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Epinephrine
Excitatory neuromodulator
Epinephrine, also known as
adrenaline, is an excitatory neurotransmitter and
hormone essential for lipolysis, which is a process
in which the body metabolizes fat. Epinephrine is
derived from the amine norepinephrine. As a
neurotransmitter, epinephrine regulates
attentiveness and mental focus. Epinephrine is
synthesized from norepinephrine.As a hormone,
epinephrine is secreted along with norepinephrine
principally by the medulla of the adrenal gland.
Heightened secretion can occur in response to fear
or anger and will result in increased heart rate and
the hydrolysis of glycogen to glucose. This
reaction, referred to as the “fight or flight”
response, prepares the body for strenuous activity.
Epinephrine is used medicinally as a stimulant in
cardiac arrest, as a vasoconstrictor in shock, as a
bronchodilator and antispasmodic in bronchial
asthma, and anaphylaxis. Commonly, epinephrine
levels will be low due to adrenal fatigue (a pattern
in which the adrenal output is suppressed due to
chronic stress). Therefore, symptoms can be
presented as fatigue with low epinephrine levels.
Low levels of epinephrine can also contribute to
weight gain and poor concentration. Elevated levels
of epinephrine can be factors contributing to
restlessness, anxiety, sleep problems, or acute
stress.
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Norepinephrine
Excitatory
neuromodulator
Norepinephrine is an excitatory
neurotransmitter that is important
for attention and focus.
Norepinephrine is synthesized from
dopamine by means of the enzyme
dopamine beta-hydroxylase, with
oxygen, copper, and vitamin C as
co-factors. Dopamine is synthesized
in the cytoplasm, but norepinephrine
is synthesized in the
neurotransmitter storage vesicles.;
Cells that use norepinephrine for
formation of epinephrine use SAMe as
a methyl group donor. Levels of
epinephrine in the CNS are only
about 10% of the levels of
norepinephrine.
The
noradrenergic system is most active
when an individual is awake, which
is important for focused attention.
Elevated norepinephrine activity
seems to be a contributor to
anxiousness. Also, brain
norepinephrine turnover is increased
in conditions of stress.
Interestingly, benzodiazepines, the
primary anxiolytic drugs, decrease
firing of norepinephrine neurons.
This may also help explain the
reasoning for benzodiazepine use to
induce sleep.
Norepinephrine acts as an excitatory
neurotransmitter and modulates
neuron voltage potentials to favor
glutamate activity and
neurotransmitter firing.
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Dopamine
Excitatory
neuromodulator
Dopamine is an excitatory and
inhibitory neurotransmitter,
depending on the dopaminergic
receptor it binds to. It is derived
from the amino acid tyrosine.
Dopamine is the precursor to
norepinephrine and epinephrine,
which are all catecholamines. The
function of dopamine is diverse but
plays a large role in the
pleasure/reward pathway (addiction
and thrills), memory, and motor
control. Dopamine, like
norepinephrine and epinephrine, is
stored in vesicles in the axon
terminal. Dopamine plays a
significant role in the
cardiovascular, renal, hormonal, and
central nervous systems. The
dopaminergic neurons have dendrites
that extend into various regions of
the brain, controlling different
functions through the stimulation of
adrenergic and dopaminergic
receptors (D1 –D5). Common symptoms
with low dopamine levels are loss of
motor control, addictions, cravings,
compulsions, and loss of
satisfaction. When dopamine levels
are elevated symptoms may manifest
in the form of anxiety or
hyperactivity. Some therapies
utilize L-DOPA for parkinsonian
symptoms which can also cause
elevations in dopamine.
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DOPAC
Dopamine Metabolite
After neuronal
dopamine is released
it is inactivated
primarily via
reuptake mechanisms
that remove it from
the synapse and the
extraneuronal space
and return it to the
presynaptic
dopaminergic neuron
or adjacent
noradrenergic
neurons. Some of the
enzymes that degrade
dopamine are only
found in specific
regions of the body.
As such some
dopamine metabolites
are only produced in
specific tissues.
Understanding how
and where these
enzymes function can
provide valuable
insight about how
dopamine is
functioning in
specific regions of
the body. In order
to understand these
functions one must
first realize
Monoamine oxidase
(MAO) is an enzyme
present within the
cytoplasm of neurons
that breaks down
dopamine to DOPAL.
DOPAL in turn is
very rapidly
converted to DOPAC
by a second
cytoplasmic enzyme
aldehyde
dehydrogenase (AD).
Because both of
these enzymes are
primarily found
inside neurons,
DOPAC levels are
dependent on the
amount of
cytoplasmic
dopamine. Combined
measurements of
DOPAC and dopamine
have been used to
assess the activity
of dopaminergic
neurons. This
combination provides
additional
information than
either parameter
alone because a
large portion of
DOPAC is formed from
dopamine without
ever being released
to the synaptic
cleft. This suggests
that DOPAC may be
more closely related
to the presynaptic
dopamine levels
while dopamine and
similarly HVA
levels, another
important metabolite
of dopamine that is
formed outside of
the neuron via the
actions of
catechols-O-methyltransferase
(COMT), are related
to the rate of
neuron signaling.
Said another way,
extracellular DOPAC
is related to the
amount of dopamine
made and stored in
the presynaptic
neuron while
extracellular
dopamine levels are
related to the rate
of dopamine released
via the
depolarization of
dopamine neurons.
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Serotonin
Inhibitory
Neuromodulator
Serotonin
is
an
inhibitory
neurotransmitter
synthesized
by
enzymes
that
act
on
tryptophan
and/or
5-HTP.
Serotonin
is
stored
in
presynaptic
vesicles
and
released
to
transmit
electrochemical
signals
across
the
synapse.
Extensive
research
has
been
conducted
surrounding
serotonin
and
acts
as a
target
for
symptoms
like
low
mood,
compulsions,
anxiousness,
and
headaches.
Serotonin
acts,
in
most
cases,
as
an
inhibitory
neurotransmitter
and,
like
GABA,
modulates
neuron
voltage
potentials
to
inhibit
glutamate
activity
and
neurotransmitter
firing.
Serotonin
neurons
have
large
numbers
of
axons
and
are
important
in
integrating
neural
circuits.
This
also
provides
an
explanation
for
serotonin’s
role
in
so
many
health
concerns.
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5-HIAA Serotonin Metabolite
5-Hydroxyindoleacetic acid (5-HIAA) is a major metabolite of serotonin, generated via a two step process, involving monoamine oxidase A (MAO-A) and aldehyde dehydrogenase. Measurement of 5-HIAA in combination with serotonin may offer insight into mechanisms underlying various clinical symptoms. The ratio of serotonin to 5-HIAA may be used to evaluate serotonin turnover and monoamine oxidase activity. Abnormal levels of 5-HIAA have been associated with depression, suicidal behaviors, aggression, chronic psychotropic medication use, and Parkinson’s Disease.
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Glycine Inhibitory Neuromodulator
Glycine is a principal inhibitory amino acid in the brainstem and spinal cord that regulates excitatory neurotransmission in much the same way as GABA. Glycine, much like GABA and taurine, can become elevated to compensate for elevations in excitatory neurotransmitters, primarily, glutamate and aspartic acid. This non-essential amino acid is common in protein-based foods, and can be synthesized metabolically from a number of different amino acids, including serine and threonine.; Curiously, glycine is a necessary cofactor in the activation of the glutamate receptor, NMDA. It seems paradoxical that a primarily inhibitory amino acid facilitates the activation of an excitatory receptor. It has been postulated that glycine’s inhibitory and excitatory actions are part of the many checks and balances the body has for regulating neurotransmission.
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Taurine Inhibitory Neuromodulator
Taurine is an inhibitory neurotransmitter involved in neuromodulatory and neuroprotective actions. Supplementing with taurine can have a specific effect on GABA function.There are two primary ways in which taurine affects GABA.; First, it can inhibit GABA transaminase, an enzyme that metabolizes GABA. This allows GABA to stay in the synaptic cleft longer to bind to the postsynaptic receptor. Second, taurine can bind to the GABAAreceptor mimicking the effects of GABA. By helping GABA function, taurine is an important neuromodulator for prevention of excitoxicity. Excitability occurs when glutamate binds to its receptor, in this case, the NMDA receptor. Once glutamate activates the NMDA receptor there is an increase in intracellular Ca++ causing depolarization or cell excitability. With glutamate release, there is also simultaneous GABA and taurine release. When the inhibitory neurotransmitters, GABA and taurine, activate the GABAA receptor, the result is an increase in intracellular Cl- ions. This results in hyperpolarization which reduces cell excitability. Thus, the overall effect of taurine supplementation is to support GABA function. The relevance of GABA support is to prevent overstimulation due to high levels of excitatory amino acids. Therefore, taurine and GABA constitute an important protective mechanism against excessive excitatory amino acids. Similarly, taurine is increased in response to the exposure of free radicals elucidating its neuroprotective actions. Exposure to free radicals increases glutamate excretion, further potentiation NMDA receptor activation. Taurine modulates this effect to prevent cell excitability by keeping the cell hyperpolarized. The supplementation of taurine can help alleviate some excitability issues associated with elevated excitatory amino acids as well as play a role in regulating the effect of free radicals.
| GABA Inhibitory Neurotransmitter GABA is a true neurotransmitter and is the major inhibitory neurotransmitter of the brain, occurring in 30-40% of all synapses. GABA is second only to glutamate, the brain’s major excitatory neurotransmitter. The GABA concentration in the brain is 200-1000 times greater than that of the monoamines or acetylcholine. The primary function of GABA is to prevent overstimulation. It does so by compensating for glutamate activity.; When GABA activates its receptor it causes negative ions to flow into the cell preventing depolarization. Glutamate can depolarize the cell and form an action potential by causing positive ions to flow into the cell when it activates its receptors. Overall, GABA regulates the activity of glutamate by preventing depolarization of the cell, therefore, preventing overstimulation.
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Glutamate Excitatory Neurotransmitter
Glutamate is the major excitatory neurotransmitter in the brain which is necessary for memory and learning. In fact, it is believed that 70% of the fast excitatory CNS synapses utilize glutamate as a transmitter. Excitatory neurotransmitters increase the activity of signal-receiving neurons and play a major role in controlling brain function. Glutamate exerts its effects on cells, in part, through three types of receptors that, when activated, allow the flow of positively charged ions into the cell. These include the ionotropic receptors: kianate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and N-methyl-D-aspartate (NMDA) receptors. There are also series metabotropic glutamate receptors that do not directly manipulate an ion channel.; Of the ionotropic receptors, the N-methyl-D-aspartate (NMDA) receptor plays a particularly important role in controlling the brain’s ability to adapt to environmental and genetic influences which is important for learning and memory.
An event or process that dramatically increases the activity of glutamate often induces the death of neurons. Such a scenario is believed to take place in e.g. ischemia, trauma, hypoxia, hypoglycemia, and hepatic encephalopathy.; More mild but chronic malfunctioning of glutamatergic systems may be involved in many neurodegenerative diseases such as Huntington´s disease, Parkinson´s disease, Alzheimer´s disease, vascular dementia, amyotrophic lateral sclerosis, AIDS-neurodegeneration, Tourette´s syndrome, and Korsakoff syndrome.It is unlikely that a disturbance of glutamate homeostasis is the sole initiator of these neurodegenerative diseases, but rather that excitotoxicity plays a pivotal executive role in events triggered by other processes such as energy deficits that facilitate the neurotoxic potential of endogenous glutamate.
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PEA Excitatory Neuromodulator
Beta-phenylethylamine (PEA) is an excitatory neurotransmitter derived from the amino acid phenylalanine.Studies have found that PEA promotes energy and elevates mood. PEA also functions as a synaptic neuromodulator inhibiting the reuptake of dopamine and norepinephrine. Studies have discovered that patients with depression have decreased PEA levels while increased levels have been found in patients with psychopathic symptoms. It has also been implicated in headaches and the antidepressant effects of exercise.; One of the biochemical abnormalities resulting from phenylketonuria, the absence of the enzyme that helps to synthesize phenylalanine into tyrosine, is an increased production of PEA. This can cause an elevated level of PEA in the urine. Since PEA is lipid soluble and readily crosses the blood-brain-barrier, the administration of PEA or of its precursor, phenylalanine, has been found to improve outcome with some antidepressants. Also, supplementation to manipulate PEA can help increase focus and attention.
PEA acts as an excitatory neurotransmitter and modulates neuron voltage potentials to favorglutamate activity and neurotransmitter firing.
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Histamine Excitatory Neuromodulator
Histamine is an excitatory neurotransmitter involved in the sleep/wake cycle and inflammatory response. Depending on the receptor histamine activates a wide array of biological actions can occur. For instance, one receptor helps regulate the sleep/wake cycle whereas another receptor helps regulates norepinephrine, serotonin, and acetylcholine release. There are also other receptors that may be activated to induce inflammatory response, which is commonly associated with the exposure to an allergen.
Interestingly, histamine containing neurons have been found to have a pacemaker function within the brain. The firing rates of these neurons correlate positively with brain activity levels and displays distinct day-night rhythms. Within the posterior region of the hypothalamus, there are a large number of neurons that synthesize and utilize histamine. These neurons provide the stimulation that maintains or modulates activity in many other regions of the brain.
Histamine, like the other biogenic amines (serotonin, dopamine, norepinephrine, epinephrine, and PEA) is stored in presynaptic vesicles and is released into the synapse. Also like other amine neurotransmitters, histamine binds to transmembrane G-protein coupled receptors on the post-synaptic neurons to exert its function.
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DHEA
DHEA is the most abundant steroid in the body. It is a steroid precursor produced by the adrenal gland and converted to testosterone or the estrogens by the body’s tissues. Adequate DHEA levels give the body the building blocks necessary to produce these hormones. Levels of DHEA are inversely associated with coronary artery disease. DHEA levels decrease with age.
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Cortisol
Cortisol is the primary glucocorticoid and regulates glucose metabolism and the body’s response to stress. During times of stress, cortisol levels increase and accelerate the breakdown of proteins to provide the fuel to maintain body functions. This tearing-down needs to be balanced with periods of rebuilding to maintain good health. |
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