Graduate Psychology

II. NEUROTRANSMITTERS

in Neuropharmacology

from Encyclopedia of the Human Brain

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The known number of neurotransmitters occurring naturally in the human nervous system appears to grow progressively as our

investigational tools become more sensitive and sophisticated. Currently, Table I represents a reasonable articulation of the known

human neurotransmitters; the reader should be aware that, in another decade, this table will be, perhaps substantially, larger and will

likely include a number of surprises as our knowledge base grows.

Literally, a book chapter could be written about each of the categories of neurotransmitters in Table I. However, the clinical focus of

this article dictates that we restrict our discussion to those neurotransmitters that currently have utility in clinical medicine. Although

intense research effort is being applied to evaluating the clinical significance of many, if not all, of the neurotransmitters in the table,

our focus here will be on the amine category.

A. Serotonin

Serotonin, or 5-hydroxytryptamine (5HT), is perhaps the most widely known neurotransmitter in a popular sense. The reason for this is

the massive press given to the drug Prozac, a NA that results in an increase in the amount of serotonin available around neurons, a

feat accomplished by inhibiting the destruction of serotonin. Serotonin or 5HT was originally discovered in the gastrointestinal mucosa

in the 1940s. Its chemical structure is very similar to the amino acid tryptophan, which is, in fact, the dietary precursor of 5HT itself. 5HT

is found in virtually all vertebrate organisms, as well as in many invertebrates such as wasps, scorpions, and ocean crustaceans. It is

also found in abundance in several plant species, including bananas and pineapples. Although a neurotransmitter of major importance,

5HT is distributed throughout the body. Interestingly, approximately 90° of the total 5HT in the human body is in the gastrointestinal

tract, 8° is in blood platelets (where it is involved in the clotting process), and only 2° is in the central nervous system. 5HT is

synthesized in the terminal end of the neuron and transported to synaptic vesicles (cystlike structures that exist at the neuronal cell

membrane), from which it is released into the synapse for interaction with receptors in adjacent neurons. Once released freely into

the synaptic space, molecules of 5HT will either stimulate receptors in other neurons or they will interact with autoreceptors from their

original neuron (the neuron that produced them). Interaction with adjacent neurons results in neurotransmission of a nature specific to

the type of adjacent neuron. Interaction with autoreceptors results in an important process called re-uptake. Neurotransmitter re-

uptake results in a decrease in the amount of the neurotransmitter (in this case 5HT) that is available in the synaptic space. Through

re-uptake, the 5HT neuron can exert modulatory control over the amount of serotonergic neurotransmission generated from that

neuron: net transmission can be reduced through the production of more autoreceptors, which, in turn, trap and destroy free 5HT

molecules in the synapse. By increasing the density of autoreceptors, the neuron reduces the amount of 5HT that can exert its effect

in the synapse. On the other hand, the nerve cell can increase serotonergic transmission by reducing production of autoreceptors,

thereby destroying less 5HT and thus increasing the net amount of serotonergic neurotransmission.

Table I Neurotransmitters in the Brain

Amines Serotonin (5HT)

Dopamine (DA)

Norepinephrine (NE)

Epinephrine (EPI)

Acetylcholine (ACH)

Pituitary peptides Corticotropin (ACTH)

Growth hormone (GH)

Lipotropin

Oxytocin

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Vasopressin

Melanocyte stimulating hormone

Circulating hormones Angiotensin

Calcitonin

Glucagon

Insulin

Amino acids y-Aminobutyric acid (GABA)

Glycine

Glutamic acid

Aspartic acid

Gastrointestinal hormones Cholecystokinin

Gastrin

Motilin

Secretin

Substance P

Vasoactive intestinal peptide

Opioid peptides Dynorphin

/B-Endorphin

Met-enkephalin

Leu-enkephalin

Kyotorphin

5HT is synthesized from the amino acid tryptophan. Tryptophan is hydroxylated to L-5-hydroxytrypto-phan, which is, in turn,

decarboxylated to the serotonin molecule itself. In addition to the preceding mechanisms at the neuron's disposal for regulating

serotonergic neurotransmission, it can also modulate the production of 5HT via the regulation of the activation state of the enzyme,

tryptophan hydroxylase. Once synthesized, 5HT is involved in a wide variety of behavioral processes, including hunger and food

intake, mood regulation, aggressive behavior and its control, sleep architecture, and anxiety and its regulation.

Two decades of research have yielded a listing of the clinical conditions that have been shown to be influenced by altered

serotonergic neurotransmission. Although surely not exhaustive, the list underscores the importance of serotonergic

neurotransmission processes and documents the wide-ranging distribution of 5HT systems. The disorders include mood disorders,

anxiety disorders, eating disorders, migraine headaches, neuro-degenerative processes and aging, obsessive compulsive disorder,

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substance abuse, pain sensitivity (chronic pain), posttraumatic stress disorder, schizophrenia, sexual dysfunction, and sleep disorders.

B. The Catecholamines: Dopamine, Norepinephrine, and Epinephrine

The catecholamines, including dopamine (DA), norepinephrine (NE), and epinephrine (EPI), belong to a group of neurotransmitters

called monoamines. These molecules contain a single amine (-NH2) group, a catechol nucleus (consisting of a benzene ring with two

hydroxyl groups), and a side chain consisting of an ethylamine or a closely related derivative. EPI was originally called adrenaline and

NE was called noradrenaline, as both were initially found in the adrenal gland. Retaining these original names, neurotransmission via

EPI and NE is still termed adrenergic and noradrenergic, respectively.

Catecholamine neurotransmitters were first discovered by Walter Cannon and his associates in the 1920s. In their classic experiments

involving nervous system arousal, the researchers discovered that these substances (then called sympathins) were released

whenever sympathetic nerves were stimulated. Thus, they recognized that catecholamines were involved in nervous system arousal

and stimulatory states.

All three of the preceding catecholamines are synthesized from the amino acid tyrosine as derived dietary proteins. Tyrosine is

hydroxlated (via tyrosine hydroxylase) to DOPA, which is then decarboxylated to dopamine. Dopamine can then be transported to the

synaptic space and released for use in dopaminergic neurotransmission, or it can be further metabolized within the neuron. In the

latter case, dopamine (DA) is β-hyroxylated to norepinephrine (NE), which can, likewise, be transported and released for neurotransmission or further metabolized. If further metabolized, NE is methylated to epinephrine (EPI). Thus, DA can be used by the

neuron as a neurotransmitter or as a precursor substrate for the production of two other neurotransmitters, NE and EPI.

As was the case with the 5HT neuron, the DA neuron can control the amount of neurotransmission via its production of autoreceptors,

thereby controlling re-uptake of the catecholamines. Additionally, the DA neuron has modulatory control over DA, NE, and EPI

neurotransmission via its control over the rate-limiting enzyme, tyrosine hydroxylase. Production of NE and EPI is modulated by

regulation of the intraneuronal enzymes dopamine β-hydroxylase and phenylethanolamine N-methyltransferase, respectively. Further, the catecholamines (as well as 5HT) can be destroyed in the synaptic space by an enzyme called monoamine oxidase (MAO); thus,

neuronal production and release of MAO into the synaptic space are yet other mechanisms whereby neurotransmission can be

modulated by the neuron.

Once synthesized and released into the synaptic space, the catecholamines serve multiple functions throughout the human nervous

system, particularly the brain itself. Although it is usually an arousal-inducing neurotransmitter, DA neurotransmission varies in function

depending upon the neuroanatomic system involved. In the nigrostriatal system (with fiber tracts running from the substantia nigra to

and from the basal ganglia), for example, DA transmission controls motor behavior and its fine control. In the mesolimbic system (where

fiber tracts traverse the brain stem and the nucleus accumbens), DA transmission is involved in cognitive and affective processing and

emotional regulation. When involved in the mesocortical system (with fibers traversing the tegmentum and the frontal lobes),

dopaminergic neurotransmission plays a role in attention, arousal, and motivation. In the tuberoinfundibular pathway (with fibers

running to and from the hypothalamus and the tegmentum), DA is involved in the regulation of prolaction secretion (and, relatedly,

bone mineral metabolism), fertility, and sexual function. In the median forebrain bundle and neuronal fibers connecting to the

hypothalamus, DA appears to be intimately involved in processes of reward, pleasure, and motivation.

NE is involved in the regulation of arousal throughout the nervous system. EPI is involved with a relatively small number of neuron

systems and primarily has very rapid short-lived and localized effects. Thus, NE has more substantive neuropharmacologic significance

and will be the focus of this section. Centrally, adrenergic neurotransmission (via NE and, to a lesser extent, EPI) is involved in myriad

processes including activation, arousal, attention-concentration, hunger, and feeding behavior. Peripherally, adrenergic transmission is

involved in cardiac function, blood pressure regulation, and muscle tone, among other processes.

C. Acetylcholine

The neuroactivity of acetylcholine (ACh) has been characterized since the early 1920s, and the molecule was first discovered in the

mid-1800s. It was, thus, the first neurotransmitter to be identified and has been the focus of a massive amount of research over the

past century.

ACh is synthesized in cholinergic neurons from the precursors acetyl coenzyme A and dietary choline via the catalyst choline

acetyltransferase. Several mechanisms regulate the production of ACh, including (1) feedback inhibition wherein increasing amounts of

ACh in the nerve terminal “feed back” to the producing neuron to inhibit the activity of choline acetyltransferase, thus reducing further

ACh production, (2) the availability of dietary choline, and (3) neuronal activity wherein ACh is depleted in the nerve terminal, thus

stimulating the accelerated production of ACh. In addition to these regulatory mechanisms, ACh activity is also modulated by the

presence of enzymes that hydrolytically break down ACh. These enzymes are called acetylcholinesterases and, as will be seen later,

are the targets of various pharmacologic agents.

Once synthesized, ACh is found to be widely dispersed throughout the body, particularly in the brain and spinal motor neurons. In the

central nervous system, ACh is heavily involved in the striatal complex (e.g., the caudate-putamen region and the nucleus accumbens)

where it is, perhaps, the most important motor system neurotransmitter. In the substantia nigra region, ACh is a cofactor in

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dopaminergic neurotransmission. The basal forebrain region represents a major ACh neurotransmission area, with cholinergic fiber

projections traversing the area from the medial septal nucleus to the limbic cortex and hippocampus with involvement in memory,

cognitive processing, and emotional functions. In the diencephalon, cholinergic neurons and their projections are involved in a variety

of neuroendocrine functions, whereas the cholinergic fibers in the medulla innervate the cerebellar cortex and motor components of

some cranial nerves. In the peripheral nervous system in spinal and cranial motor neurons, ACh is involved in the movement of limbs,

head, trunk, eyes, face, tongue, and jaw. In the parasympathetic nervous system, ACh functions as a neurotransmitter in connections

between ganglionic fibers and smooth muscle tissue in virtually all systems. In the sympathetic nervous system, ACh is involved in

neurotransmission to sweat glands.

ACh is, thus, widely dispersed and nearly ubiquitously involved as a neurotransmitter. It has been demonstrated to function as a

regulator of aggressive behavior, sensory processes, learning and memory, sleep and arousal, eating behavior, digestion, and sexual

behavior. In the 1970s, several laboratories demonstrated that ACh neurotransmission tended to decline with age and that cholinergic

neurotransmission activity was particularly deficient in the brains of patients with Alzheimer's dementia. As will be seen in subsequent

sections, these findings have become the focus of an important area of research in neuropharmacology.

D. Amino Acid Neurotransmitters: GABA, Glutamate, Glycine, and Aspartate

Although the catecholamines ACh and serotonin have extremely important neurotransmitter roles in brain function, the amino acid

neurotransmitters are more common by far and exist in substantially higher nervous system concentrations. Despite their ubiquitous

distribution in mammals, these neurotransmitters have proven more difficult to study than any others. Nevertheless, there is a growing

body of literature regarding their characteristics and roles.

y-Aminobutyric acid (GABA) was originally synthesized in the 1880s and for years was thought to be exclusively a product of plant

metabolism. In the 1950s, however, it was found to be a constituent of mammalian tissue and was determined to exist in large

quantities in the brain and spinal cord. Over the past several decades, much evidence points to GABA's role as an inhibitory

neurotransmitter. GABA is synthesized in GABAergic neurons by the conversion of L-glutamate via the catalytic enzyme, glutamate

decarboxylase (GAD). GABA synthesis is regulated primarily by the presence and concentration of GAD and its cofactor, pyridoxal

phosphate (a form of vitamin B ), within the neuron. Following its synthesis and release into the synaptic space, GABA interacts with

postsynaptic receptors to exert inhibitory effects; GABA thus is a neurotransmitter that serves to dampen or depress the effects of

other neuron systems. Although there is more active research than conclusive evidence about the inhibitory effects of GABA, it is

thought to be involved in the regulation of anxiety and relaxation states and overall motor tone. A growing body of research is also

implicating GABA in seizure disorder development. The inhibitory effects of GABA appear to involve one of two processes, both of

which result in making the affected target neuron more difficult to stimulate: hyperpolarization and depolarization. Hyperpolarization

appears to be more the more common GABAergic mechanism in central cortical neurons, whereas depolarization predominates in

spinal cord neurons.

Another inhibitory amino acid neurotransmitter is glycine, the amino acid with the simplest structure. Found in all mammalian proteins

and tissues, glycine is synthesized primarily via hydroxymethylation from serine. Once synthesized, glycine functions as an inhibitory

neurotransmitter in the spinal cord and, to a lesser extent, in the brain. In the brain, glycine's role primarily appears to involve the

inhibition of neuronal activity in the striatum, substantia nigra, and cerebellum. Pharmacologically, research is still ongoing regarding the

drugs that can affect this neurotransmitter, but it is well-characterized in many of its actions due to its inhibition by the poison

strychnine. Observation of strychnine effects has led to an understanding of the various regulatory functions of glycine, including

relaxation of muscles of facial expression and mastication, limb and trunk movement, relaxation of respiratory and cardiac muscles, as

well as vascular wall musculature, and regulation of various visual, auditory, cutaneous, and vestibular functions.

Two amino acids function as excitatory neurotransmitters: glutamate and aspartate. Both are nonessential amino acids, can, thus, be

synthesized in the body, and do not require a dietary source. Glutamate is synthesized primarily as a byproduct of glucose metabolism

(the Kreb's cycle) via a transamination reaction. Once synthesized, glutamate can, interestingly, serve as the precursor for GABA, or it

can function as an excitatory neurotransmitter in the spinal cord and, literally, throughout the brain in virtually every region. It appears

to be involved in learning, memory, and the regulation of neuronal oxygenation states and is, thus, purported to be important in the

regulation of neuronal damage following strokes and heart attacks. Although aspartate is known to be excitatory, it is less well-

characterized as a neurotransmitter, and most of the research on this agent is in the early investigatory stages.

E. Histamine

The final neurotransmitter upon which we will focus here is histamine. Like serotonin and the catecholamines, histamine is a

biologically active amine derived from amino acid precursors. It is formed by the decarboxylation of the amino acid histidine and is

degraded via methylation to type B monoamine oxidase. Histamine, although heavily involved in the regulation of allergic and

inflammatory reactions, has been found to be a neurotransmitter that is involved in a wide variety of behavioral processes. It is

involved in the regulation of ingestive behavior (eating and drinking), sleep and arousal, sexual behavior, pain tolerance, learning and

memory, and blood pressure.

Copyright 2002, Elsevier Science (USA).

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APA Ii. Neurotransmitters. (2002). In V. S. Ramachandran, Encyclopedia of the human brain. Oxford, UK: Elsevier Science & Technology.

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Chicago "Ii. Neurotransmitters." In Encyclopedia of the Human Brain, by V. S. Ramachandran. Elsevier Science & Technology, 2002.

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Harvard Ii. Neurotransmitters. (2002). In V.S. Ramachandran, Encyclopedia of the human brain. [Online]. Oxford: Elsevier Science & Technology.

Available from: https://search.credoreference.com/content/entry/esthumanbrain/ii_neurotransmitters/0 [Accessed 11 January 2019].

MLA "Ii. Neurotransmitters." Encyclopedia of the Human Brain, V. S. Ramachandran, Elsevier Science & Technology, 1st edition, 2002. Credo

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