH2 NH2

HO
N
Serotonin (5-HT)
HO CH2CH2NH2
Figure 2 Biosynthetic pathway for serotonin. From Seigel GJ, Agaranoff
BW, Alberts RW, Fisher SK and Uhler MD (eds) (1998) Basic Neurochemistry:
Molecular, Cellular and Medical Aspects, 6th edn. Philadelphia: Lippincott-
Dopamine
Raven.
CC HC
Dopamine β-hydroxylase
(ascorbate, O2)

HO
MFB
SM
HO CHCH2NH2
OH

Noradrenaline (a) HY LC

Phenylethanolamine
N-methyltransferase ACC
(S-adenosylmethionine) FC

HO
ST
AIO
HO CHCH2NHCH3 SN
OH
AC
Adrenaline OT
(b) ME
Figure 1 Biosynthetic pathway for the catecholamines, dopamine,
noradrenaline and adrenaline. From Seigel GJ, Agaranoff BW, Alberts RW, Figure 3 (a) Noradrenergic pathways in the rat brain. (b) Dopaminergic
Fisher SK and Uhler MD (eds) (1998) Basic Neurochemistry: Molecular, neuronal pathways. AC, nucleus accumbens; A10, ventral tegmental area;
Cellular and Medical Aspects, 6th edn. Philadelphia: Lippincott-Raven. ACC, anterior cingulate cortex; CC, corpus callosum; FC, frontal cortex;
HC, hippocampus; HY, hypothalamus; LC, locus ceruleus; ME, median
way. DOPA is then converted to dopamine by the actions eminence; MFB, median forebrain bundle; OT, olfactory tubercle; SM, stria
medullaris; SN, substantia nigra; ST, striatum. From Seigel GJ, Agaranoff
of a more general l-aromatic amino acid decarboxylase, BW, Alberts RW, Fisher SK and Uhler MD (eds) (1998) Basic Neurochemistry:
which is dependent upon pyridoxal phosphate. As its name Molecular, Cellular and Medical Aspects, 6th edn. Philadelphia: Lippincott-
implies, this enzyme is relatively nonspecific and it also Raven.

2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
 Amine Neurotransmitters

Olfactory bulb
Cortex Hippocampus
Glomerular
layer

Spinal trigeminal
C. Put nucleus
H
B7
T B6
B8 B4
G. Pal
OT B9 B5 B2 B1
Septum B3
B3 B3
Medulla
Nucleus suprachiasmaticus Pons oblongata
Hypothalamus Substantia nigra
Median eminence Amygdala Spinal cord

Figure 4 Major serotonergic pathways in the rat brain. C. Put, nucleus caudate-putamen; G. Pal, globus pallidus; H, habenula; OT, olfactory
tuberculum; T, thalamus. From Seigel GJ, Agaranoff BW, Alberts RW, Fisher SK and Uhler MD (eds) (1998) Basic Neurochemistry: Molecular, Cellular
and Medical Aspects, 6th edn. Philadelphia: Lippincott-Raven.

serves to decarboxylase 5-hydroxytryptamine. In addition, Amino Acid Hydroxylases: Rate-limiting

some years ago it was discovered that the enzyme can
decarboxylate the antihypertensive drug a-methlydopa to
Steps in the Synthesis of Amine
form a-methyldopamine, which is then converted by Neurotransmitters
dopamine b-hydroxylase (see below) to a-methylnoradre-
naline. This latter compound can then serve as a false Tyrosine hydroxylase and tryptophan hydroxylase are
transmitter, displacing catecholamines from their storage specific enzymes, both with respect to their localization and
sites. their substrate requirements. In this regard, they are
There are normally very low levels of DOPA in the distinct from each other and from both phenylalanine
cytoplasm. This is because the amount of decarboxylase hydroxylase and tyrosinase, two other hydroxylating
enzyme (the Vmax) and its affinity for DOPA are both high enzymes. The two enzymes are rate-limiting in the
(i.e. the Km is low), and thus the decarboxylation reaction formation of amines and, as we will see, are important
proceeds very rapidly. Since the decarboxylase is present in regulatory points in the biosynthetic pathways.
great excess, it is not usually a target for drug action. These mixed-function oxidases are located in the
Once formed, dopamine is concentrated in synaptic cytoplasm and are known to be dependent upon molecular
vesicles by a vesicular monoamine transporter; it can be oxygen, iron and the cofactor tetrahydrobiopterin. They
stored there for later release. In noradrenergic neurons, function in environments with subsaturating concentra-
dopamine is metabolized within the vesicles to noradrena- tions of most, if not all, of their substrate, and thus their
line by dopamine b-hydroxylase, which requires ascorbic rate of formation can be influenced by fluctuations in
acid. Dopamine b-hydroxylase can be inhibited by substrate availability. The essential cofactor tetrahydro-
disulfiram. biopterin is formed by the actions of dihydropteridine
In adrenergic neurons and in adrenal medullary reductase, an enzyme requiring a reduced pyridine
chromafin cells most of the noradrenaline exits from nucleotide such as the reduced form of nicotinamide-
the vesicles into the cytoplasm, where it is converted adenine dinucleotide (NADH).
to adrenaline by phenylethanolamine-N-methyltransfer- Tyrosine hydroxylase is a highly specific enzyme but can
ase before being resequestered in the vesicles. This also hydroxylate phenylalanine to tyrosine. Tyrosine
occurs in the presence of S-adenosylmethionine and hydroxylase can be competitively inhibited by the drug a-
can be stimulated by glucocorticoids from the adrenal methyl-r-tyrosine, an analogue of tyrosine, and by
cortex. catechols, including dopamine and noradrenaline. Tryp-
Serotonin is synthesized from the amino acid trypto- tophan hydroxylase is also specific and can be inhibited by
phan in a series of steps closely resembling dopamine the drug p-chlorophenylalanine.
synthesis (Figure 2). First, the amino acid tryptophan is
taken up by the same transport system used by
tyrosine (and other aromatic amino acids) into the
cytoplasm. Next, it is converted to 5-hydroxytryptophan Storage and Release of Amines
by tryptophan hydroxylase. This 5-hydroxytryptophan is
then rapidly converted to serotonin by amino acid After their synthesis, amines may either be packaged into
decarboxylase. vesicles or remain free in the cytoplasm, where they are

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 Amine Neurotransmitters

subject to degradation by enzymes. Uptake into vesicles hypertension or depression, care must be taken to avoid
occurs via a general monoamine vesicular transporter diets high in compounds such as tyramine. Without rapid
located on the vesicular membrane and is dependent upon deamination by MAO-B, such compounds can act as false
adenosine triphosphate (ATP) and Mg2 1 . These trans- transmitters, displacing endogenous catecholamines and
porters function by pumping protons into the vesicle, causing an acute hypertensive crisis.
creating an electrochemical gradient that drives the entry Extracellular catecholamines can be metabolized by
of neurotransmitter into the vesicle. COMT, which depends upon magnesium and S-adenoyl-
There are several drugs that may interfere with the methionine. This enzyme converts extracellular dopamine
function of the monoamine transporters. Reserpine, for into 3-methoxy-tyramine (3-MT) and noradrenaline into
instance, inhibits the transporter and thereby prevents normetanephrine. Both MAO and COMT can act on the
amines from being packaged into vesicles. Thus, in products of the other. Thus, for example, COMT can also
reserpinized animals amine levels become severely de- O-methylate DHPG to form 3-methoxy-4-hydroxyphe-
pleted, and these animals have been used as an experi- nylglycol (MHPG).
mental model of Parkinson disease.
Once in a vesicle, amines are available for release. In
general, this process is dependent on the influx of Ca2 1
into the nerve terminal in response to an action potential Inactivation of Amine
that opens voltage-sensitive Ca2 1 channels. This influx of Neurotransmitters by High-affinity
Ca2 1 promotes the fusion of the vesicle to the neuronal
membrane, resulting in the release of neurotransmitter into Uptake
the extracellular space through a process called exocytosis.
Exocytosis may be blocked by inhibitors of calcium- Julius Axelrod, who discovered COMT (1957), also
binding proteins. Vesicles that have released their contents discovered reuptake (1959), the capacity of aminergic
into the synapse are then retrieved and recycled. neurons to transport their transmitters from extracellular
Amine neurotransmitters may also be released by a space back into the nerve terminal. This is a major form of
process that is independent of Ca2 1 and exocytosis. For inactivation of released amine neurotransmitters and
example, amphetamine disrupts the vesicular storage of involves specific transporter systems located on the outer
amines and promotes release from the nerve terminal by membrane of the neuron. Dopamine, noradrenaline and
leakage or by reversing the normally inward-directed high- serotonin in the extracellular environment that do not
affinity uptake transporters. It has been suggested that diffuse away or get metabolized can be taken back up via
reverse (or carrier-mediated) transport can also occur in presynaptic transporters into the cytoplasm. This process,
response to physiological stimuli. often termed high-affinity uptake, is sodium-and tempera-
ture-dependent and can be inhibited by agents that
interfere with sodium gradients, such as ouabain and
veratridine.
Amine Catabolism by Monoamine There are specific high-affinity transporters for dopa-
Oxidase mine, noradrenaline and serotonin; however, these trans-
porters show considerable structural homology and each
The catabolism of amines is carried out by several enzymes, consists of 12 membrane-spanning regions. Once an amine
the principal ones being monoamine oxidase (MAO) and, has been taken back up into the terminal by high-affinity
in the case of catecholamines, catechol-O-methyltransfer- transporters the neurotransmitter is again subject to
ase (COMT). MAO is a flavin-containing enzyme found on degradation by intracellular enzymes or may be repack-
the outer membranes of mitochondria. This intracellular aged into vesicles. Several drugs act by inhibiting one or
enzyme metabolizes cytoplasmic dopamine into dihydro- more of these high-affinity transporters: nomifensine
phenylacetic acid (DOPAC) noradrenaline into 3,4-dihy- inhibits the dopamine transporter; desipramine, the uptake
droxyphenylglycol (DHPG), and serotonin into 5- of noradrenaline; cocaine, the transport of both catecho-
hydroxyindolacetic acid (5-HIAA). There are two main lamines; and fluoxetine, the uptake of serotonin.
isozymes of MAO, MAO-A and MAO-B. MAO-A
preferentially metabolizes serotonin and noradrenaline.
MAO-B is a less specific inhibitor; in addition to
deaminating dopamine, it also acts on amines such as
Postsynaptic Actions of Biogenic
tyramine, which are present in many foods. Amines
Pargyline inhibits both isoforms of MAO, whereas
clorgyline acts selectively on MAO-A and deprenyl acts on Neurotransmitter receptors can be roughly divided into
MAO-B. When an MAO inhibitor that affects MAO-B two categories: ionotropic and metabotropic receptors.
(e.g. pargyline or deprenyl) is used in the treatment of Ionotropic receptors are coupled to ion channels and have

4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
 Amine Neurotransmitters

a rapid and direct impact on transmitter release. In

contrast, metabotropic receptors act via second messenger
systems and have a comparatively slow effect on the
postsynaptic cell, usually by modulating the actions of
ionotropic receptors. The amines act exclusively on 2b
families of metabotropic receptors, most of which are G- 4 2a
protein coupled, seven-transmembrane proteins. Presently 6
at least five such receptors exist for dopamine (D1–5), two 3a
for noradrenaline (a and b) and seven for serotonin (5- 3b
HT1–7). Actually, many of these receptors can exist in 5
1
several subtypes. For example, five subtypes of the 5-HT1
receptor have been identified to date.
In some instances these receptors may be immediately
postsynaptic to the aminergic terminal from which the
transmitter is released. In other cases, however, the Figure 5 Regulatory pathways influencing amine release. Some of the
receptors may be some distance away. The resulting feedback loops that act to keep the output of a neuron relatively constant
are shown. These may include: (1) terminal autoreceptor regulation;
nonsynaptic transmission (or ‘volume transmission’) (2a12b) terminal–terminal heteroreceptor regulation; (3a13b)
would be expected to act even more slowly than does more multisynaptic feedback loops; (4) axon collaterals; (513b) dendritic–
classical metabotropic synaptic transmission. terminal heteroreceptor regulation; and (6) dendritic autoreceptor
A large group of drugs act by inhibiting one or more of regulation. Not shown are even longer feedback systems that may involve
the aminergic receptors; for example, most dopamine physiological or regulatory pathways for amine synthesis or the sensitivity
of target cells to the transmitter. From Bloom FE and Kupfer DJ (eds) (1995)
receptors are blocked by chlorpromazine, whereas halo- Psychopharmacology: The Fourth Generation of Progress.
peridol only acts on a subset of dopamine receptors,
termed the D2 family, ketanserin selectively blocks 5-HT2 However, for this to occur, several additional steps must
receptors and propranolol blocks the b2 receptor. A few take place. Once new mRNA has been formed (transcrip-
drugs act as receptor agonists; for example, apomorphine tion), the synthesis of new hydroxylase protein must occur
activates dopamine receptors and isoproterenol activates (translation), followed by the transport of that protein to
noradrenergic b receptors. the nerve terminal (axonal transport) and its activation
(posttranslational modification). Thus, the complete pro-
cess may take several days.
For very rapid responses to increased demand for amine,
Regulation of Aminergic Function many neurons can act by directly increasing the activity of
the hydroxylase enzyme. Short-term regulation of amine
Aminergic neurons are essential for normal life. Without
synthesis can happen in at least two ways. First, high levels
them, many physiological and behavioural functions are
of neuronal amines may compete directly at the biopterin
severely impaired. Thus, it should not be surprising that a
site on the hydroxylase molecule to inhibit the activity of
host of processes exist to regulate virtually every aspect of
the enzyme. This is called end-product inhibition. In-
aminergic function, including the rate of synthesis, release
creased transmitter release can reduce the cytoplasmic
and inactivation of the amine transmitters as well as the
concentration of amine, decrease end-product inhibition,
sensitivity of target cells to the transmitters (Figure 5).
and increase amine synthesis.
A second process by which synthesis can be increased in
Synthesis some aminergic neurons is by the covalent modification of
the hydroxylases, a process that involves phosphorylation
The amount of neurotransmitter available for release is and serves to increase the affinity of the enzyme for
itself subject to regulation at many levels. One way to biopterin cofactor. The mechanism by which this post-
modulate neuronal levels of amines is to alter amine translational modification occurs is not clear but it may
synthesis. When the trans-synaptic input to an aminergic involve a depolarization-induced increase in cytoplasmic
neuron remains high for more than a few minutes, many cyclic adenosine monophosphate (cAMP) and/or Ca2 1 .
neurons will respond by increasing the formation of the
messenger ribonucleic acid (mRNA) coding for the
hydroxylase enzymes. Conversely, when the input to these Release
neurons is low, the rate of formation of the specific mRNAs
is decreased. The rate at which amines are released is also regulated in
Regulating mRNA levels of enzymes is the first in a several ways. First and foremost, exocytosis is driven by
sequence of steps that presumably function to maintain a the rate at which action potentials arrive at the nerve
constant store of amines within the nerve terminal. terminal. In addition, however, the levels of neurotrans-

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 Amine Neurotransmitters

Table 1 Selected characteristics of neurotransmitters

Reuptake into
Location of synthesis Membrane receptor terminal Nature of action
Acetylcholine Terminal Yes No Ionotropic, Metabo-
tropic
Amines Terminal Yes Yes Metabotropic
Amino acids Terminal Yes Sometimes Ionotropic, Metabo-
tropic
Nitric oxide Terminal No No
Peptides Cell body and axon Yes No Metabotropic

mitters within the extracellular space can alter this system uses amino acids, peptides, gases such as nitric
response. For example, a high concentration of extra- oxide, and acetylcholine. Each class has a unique
cellular amines results in the activation of presynaptic combination of properties (see Table 1). For example,
autoreceptors which can, in turn, decrease the release (and whereas amines and most other transmitters are synthe-
the synthesis) of amine in response to a subsequent action sized in nerve terminals, peptide biosynthesis is initiated in
potential. In addition, other transmitters, such as acet- the cell body and completed along the axon. Several
ylcholine and glutamate, can influence the rate of release at transmitters, including all of the amines, are inactivated by
many aminergic neurons via an action on presynaptic being taken back up into nerve terminals; however, some
heteroreceptors. are not. Also, although the amines act on membrane
receptors through second messengers resulting in an action
that has a slow onset and a long duration (metabotropic),
Inactivation some transmitters act on membrane receptors to cause very
rapid, short-duration charges in ion channels (ionotropic).
It is also possible that transport is regulated by physiolo-
The combination of properties exhibited by a class of
gical events. For example, high-affinity uptake into a
transmitters underlies the unique functions that those
neuron is inhibited during depolarization of the neuron,
transmitters play. In the case of amines, these functions
whereas repetitive stimulation of some dopaminergic
involve the highly regulated, gradual modulation of the
neurons can interfere with the clearance of extracellular
action of other transmitters that exert much more rapid
dopamine by blocking the dopamine transporter.
influences on their targets.

Target cell sensitivity

Regulation of synthesis, release and inactivation deter- Summary
mines the availability of transmitter; regulation of
receptors on the target determines the extent to which that Amine neurotransmitters play important roles in both the
transmitter is transduced into a postsynaptic signal. peripheral and central nervous systems, being involved in
Postsynaptic regulatory processes may involve altering such varied processes as regulation of blood pressure and
the number of postsynaptic receptors or influencing the reinforcement of behavioural acts. The amines share many
coupling of receptor activation to second messenger similarities in their synthesis, release, inactivation and
systems. For example, a long-term reduction in the receptors, processes that are often highly regulated in a
availability of a particular amine, such as might occur manner that appears homeostatic in nature. Amines seem
with chronic receptor antagonist or the degeneration of the to act primarily to modulate the actions of other
aminergic neuron, can lead to an increase in receptor transmitters and may sometimes act at a considerable
number (receptor upregulation). Likewise, excessive sti- distance from their site of release. Dysfunction in amine
mulation of a target can cause receptor downregulation in systems can lead to a variety of physiological, neurological
some systems. On the other hand, under certain conditions or psychiatric disorders, and many drugs used in the
continual activation of an aminergic neuron can cause treatment of these conditions act to either increase or
sensitization, by which the responsiveness of a target to decrease function at aminergic synapses. It seems likely
subsequent amine is actually increased. that further understanding of the amines will provide
The nervous system utilizes several different classes of additional insights into normal processes as well as the
neurotransmitters. In addition to the amines, the nervous aetiology and treatment of disease.

6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2002 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net
 Amine Neurotransmitters

Further Reading Frazer A and Hensler JG (1998) Serotonin. In: Seigel GJ, Agranoff BW,
Albers RW, Fisher SK and Uhler MD (eds) Basic Neurochemistry, 6th
Cooper JR, Bloom FE and Roth RH (1996) The Biochemical Basis of edn, pp. 263–292. Philadelphia: Lippincott-Raven.
Neuropharmacology, 7th edn. New York: Oxford University Press. Kuhar MJ, Couceyro PR and Lambert PD (1998) Catecholamines. In:
Deutch AY and Roth RH (1999) Neurotransmitters. In: Zigmond MJ, Seigel GJ, Agranoff BW, Albers RW, Fisher SK and Uhler MD (eds)
Bloom FE, Landis SC, Roberts JL and Squire LR (eds) Fundamental Basic Neurochemistry, 6th edn, pp. 243–261. Philadelphia: Lippincott-
Neuroscience, pp. 193–234. San Diego: Academic Press. Raven.

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