Amino Acids
Cannabinoids
Glutamate
Acetylcholine
2-arachidonylglycerol
GABA
Gasses
Nitric Oxide
BowTiedNeuron’s
Introduction to
Neurotransmitters
Anandamide
Monoamines
Catecholemines
Dopamine
Norepinephrine
Indolamine
Serotonin
Histamine
What is on each page:
Contents:
An advanced introduction to the
following neurotransmitters in
this order:
-A brief introduction to each molecule
-Glutamate
-How it is synthesized
-GABA
-Dopamine
-Norepinephrine
-Serotonin
-Histamine
-Acetylcholine
-Cannabinoids
-Nitric Oxide
-Their molecular structure
-How it is removed from the synapse
-The major receptor types and what they do
-That molecules function in the brain
-Location in the brain (if applicable)
-A brief conclusion
What you need to know:
Adenylyl cyclase is an enzyme that converts ATP into cAMP, a key
signaling molecule in neurons. cAMP can go on to activate enzymes,
modulate receptors and more. PLC is another enzyme that starts a
signaling cascade activating PKC and CaMK.
5 Major Receptor Types:
AMPA: excitatory ionotropic receptor, when activated allows
sodium (Na+) into the neuron making it more positive and more
likely to fire an action potential
Glutamate
Glutamate is the primary
excitatory neurotransmitter
in the brain.
Synthesis
Glutamate is an amino acid
synthesized from other amino
acids, like glutamine and
aspartate, or intermediates
from the citric acid cycle like αketoglutarate.
1 Method of Removal
from Synapse
Reuptake by a glutamate
transporter, Excitatory
Amino Acid Transporter
(EAAT), on the presynaptic
neuron or nearby astrocyte
NMDA: highly unique excitatory ionotropic receptor, requires
binding of co-agonist (serine or glycine), removal of a magnesium
ion block, and glutamate binding to open; allows both Na+ and Ca2+
into the neuron making it more positive and more likely to fire an
action potential, Ca2+ also functions as a signaling molecule inside
neurons making this more than your typical ionotropic receptor
Kainate: excitatory ionotropic receptor; also involved in inhibiting
neurotransmission (especially GABA) when located on presynaptic
neurons
Group 1 mGluR: stimulatory metabotropic receptor, upregulates
phospholipase C, increases excitability of postsynaptic neuron and
NMDA receptor activity
Group 2/3 mGluR: inhibitory metabotropic receptors, inhibits
adenylyl cyclase, generally a presynaptic inhibitory autoreceptor
that inhibits glutamate release
Conclusion
Glutamate’s function is simple. It acts as the primary excitatory
neurotransmitter in the brain, driving action potentials in other neurons.
Things get complex when you begin to look at the function of the NMDA
receptor. It is heavily implicated in plasticity at those synapses since it
allows calcium into neurons, and as a result plays a large role in learning
and memory. Though excess glutamate activity is detrimental and the
excess calcium influx that follows can cause excitotoxicity and cell
death. Just another reason to take more magnesium, sufficiently block
your NMDA channels.
2 Major Receptor Types:
GABA
GABA is the primary
inhibitory neurotransmitter
in the brain.
Synthesis
GABA is an amino acid
synthesized from glutamate via
the enzyme glutamic acid
decarboxylase (GAD)
2 Methods of Removal
from Synapse
Reuptake by a GABA
transporter on the presynaptic
neuron or nearby astrocyte
GABA Transmaminase, the
enzyme that breaks it down
GABAA: inhibitory ionotropic receptor; the main
source of ‘fast’ inhibitory neurotransmission in the
brain, allows chloride (Cl-) into the neuron making it
more negative and less likely to fire an action
potential
There is a huge diversity of GABAA subtypes localized
to different areas in the brain with different subunit
compositions. This affects binding affinity for GABA
and drugs that act on these receptors (i.e.
benzodiazepines, barbiturates).
GABAB: inhibitory metabotropic receptor, inhibits
activity of adenylyl cyclase, activate inhibitory
potassium (K+) channels, can function as inhibitory
autoreceptor on the presynaptic neuron decreasing
neurotransmitter release
Conclusion
GABA is a simple molecule. As the primary inhibitory
neurotransmitter in the brain its chief job is to decrease
excitability of neurons, reducing their chance of firing an
action potential. It does so directly through the GABAA
receptor or indirectly through the GABAB receptor. In general,
an increase in GABA activity will decrease overall neuronal
activity, and vice versa.
2 Major Receptor Types:
D1: stimulatory, upregulates adenylyl cyclase
Dopamine
Dopamine is a catecholamine,
a subtype of monoamine,
along with norepinephrine
and epinephrine.
Synthesis
Catecholamines all come from
the same synthesis pathway
L-Tyrosine → L-Dopa → Dopamine
→ Norepinephrine → Epinephrine
2 Methods of Removal
from Synapse
Reuptake into the presynaptic
neuron by a Dopamine
transporter, DAT
Monoamine oxidase, the enzyme
that breaks it down
D2: inhibitory, downregulates adenylyl cyclase, activates inhibitory
ion channels in postsynaptic cell; generally a presynaptic
autoreceptor, inhibitng dopamine release
3 Major Pathways
Nigrostraital (Substantia nigra →Striatum): This pathway contains most
of the dopamine neurons in the brain and is involved in motor planning
and movement. The striatum is part of the basal ganglia, the region of
the brain responsible for initiating and stopping movement.
Mesolimbic (VTA→Limbic system): This pathway is commonly referred
to as the reward pathway and contains projections from the VTA to the
nucleus accumbens (NAc), the primary reward synapse in the brain. The
NAc is very important for motivation and taking action on it, primarily
for natural rewards. This is the 'stereotypical dopamine' pathway, and is
the same one that's responsible for addiction.
Mesocortical(VTA→ Cortex): This pathway projects to the cortex, most
importantly the frontal cortex. It has a large variety of functions
including modulating attention, executive function, working memory
and more.
Conclusion
Dopamine and its pathways are crucial for coordinating a
response to specific stimuli, typically related to reward of some
kind. This includes placing value on rewards and cues that predict
them, influencing learning and memory, and turning goals into
motor outputs.
3 Major Receptor Types:
α1: stimulatory metabotropic receptor, upregulates phospholipase
C (PLC)
Norepinephrine
Norepinephrine is a
catecholamine, a subtype of
monoamine, along with
dopamine and epinephrine.
Synthesis
Catecholamines all come from
the same synthesis pathway
L-Tyrosine → L-Dopa → Dopamine
→ Norepinephrine → Epinephrine
2 Methods of Removal
from Synapse
Reuptake into the presynaptic
neuron by a Norepinephrine
transporter, NET
Monoamine oxidase, the enzyme
that breaks it down
α2: inhibitory metabotropic receptor, inhibits adenylyl cyclase,
generally acts as an autoreceptor inhibiting NE synthesis and
release
β1/2/3: stimulatory metabotropic receptor, upregulates adenylyl
cyclase
1 Major Pathway
Almost all norepinephrine neurons are located in the locus
ceruleus, a part of the pons.
Locus Ceruleus → Cortex, Amygdala, Hippocampus,
Hypothalamus, Thalamus
As a result, norepinephrine is involved in arousal, attention,
threat response, promoting wakefulness, and memory
Conclusion
Norepinephrine is a molecule responsible for the ‘fight or flight’
response in the brain. It and epinephrine do this in the periphery as well
working in the autonomic nervous system
Its receptors are all metabotropic, likely working to increase excitability
of the postsynaptic neuron so they can fire easier. Its main role is to
promote arousal, and if you’ve ever taken an α2 antagonist like
yohimbine you’ll agree (remember α2 receptors are generally
autoreceptors, inhibiting an inhibitor will increase NE release).
4 Major Receptor Types:
5-HT 4/6/7: stimulatory metabotropic receptors, upregulate
adenylyl cyclase
Serotonin
Serotonin or 5-Hydroxytryptamine
(5-HT) is a monoamine, more
specifically an indolamine.
5-HT 1A-1F/5: inhibitory metabotropic receptors, downregulate
adenyylyl cyclase or open inhibitory ion channels, 5-HT1B/D are
presynaptic autoreceptors and inhibit serotonin synthesis and
release
5-HT 2A/B/C: stimulatory metabotropic receptor, upregulates PLC
and subsequently PKC, and CaMK
5-HT 3: excitatory ionotropic receptor, ligand gated ion channel
that allows Na+ and Ca2+ through exciting the neuron
Synthesis
Serotonin is synthesized
from the amino acid
tryptophan, and is also a
precursor to melotonin.
2 Methods of Removal
from Synapse
Reuptake into the presynaptic
neuron by a Serotonin
transporter, SERT
Monoamine oxidase, the enzyme
that breaks it down
2 Major Pathway
Dorsal Raphe → Cortex, amygdala, midbrain
Median Raphe → Hippocampus, hypothalamus, thalamus
As a result, serotonin plays a role in sleep, attention,
mood/emotion, social behavior (and aggression, risk taking
behavior), sensory processing (psychedelics are 5-HT agonists),
arousal, learning and memory, and more.
Conclusion
Serotonin is an interesting neurotransmitter with a wide range
of functionality, and we are still learning more about it.
It is most well known for its effects on mood, given the use of
SSRIs in treatment of depression and anxiety disorders, but it
is crucial for proper functioning of other behaviors as well.
4 Major Receptor Types:
H1: stimulatory metabotropic receptor, activates phospholipase C
starting a signaling cascade in the cell, one of primary actions is to
increase excitability of the neuron by closing potassium channels
Histamine
Histamine is a monoamine like
dopamine and serotonin, but
does not fall under a more
specific group like catecholamine
or indolamine.
Synthesis
Histamine is synthesized
from the amino acid
histidine.
H2: stimulatory metabotropic receptor, activates adenylyl cyclase,
one of primary actions is to increase excitability of the neuron by
closing potassium channels, also control release of stomach acid
H3: inhibitory metabotropic receptor, typically autoreceptors that
inhibit histamine release
H4: plays a role in inflammation outside of the nervous system, not
really relevant in the brain
1 Major Pathway
All histamine neurons are located in the tuberomammillary
nucleus (TMN) of the hypothalamus. They project all over the
brain to the striatum, cortex, hippocampus, and parts of the
hypothalamus.
As a result histamine is involved in, sleep/wake cycles, arousal,
feeding, learning, and memory
1 Method of Removal
from Synapse
Histamine nmethyltransferase, the
enzyme that breaks it down
Conclusion
Histamine is a neurotransmitter with a smaller range of
functions than others. Despite this, its function is extremely
influential on our daily lives through its effects on the
sleep/wake cycle. Its functions are not exclusive to the brain
though as it's an important signaling molecule involved in
inflammation in the periphery, and even causes secretion of
stomach acid.
4 Major Receptor Types:
Nicotinic α1 and β1: Expressed at the neuromuscular junction
Nicotinic α2-9 and β1: Expressed throughout the brain
Acetylcholine
Acetylcholine is a unique moleucle
that functions as a
neurotransmitter in the brain and
at muscles, causing muscle
contraction
Synthesis
Acetylcholine is
synthesized from the
precursors choline and
acetyl coenzyme A.
1 Method of Removal
from Synapse
Acetylcholinesterase, the
enzyme that breaks it down
There is no acetylcholine
transporter, only for choline
All nicotinic receptors are excitatory ionotropic receptors, permeable
to sodium and calcium. They’re composed of 5 subunits, generally that
are different based on location in the brain. This affects the affinity of
drugs, nicotine is not an agonist at muscle for example.
Muscarinic M1,M3,M5: stimulatory metabotropic receptors,
upregulates phospholipase C
Muscarinic M2, M4: inhibitory metabotropic receptors, downregulates
adenylyl cyclase or opens inhibitory ion channels, M2 generally acts as
an autoreceptor inhibiting acetylcholine release
2 Major Pathways
Basal forebrain → Cortex, limbic system, hippocampus
Brainstem nuclei → VTA, thalamus, other areas in brainstem
As a result, acetylcholine plays a role in learning and memory,
arousal, emotional states, sensory processing, reward,
sleep/wake, and movement (both in striatum and at muscles)
Conclusion
Acetylcholine is a fascinating neurotransmitter with a wide range
of functions not only in the brain, but also at the neuromuscular
junction as the neurotransmitter responsible for initiating muscle
contraction. Its effects outside of the NMJ are mostly known for
its positive influence on learning and memory, making it a useful
target fo nootropics (i.e. nicotine, huperzine-a), but it also plays a
very important role in the sleep wake cycle
Cannabinoids
2 Major Receptor Types:
CB1: inhibitory metabotropic receptor, located on
presynatpic terminals, inhibits neurotransmitter release by
inhibiting calcium channels and/or opening inhibitory
potassium channels, source of psychoactive effects of THC
2-arachidonylglycerol
CB2: low levels in CNS, mostly in periphery involved in
inflammation and immune system
How They Work
Cannabinoids function as retrograde messengers, meaning they
are synthesized in the postsynaptic neuron and travel to the
presynaptic neuron to elicit their effect. Once synthesized they
are immediately released, and they're not stored in vesicles.
Anandamide
Synthesis
Cannabinoid synthesis is caused
by activation of specific
metabotropic receptors on the
post synaptic neuron or a strong
influx of calcium.
Their action on neurons is inhibitory, specifically inhibiting
neurotransmitter release. In this way, it functions as part of a
negative feedback loop. Strong signal from the presynaptic
neuron causes its synthesis, it travels back and inhibits release
through its action on CB1.
Conclusion
This is a very complex neurotransmitter system and more is
still being learned about it to this day, but this should be a
They're synthesiezd from lipid
good introduction to understanding what they are and how
precursors in the postsynaptic
they work within the brain. The important takeaway being that
neuron. Different cannabinoid
they function in a negative feedback loop to decrease
molecules have different synthesis
neurotransmitter release. .
pathways
How It Works
.
Nitric Oxide
Nitric Oxide functions as a retrograde messenger,
although it doesn’t have receptors like cannabinoids.
Synthesis
When it is synthesized in the postsynaptic neuron, it
immediately travels to the presynaptic neuron
where it upregulates guanylyl cyclase, an enzyme
that produces cyclic GMP (cGMP).
Nitric Oxide is a gaseous
neurotransmitter that is very
unique in its mechanism of
action
Nitric Oxide is synthesized
in response to glutamate
NMDA receptor activation.
They allow calcium into the
postsynaptic neuron. It
binds to calmodulin,
activating neuronal nitric
oxide synthase (nNOS).
nNOS then converts the
amino acid arginine into
nitric oxide.
The effect this has is that it increases
neurotransmitter release. It is part of a positive
feedback loop, where strong glutamate signaling
triggers its synthesis, then it goes on to stimulate
more glutamate release.
This feedback loop helps induce long-term
potentiation (LTP), a form of plasticity that increases
the strength of synapses. The increase in glutamate
signaling it causes increases
. calcium influx which will
have other effects, like altering gene expression and
inserting more receptors into the membrane. This
physical change in the synapse plays a large part in
learning and memory