Neurotransmitter

Structure of a typical chemical synapse

Postsynaptic
density
Voltage-
gated Ca++
channel
Synaptic
vesicle
Neurotransmitter
transporter
Receptor
Neurotransmitter
Axon terminal
Synaptic cleft
Dendrite

Neurotransmitters are endogenous chemicals that enable neurotransmission. It is a type of

chemical messenger which transmits signals across a chemical synapse, such as a neuromuscular
junction, from one neuron (nerve cell) to another "target" neuron, muscle cell, or gland cell.
Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where
they are received by neurotransmitter receptors on the target cells. Many neurotransmitters are
synthesized from simple and plentiful precursors such as amino acids, which are readily
available from the diet and only require a small number of biosynthetic steps for conversion.
Neurotransmitters play a major role in shaping everyday life and functions. Their exact numbers
are unknown, but more than 200 chemical messengers have been uniquely identified.

Contents

 1 Mechanism
 2 Discovery
 3 Identification
 4 Types
o 4.1 List of neurotransmitters, peptides, and gaseous signaling molecules
 5 Actions
o 5.1 Excitatory and inhibitory
o 5.2 Examples of important neurotransmitter actions
 6 Brain neurotransmitter systems
 7 Drug effects
o 7.1 Agonists
o 7.2 Antagonists
 7.2.1 Drug antagonists
o 7.3 Precursors
 7.3.1 Catecholamine and trace amine precursors
 7.3.2 Serotonin precursors
 8 Diseases and disorders
 9 Neurotransmitter imbalance
 10 Elimination of neurotransmitters
 11 See also
 12 Notes
 13 References
 14 External links
Mechanism

Neurotransmitters are stored in a synapse in synaptic vesicles, clustered beneath the membrane in
the axon terminal located at the presynaptic side of the synapse. Neurotransmitters are released
into and diffused across the synaptic cleft, where they bind to specific receptors in the membrane
on the postsynaptic side of the synapse.

Most neurotransmitters are about the size of a single amino acid, however, some
neurotransmitters may be the size of larger proteins or peptides. A released neurotransmitter is
typically available in the synaptic cleft for a short time before it is metabolized by enzymes,
pulled back into the presynaptic neuron through reuptake, or bound to a postsynaptic receptor.
Nevertheless, short-term exposure of the receptor to a neurotransmitter is typically sufficient for
causing a postsynaptic response by way of synaptic transmission.

In response to a threshold action potential or graded electrical potential, a neurotransmitter is

released at the presynaptic terminal. Low level "baseline" release also occurs without electrical
stimulation. The released neurotransmitter may then move across the synapse to be detected by
and bind with receptors in the postsynaptic neuron. Binding of neurotransmitters may influence
the postsynaptic neuron in either an inhibitory or excitatory way. This neuron may be connected
to many more neurons, and if the total of excitatory influences are greater than those of
inhibitory influences, the neuron will also "fire". Ultimately it will create a new action potential
at its axon hillock to release neurotransmitters and pass on the information to yet another
neighboring neuron.

Identification

There are four main criteria for identifying neurotransmitters:

1. The chemical must be synthesized in the neuron or otherwise be present in it.

2. When the neuron is active, the chemical must be released and produce a response in some
target.
3. The same response must be obtained when the chemical is experimentally placed on the
target.
 4. A mechanism must exist for removing the chemical from its site of activation after its
work is done.

However, given advances in pharmacology, genetics, and chemical neuroanatomy, the term
"neurotransmitter" can be applied to chemicals that:

 Carry messages between neurons via influence on the postsynaptic membrane.

 Have little or no effect on membrane voltage, but have a common carrying function such
as changing the structure of the synapse.
 Communicate by sending reverse-direction messages that affect the release or reuptake of
transmitters.

The anatomical localization of neurotransmitters is typically determined using

immunocytochemical techniques, which identify the location of either the transmitter substances
themselves, or of the enzymes that are involved in their synthesis. Immunocytochemical
techniques have also revealed that many transmitters, particularly the neuropeptides, are co-
localized, that is, one neuron may release more than one transmitter from its synaptic terminal.
Various techniques and experiments such as staining, stimulating, and collecting can be used to
identify neurotransmitters throughout the central nervous system.

Types

There are many different ways to classify neurotransmitters. Dividing them into amino acids,
peptides, and monoamines is sufficient for some classification purposes.

Major neurotransmitters:

 Amino acids: glutamate,[6] aspartate, D-serine, γ-aminobutyric acid (GABA), glycine

 Gasotransmitters: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S)
 Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine
(adrenaline), histamine, serotonin (SER, 5-HT)
 Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine,
octopamine, tryptamine, etc.
  Peptides: somatostatin, substance P, cocaine and amphetamine regulated transcript,
opioid peptides[11]
 Purines: adenosine triphosphate (ATP), adenosine
 Others: acetylcholine (ACh), anandamide, etc.

In addition, over 50 neuroactive peptides have been found, and new ones are discovered
regularly. Many of these are "co-released" along with a small-molecule transmitter.
Nevertheless, in some cases a peptide is the primary transmitter at a synapse. β-endorphin is a
relatively well-known example of a peptide neurotransmitter because it engages in highly
specific interactions with opioid receptors in the central nervous system.

Single ions (such as synaptically released zinc) are also considered neurotransmitters by some, [12]
as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and
hydrogen sulfide (H2S). The gases are produced in the neural cytoplasm and are immediately
diffused through the cell membrane into the extracellular fluid and into nearby cells to stimulate
production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act
rapidly and are immediately broken down, existing for only a few seconds.

The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses
in the human brain.[6] The next most prevalent is Gamma-Aminobutyric Acid, or GABA, which
is inhibitory at more than 90% of the synapses that do not use glutamate. Although other
transmitters are used in fewer synapses, they may be very important functionally: the great
majority of psychoactive drugs exert their effects by altering the actions of some
neurotransmitter systems, often acting through transmitters other than glutamate or GABA.
Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine
system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid
peptides, which, in turn, regulate dopamine levels.

Actions

Neurons form elaborate networks through which nerve impulses—action potentials—travel.

Each neuron has as many as 15,000 connections with neighboring neurons.
Neurons do not touch each other (except in the case of an electrical synapse through a gap
junction); instead, neurons interact at contact points called synapses: a junction within two nerve
cells, consisting of a miniature gap within which impulses are carried by a neurotransmitter. A
neuron transports its information by way of a nerve impulse called an action potential. When an
action potential arrives at the synapse's presynaptic terminal button, it may stimulate the release
of neurotransmitters. These neurotransmitters are released into the synaptic cleft to bind onto the
receptors of the postsynaptic membrane and influence another cell, either in an inhibitory or
excitatory way. The next neuron may be connected to many more neurons, and if the total of
excitatory influences minus inhibitory influences is great enough, it will also "fire". That is to
say, it will create a new action potential at its axon hillock, releasing neurotransmitters and
passing on the information to yet another neighboring neuron.

Excitatory and inhibitory

A neurotransmitter can influence the function of a neuron through a remarkable number of

mechanisms. In its direct actions in influencing a neuron’s electrical excitability, however, a
neurotransmitter acts in only one of two ways: excitatory or inhibitory. A neurotransmitter
influences trans-membrane ion flow either to increase (excitatory) or to decrease (inhibitory) the
probability that the cell with which it comes in contact will produce an action potential. Thus,
despite the wide variety of synapses, they all convey messages of only these two types, and they
are labeled as such. Type I synapses are excitatory in their actions, whereas type II synapses are
inhibitory. Each type has a different appearance and is located on different parts of the neurons
under its influence. Each neuron receives thousands of excitatory and inhibitory signals every
second.

Type I (excitatory) synapses are typically located on the shafts or the spines of dendrites,
whereas type II (inhibitory) synapses are typically located on a cell body. In addition, Type I
synapses have round synaptic vesicles, whereas the vesicles of type II synapses are flattened. The
material on the presynaptic and post-synaptic membranes is denser in a Type I synapse than it is
in a type II, and the type I synaptic cleft is wider. Finally, the active zone on a Type I synapse is
larger than that on a Type II synapse.
The different locations of type I and type II synapses divide a neuron into two zones: an
excitatory dendritic tree and an inhibitory cell body. From an inhibitory perspective, excitation
comes in over the dendrites and spreads to the axon hillock to trigger an action potential. If the
message is to be stopped, it is best stopped by applying inhibition on the cell body, close to the
axon hillock where the action potential originates. Another way to conceptualize excitatory–
inhibitory interaction is to picture excitation overcoming inhibition. If the cell body is normally
in an inhibited state, the only way to generate an action potential at the axon hillock is to reduce
the cell body’s inhibition. In this "open the gates" strategy, the excitatory message is like a
racehorse ready to run down the track, but first the inhibitory starting gate must be removed

Brain neurotransmitter systems

Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where
activation of the system affects large volumes of the brain, called volume transmission. Major
neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine
system, the serotonin system, and the cholinergic system, among others. Trace amines have a
modulatory effect on neurotransmission in monoamine pathways (i.e., dopamine,
norepinephrine, and serotonin pathways) throughout the brain via signaling through trace amine-
associated receptor 1.A brief comparison of these systems follows:

Neurotransmitter systems in the brain

Regulated cognitive processes
System Pathway origin and projections
and behaviors
Noradrenaline Noradrenergic pathways:  anxiety
system  arousal (wakefulness)
 Locus coeruleus (LC)
 circadian rhythm
projections
 cognitive control and

 LC → Amygdala working memory (co-

and Hippocampus regulated by dopamine)

 LC → Brain stem  feeding and energy

and Spinal cord homeostasis

 LC → Cerebellum  medullary control of

  LC → Cerebral
cortex
 LC → Hypothalamus
 LC → Tectum
 LC → Thalamus respiration
 LC → Ventral  negative emotional
tegmental area memory
 nociception (perception
 Lateral tegmental field
of pain)
(LTF) projections
 reward (minor role)

 LTF → Brain stem

and Spinal cord
 LTF → Olfactory
bulb

Dopamine system Dopaminergic pathways:  arousal (wakefulness)

 aversion
 Ventral tegmental area
 cognitive control and
(VTA) projections
working memory (co-

 VTA → Amygdala regulated by

norepinephrine)
 VTA → Cingulate
 emotion and mood
cortex
 VTA →  motivation

Hippocampus (motivational salience)

 VTA → Ventral  motor function

striatum  positive reinforcement

(Mesolimbic  reward (primary

pathway) mediator)

 VTA → Olfactory  sexual arousal, orgasm,

bulb and refractory period
  VTA → Prefrontal
cortex (Mesocortical
pathway)

 Nigrostriatal pathway

 Substantia nigra pars (via neuroendocrine

compacta → Dorsal regulation)
striatum

 Tuberoinfundibular pathway

 Arcuate nucleus →
Median eminence

Histaminergic pathways:

 Tuberomammillary nucleus
(TMN) projections

 TMN → Cerebral
cortex  arousal (wakefulness)

 TMN →  feeding and energy

Histamine system homeostasis
Hippocampus
[29][30][35]
 TMN →  learning
Neostriatum  memory
 TMN → Nucleus
accumbens
 TMN → Amygdala
 TMN →
Hypothalamus

Serotonin system Serotonergic pathways:  arousal (wakefulness)

[26][28][29][30][36][37][38]
  body temperature
Caudal nuclei (CN):
regulation
Raphe magnus, raphe pallidus, and
 emotion and mood,
raphe obscurus
potentially including
aggression
 Caudal projections
 feeding and energy
 CN → Cerebral homeostasis
cortex  reward (minor role)
 CN → Thalamus  sensory perception
 CN → Caudate-
putamen and nucleus
accumbens
 CN → Substantia
nigra and ventral
tegmental area

Rostral nuclei (RN):

Nucleus linearis, dorsal raphe,
medial raphe, and raphe pontis

 Rostral projections

 RN → Amygdala
 RN → Cingulate
cortex
 RN → Hippocampus
 RN →
Hypothalamus
 RN → Neocortex
 RN → Septum
 RN → Thalamus
  RN → Ventral
tegmental area

Cholinergic pathways:

Forebrain cholinergic nuclei (FCN):

Nucleus basalis of Meynert, medial
septal nucleus, and diagonal band

 Forebrain nuclei projections

 FCN →
Hippocampus
 FCN → Cerebral  arousal (wakefulness)
cortex  emotion and mood
 FCN → Limbic  learning
Acetylcholine cortex and sensory  motor function
system cortex  motivation
(motivational salience)
Brainstem cholinergic nuclei
 short-term memory
(BCN):
 reward (minor role)
Pedunculopontine nucleus,
laterodorsal tegmentum, medial
habenula, and
parabigeminal nucleus

 Brainstem nuclei projections

 BCN → Ventral
tegmental area
 BCN → Thalamus

.
Agonists

This section needs expansion with: coverage of full agonists and their distinction from partial
agonist and inverse agonist.. You can help by adding to it. (August 2015)

An agonist is a chemical capable of binding to a receptor, such as a neurotransmitter receptor,

and initiating the same reaction typically produced by the binding of the endogenous substance.
[45]
An agonist of a neurotransmitter will thus initiate the same receptor response as the
transmitter. In neurons, an agonist drug may activate neurotransmitter receptors either directly or
indirectly. Direct-binding agonists can be further characterized as full agonists, partial agonists,
inverse agonists. Direct agonists act similar to a neurotransmitter by binding directly to its
associated receptor site(s), which may be located on the presynaptic neuron or postsynaptic
neuron, or both.[46] Typically, neurotransmitter receptors are located on the postsynaptic neuron,
while neurotransmitter autoreceptors are located on the presynaptic neuron, as is the case for
monoamine neurotransmitters;[24] in some cases, a neurotransmitter utilizes retrograde
neurotransmission, a type of feedback signaling in neurons where the neurotransmitter is
released postsynaptically and binds to target receptors located on the presynaptic neuron
Nicotine, a compound found in tobacco, is a direct agonist of most nicotinic acetylcholine
receptors, mainly located in cholinergic neurons Opiates, such as morphine, heroin,
hydrocodone, oxycodone, codeine, and methadone, are μ-opioid receptor agonists; this action
mediates their euphoriant and pain relieving properties.

Indirect agonists increase the binding of neurotransmitters at their target receptors by stimulating
the release or preventing the reuptake of neurotransmitters.[46] Some indirect agonists trigger
neurotransmitter release and prevent neurotransmitter reuptake. Amphetamine, for example, is an
indirect agonist of postsynaptic dopamine, norepinephrine, and serotonin receptors in each their
respective neurons it produces both neurotransmitter release into the presynaptic neuron and
subsequently the synaptic cleft and prevents their reuptake from the synaptic cleft by activating
TAAR1, a presynaptic G protein-coupled receptor, and binding to a site on VMAT2, a type of
monoamine transporter located on synaptic vesicles within monoamine neurons.

Antagonists
Main article: Receptor antagonist

An antagonist is a chemical that acts within the body to reduce the physiological activity of
another chemical substance (as an opiate); especially one that opposes the action on the nervous
system of a drug or a substance occurring naturally in the body by combining with and blocking
its nervous receptor.

There are two main types of antagonist: direct-acting Antagonist and indirect-acting Antagonists:

1. Direct-acting antagonist- which takes up space present on receptors which are otherwise
taken up by neurotransmitters themselves. This results in neurotransmitters being blocked
from binding to the receptors. The most common is called Atropine.
2. Indirect-acting antagonist- drugs that inhibit the release/production of neurotransmitters
(e.g., Reserpine).

Drug antagonists

An antagonist drug is one that attaches (or binds) to a site called a receptor without activating
that receptor to produce a biological response. It is therefore said to have no intrinsic activity. An
antagonist may also be called a receptor "blocker" because they block the effect of an agonist at
the site. The pharmacological effects of an antagonist therefore result in preventing the
corresponding receptor site's agonists (e.g., drugs, hormones, neurotransmitters) from binding to
and activating it. Antagonists may be "competitive" or "irreversible".

A competitive antagonist competes with an agonist for binding to the receptor. As the
concentration of antagonist increases, the binding of the agonist is progressively inhibited,
resulting in a decrease in the physiological response. High concentration of an antagonist can
completely inhibit the response. This inhibition can be reversed, however, by an increase of the
concentration of the agonist, since the agonist and antagonist compete for binding to the receptor.
Competitive antagonists, therefore, can be characterized as shifting the dose-response
relationship for the agonist to the right. In the presence of a competitive antagonist, it takes an
increased concentration of the agonist to produce the same response observed in the absence of
the antagonist.
An irreversible antagonist binds so strongly to the receptor as to render the receptor unavailable
for binding to the agonist. Irreversible antagonists may even form covalent chemical bonds with
the receptor. In either case, if the concentration of the irreversible antagonist is high enough, the
number of unbound receptors remaining for agonist binding may be so low that even high
concentrations of the agonist do not produce the maximum biological response

References

1.

 Lodish, H.; Berk, A.; Zipursky, S.L. (2000). Molecular Cell Biology: Section
21.4Neurotransmitters, Synapses, and Impulse Transmission (4th ed.). New York: W. H.
Freeman.
  Cherry, Kendra. "What is a Neurotransmitter?". Retrieved 6 October 2014.
  "Neuropeptide database".
  "Neuropeptides. IUPHAR/BPS Guide to pharmacology".
  Elias, L. J, & Saucier, D. M. (2005). Neuropsychology: Clinical and Experimental
Foundations. Boston: Pearson
  Robert Sapolsky (2005). "Biology and Human Behavior: The Neurological Origins of
Individuality, 2nd edition". The Teaching Company. see pages 13 & 14 of Guide Book
  Saladin, Kenneth S. Anatomy and Physiology: The Unity of Form and Function. McGraw
Hill. 2009 ISBN 0-07-727620-5
  "Junctions Between Cells". Retrieved 22 November 2010.