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NEUROTRANSMITTER

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A neurotransmitter is technically
defined by meeting three criteria:
1. The substance must be stored in the
presynaptic neuron.
2. It must be released with depolarization
of the presynaptic neuron induced by
the influx of Ca2+.
3. The substance must bind with a
specific receptor on the postsynaptic
neuron
Neuroscience of Clinical Psychiatry,
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CLASSIFICATION OF
NEUROTRANSMITTER

1. The classic neurotransmitters:


1. Amino acids:
1.
2.

Glutamate
GABA and Glycine

2. Monoamines
1.

Catecholamines
1.
2.
3.

2.

Dopamine
Norepineprhine
Epinephrine

Indoleamines
1.
2.
3.

Serotonin
Melatonin
Histamine

3. Acetylcholine

2. Neuropeptides.
3. Unconventional neurotransmitters
1. Gases : Nitric oxide (NO)
2. Endocannabinoids
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Neuropeptides
Neuropeptides

Example
Substance P
Gut-brain peptides
Cholecystokinin
Galanin
Adrenocorticotropic hormone
Pituitary peptides
(ACTH)
Luteinizing hormone (LH)
Oxytocin
Vasopressin
Hypothalamic releasing peptides Corticotropin-releasing factor (CRF)
Gonadotropin-releasing hormone
(GnRH)
Thyroidtropin-releasing hormone
(TRH)
Somatostatin
Endorphin
Opioid peptides
Enkephalins
Other peptides
Angiotensin
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The: The Pathophysiology of
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Unconventional
neurotransmitters
1. Gases
2. Endocannabinoids

Neuroscience of Clinical Psychiatry,


The: The Pathophysiology of
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Neuroscience of Clinical Psychiatry,


The: The Pathophysiology of
Behavior and Mental Illness, 1st

Catecholamines are
synthesized from the
essential amino acid
tyrosine that must be
obtained from the diet.
Note that L-dopa is
synthesized into DA. This
shows why L-dopa can be
given as a treatment for
Parkinson's disease.
The trick is to allow the
synthesis in the CNS, but
inhibit the enzyme dopa
decarboxylase in the
periphery so that the
patient is not too
nauseated.

The synthesis of catecholamines


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The relative size of


-A : the amino acids
-B : two of the amines
-C : neuropeptide

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Glutamate
This is the major workhorse of the brain, with glutamate
neurons making up more than half of the excitatory
neurons. Without glutamate the brain does not get
started or keep running.
Glutamate and another excitatory transmitter aspartate
are nonessential amino acids that do not cross the
blood-brain barrier. Consequently, glutamate must be
synthesized in the brain from glucose and other
precursors.
Glial cells assist in the reuptake, degradation, and
resupply of glutamate for neurons.
Disorders:
Too much glutamate (as in stroke) is toxic to the nerve
cells
glutamatergic dysregulation may be present in patients
with schizophrenia
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GABA and Glycine


GABA is the major inhibitory transmitter
in the brain and is used by approximately
25% of the cortical neurons.
Glycine is the other inhibitory amino acid,
but is less common.
GABA puts the brakes on the brain: not
enough GABA and one can have seizures.
The GABA neurons are primarily the
interneurons in the gray matter providing
local constraint over cortical circuitry.
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Dopamine (DA)
There are 3 dopaminergic system in the brain:
1.Nigrostriatal system or Mesostriatal system :

From Substantia nigra to striatum (nucleus


Caudatus and Putamen)Parkinson disease

2.Mesolimbocortical DA system:
1. Mesolimbic : from ventral tegmental area (VTA)
to nucleus accumbens, amygdala, and
hippocampus.
2. Mesocortical : from VTA to prefrontal cortex

3.Tuberoinfundibular DA system :

From Arcuate nucleus to hypophysis inhibit


synthesis and release of prolactin.
antipsychotic medications that block the DA
receptor can cause an increase in prolactin
(hyperprolactinemia)
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Dopamine (cont.)
The branches to the nucleus accumbens are
involved with reward and substance abuse.
The branches to the prefrontal cortex are
involved with attention and cognition, and
seem to be impaired in patients with
attention deficit hyperactivity disorder
(ADHD).
Some speculate that problems with the
mesolimbic system cause the positive
symptoms of schizophrenia whereas
negative symptoms are caused by
impairment in the mesocortical system.
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The dopaminergic system


The substantia nigra forms the nigrostriatal pathways to the caudate
and putamen. The ventral tegmental area projects to the nucleus
accumbens and cortex. The arcuate nucleus of the hypothalamus
projects to the tuberoinfundibular
the hypothalamus
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Norepinephrine (NE)
NE neurons contain an additional enzyme in
their terminals that converts DA to NE.
Approximately 50% of the NE neurons are
located in the locus coeruleus. There are
approximately 12,000 neurons in each
nucleus.
The remainder of the NE neurons is found in
loose clusters in the medullary reticular
formation .
Plays an important role in anxiety and
depression.
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Norepinephrine (cont.)
The NE neurons play an important role in
alertness.
The firing of the locus coeruleus increases
along a spectrum from drowsy to alert, with
the lowest found when we sleep and the
highest when we are hypervigilant.
The noradrenergic neurons are important in
handling danger. In a threatening situation, the
locus coeruleus is active as are the
sympathetic neurons of the autonomic nervous
system (ANS) where the peripheral
noradrenergic neurons are found.
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The noradrenergic system.


With projections to almost every area of the brain and spinal
cord, the NE system plays an important role in alertness and
anxiety.
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Epinephrine
The epinephrine (or adrenaline) neurons
are few and play a minor role in the
CNS.
Most of the epinephrine in the body is
produced in the adrenal medulla and
excreted with sympathetic stimulation.
Therefore, epinephrine plays a much
greater role outside of the brain as a
hormone, than within as a
neurotransmitter
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Serotonin synthesis

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Serotonin (5hydroxytryptamine)
Serotonin is found in many parts of the body outside of

the CNS, such as platelets and mast cells. Only


approximately 1% to 2% of the body's serotonin in
located in the brain.
The most closely associated neurotransmitter with
modern neuropsychopharmacology.
Serotonin is synthesized from tryptophan that must be
obtained in the diet .
In the pineal gland there are two additional enzymes that
convert serotonin to melatonin.
The serotonin neurons are relatively few in number
(approximately 200,000) and reside in the raphe nuclei
in the brain stem.
As with NE, the serotonin neurons project to virtually all
areas of the brain.
Plays an important role in depression and anxiety, and
also in the sleep-wake cycle.
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The serotonergic system


The cluster of Raphe nuclei along the brainstem has projections to
most of the brain and spinal cord. These neurons play an important
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Histamine
Histamine in the brain is involved in arousal and
attention.
Most of the cell bodies start in the
tuberomammilary nucleus of the posterior
hypothalamus, with sparse but widespread
projects to all regions of the brain and spinal cord.
When animals are alert, the histamine neurons are
active. Histamine neurons are quiet when animals
are sleeping.
More recently, there has been increased interest in
activating the histamine neurons as a treatment
for fatigue. Modafinil, the only agent in the class,
indirectly activates the histamine neurons and has
been used successfully as a treatment for
narcolepsy, excessive sleepiness, and ADHD.
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Acetylcholine
Acetylcholine (ACh) was the first neurotransmitter identified
(1920)
ACh is a small molecule transmitter but it is not an amino acid
nor a monoamine.
ACh plays a prominent role :
in the peripheral autonomic nervous system (ANS)
at the neuromuscular junction.

In the CNS arises from cell bodies in the brain stem and forebrain
with prominent projects to the cortex and hippocampus.
Projections to the hippocampus are involved with learning and
memory and are disrupted in Alzheimer's disease.
ACh, unlike the catecholamines and indoleamines, is also
synthesized in interneurons in the CNS.
In the striatum, the ACh neurons balance the dopaminergic input
from the substantia nigra to coordinate extrapyramidal motor
control. Disruption of this balance with DA-blocking
antipsychotic agents can result in extrapyramidal side effects.
The anticholinergic agents are administered to restore the
ACh/DA balance and allow normal movement.
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Neuropeptides
The neuropeptides are small chains of amino acids but larger
than the classic neurotransmitters. Peptides are synthesized in
nerve cells and have effects on behaviors such as learning,
attachment, mood, and anxiety.
Some have important endocrine functions in the body, such as
the regulation of reproduction, growth, water intake, salt
metabolism, temperature control.
The formation, release, and inactivation of the neuropeptides
differ from that of the monoamines. Peptides must be
transcribed from mRNA on the ribosomes of the endoplasmic
reticulum. Initially the peptide is a large propeptide precursor,
which is cleaved into an active neuropeptide as it is moved
from the Golgi apparatus into large dense core vesicles that
are stored at the terminal bud of the neuron.
Unlike the monoamines, neuropeptides are not recycled by the
neuron, but are rather broken down by degradative enzymes
(peptidases) on the receptor membrane.
Neuroscience of Clinical Psychiatry,
The: The Pathophysiology of
Behavior and Mental Illness, 1st

Neuropeptides
Neuropeptides

Example
Substance P
Gut-brain peptides
Cholecystokinin
Galanin
Adrenocorticotropic hormone
Pituitary peptides
(ACTH)
Luteinizing hormone (LH)
Oxytocin
Vasopressin
Hypothalamic releasing peptides Corticotropin-releasing factor (CRF)
Gonadotropin-releasing hormone
(GnRH)
Thyroidtropin-releasing hormone
(TRH)
Somatostatin
Endorphin
Opioid peptides
Enkephalins
Other peptides
Angiotensin
Neuroscience of Clinical
Psychiatry,
Bradykinin
The: The Pathophysiology of
Behavior and Mental Illness, 1st

Neuroscience of Clinical Psychiatry,


The: The Pathophysiology of
Behavior and Mental Illness, 1st

Unconventional
Neurotransmitters
Nitric oxide (NO) :
most commonly associated with erectile dysfunction,
is a gas that is formed in glutamate neurons when arginine is
converted into citrulline and NO.
NO has the ability to diffuse (without obstruction) out of the
originating cell, through the extracellular medium and into any
neighboring cell that it meets.
NO converts guanosine triphosphate (GTP) into cyclic
guanosine monophosphate (GMP) that acts as a second
messenger.
Cells containing the NO synthase (the enzyme that creates NO)
constitute only approximately 1% of neuronal cells in the brain,
but reach out so extensively that nearly every cell in the brain
may encounter NO.
NO may be involved with aggression and sexual behavior, as
well as migraine headaches. NO may restrain aggressive and
sexual behavior.
It is worth noting that the medications for erectile dysfunction
have not been associated with any adverse effects on mental
function. This may be due to the inability of these medications
in their current form to cross the blood-brain barrier.
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Unconventional Neurotransmitters
(cont.)

Endocannabinoids:

The cannabinoid receptor (CB1) is widely


expressed throughout the brain on presynaptic
terminals.
The effect of activating CB1 receptors results in
inhibition of that neuron and in a simple way
explains the calming effect of marijuana.
Blocking the CB1 receptor can inhibit appetite.
Rimonabant, a potent and selective blocker
(antagonist) of the CB1 receptor, has been
shown in clinical studies to facilitate weight
loss.
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