NEUROTRANSMITTERS

and MENTAL HEALTH

Major neurotransmitters
Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine
(adrenaline), histamine, serotonin (SE, 5-HT), melatonin
Monoamines may be very important
functionallythe great majority of psychoactive
drugs exert their effects by altering the actions of
some neurotransmitter systems. Addictive drugs
such as cocaine and amphetamine exert their
effects primarily on the dopamine system. The
addictive opiate drugs exert their effects primarily
on opioid peptides, which regulate dopamine
levels.
Dopamine has a number of important functions
in the brain. It plays
a critical role in the
reward system, but
dysfunction of the
dopamine system is
also implicated in
Parkinson's disease
and schizophrenia.
Dopamines association with the reward system of the brain involves providing feelings of
enjoyment and reinforcement to motivate certain activities. Dopamine is released (particularly in
areas such as the nucleus accumbens and prefrontal cortex) by rewarding experiences such as
food, sex, drugs, and neutral stimuli that become associated with them. Recent studies indicate
that aggression may also stimulate the release of dopamine in this way. This theory is often
discussed in terms of drugs such as cocaine, nicotine, and amphetamines, which directly or
indirectly lead to an increase of dopamine in the mesolimbic reward pathway of the brain, and in
relation to neurobiological theories of chemical addiction (not to be confused with psychological
dependence), arguing that this dopamine pathway is pathologically altered in addicted persons.

1 Printed 04/17/16

Dopaminergic neurons of the

midbrain are the main source of
dopamine in the brain. Dopamine has
been shown to be involved in the
control of movements, the signaling
of error in prediction of reward,
motivation, and cognition. Cerebral
dopamine depletion is the hallmark of
Parkinson's disease. Other
pathological states have also been
associated with dopamine
dysfunction, such as schizophrenia,
autism, and attention deficit
hyperactivity disorder, as well as
drug abuse.
Dopamine is closely associated with reward-seeking behaviors, such as approach,
consumption, and addiction. Recent researches suggest that the firing of dopaminergic neurons is
a motivational substance as a consequence of reward-anticipation. This hypothesis is based on the
evidence that, when a reward is greater than expected, the firing of certain dopaminergic neurons
increases, which consequently increases desire or motivation towards the reward. However,
recent research finds that while some dopaminergic neurons react in the way expected of reward
neurons, others do not and seem to respond in regard to unpredictability.
In humans, drugs that reduce dopamine activity (neuroleptics, e.g. antipsychotics) have been
shown to reduce motivation, cause anhedonia (inability to experience pleasure), and long-term
use has been associated with the irreversible movement disorder, tardive dyskinesia. Furthermore,
antipsychotic drugs are associated with weight gain, diabetes, lactation, gynecomastia, drooling,
dysphoria, fatigue, sexual dysfunction, and heart rhythm problems.
Sociability is also closely tied to dopamine neurotransmission. Low D2 receptor-binding is
found in people with social anxiety. Traits common to negative schizophrenia (social withdrawal,
apathy, anhedonia) are thought to be related to a hypodopaminergic state in certain areas of the
brain. In instances of bipolar disorder, manic subjects can become hypersocial, as well as
hypersexual.[citation needed] This is credited to an increase in dopamine, because mania can be
reduced by dopamine-blocking anti-psychotics.

Dopamine has been demonstrated to play a role in pain processing in multiple levels of the
central nervous system including the spinal cord, periaqueductal gray (PAG), thalamus, basal
ganglia, insular cortex, and cingulate cortex. Accordingly, decreased levels of dopamine have
been associated with painful symptoms that frequently occur in Parkinson's disease.
Abnormalities in dopaminergic neurotransmission have also been demonstrated in painful clinical
conditions, including burning mouth syndrome, fibromyalgia, and restless legs syndrome.
Dopaminergic pathways
have a role in inhibitory
action control and the
inhibition of the tendency
to make unwanted actions.
The dopaminergic
mind hypothesis seeks to
explain the differences
between modern humans
and their hominid relatives
by focusing on changes in
dopamine. It theorizes that
increased levels of
dopamine were part of a general physiological adaptation due to an increased consumption of
meat around two million years ago in Homo habilis, and later enhanced by changes in diet and
other environmental and social factors beginning approximately 80,000 years ago. Under this
theory, the "high-dopamine" personality is characterized by high intelligence, a sense of personal
destiny, a religious/cosmic preoccupation, an obsession with achieving goals and conquests, an
emotional detachment that in many cases leads to ruthlessness, and a risk-taking mentality. High
levels of dopamine are proposed to underlie increased psychological disorders in industrialized
societies.
According to this hypothesis, a "dopaminergic society" is an extremely goal-oriented, fastpaced, and even manic society, "given that dopamine is known to increase activity levels, speed
up our internal clocks and create a preference for novel over unchanging environments." In the
same way that high-dopamine individuals lack empathy and exhibit a more masculine behavioral
style, dopaminergic societies are "typified by more conquest, competition, and aggression than
nurturance and communality." Although behavioral evidence and some indirect anatomical
evidence (e..g, enlargement of the dopamine-rich striatum in humans) support a dopaminergic

expansion in humans, there is still no direct evidence that dopamine levels are markedly higher in
humans relative to other apes.
However, recent discoveries about
the sea-side settlements of early
man may provide evidence of
dietary changes consistent with this
hypothesis.
Drugs targeting the
neurotransmitter of such systems
affect the whole system; this fact explains the complexity of action of some drugs. Cocaine, for
example, blocks the reuptake of dopamine back into the presynaptic neuron, leaving the
neurotransmitter molecules in the synaptic gap longer. Since the dopamine remains in the synapse
longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron,
eliciting a pleasurable emotional response. Physical addiction to cocaine may result from
prolonged exposure to excess dopamine in the synapses, causing the body to down-regulate some
postsynaptic receptors. After the effects of the drug wear off, one might feel depressed because of
the decreased probability of the neurotransmitter binding to a receptor.
Dopamine has many functions in the brain, including important roles in behavior and
cognition, voluntary movement, motivation, punishment and reward, inhibition of prolactin
production (involved in lactation and sexual gratification), sleep, mood, attention, working
memory, and learning. Dopaminergic neurons (i.e., neurons whose primary neurotransmitter is
dopamine) are present chiefly in the ventral tegmental area (VTA) of the midbrain, the substantia
nigra pars compacta, and the arcuate nucleus of the hypothalamus.
It has been hypothesized that dopamine transmits reward prediction error, although this has
been questioned. According to this hypothesis, the phasic responses of dopamine neurons are
observed when an unexpected reward is presented. These responses transfer to the onset of a
conditioned stimulus after repeated pairings with the reward. Further, dopamine neurons are
depressed when the expected reward is omitted. Thus, dopamine neurons seem to encode the
prediction error of rewarding outcomes. In nature, we learn to repeat behaviors that lead to
maximizing rewards. Dopamine is therefore believed to provide a teaching signal to parts of the
brain responsible for acquiring new behavior. Temporal difference learning provides a
computational model describing how the prediction error of dopamine neurons is used as a
teaching signal.

Serotonin is a monoamine
neurotransmitter. Most is produced
by and found in the intestine
(approximately 90%), and the
remainder in central nervous
system neurons. It functions to
regulate appetite, sleep, memory
and learning, temperature, mood,
behavior, muscle contraction, and
function of the cardiovascular
system and endocrine system. It is speculated to have a role in depression, as some depressed
patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal
fluid and brain tissue.
Serotonin is a monoamine neurotransmitter, biochemically derived from tryptophan, that is
primarily found in the gastrointestinal (GI) tract, platelets, and central nervous system (CNS) of
humans and animals. It is a well-known contributor to feelings of well-being.
Approximately 80 percent of the human body's total serotonin is located in the
enterochromaffin cells in the gut, where it is used to regulate intestinal movements. The
remainder is synthesized in serotonergic neurons in the CNS where it has various functions,
including the regulation of mood, appetite, sleep, muscle contraction, and some cognitive
functions including memory and learning.
In addition to animals, serotonin is also found in fungi and plants. Serotonin's presence in
insect venoms and plant spines serves to cause pain, which is a side effect of serotonin injection.
Serotonin is produced by pathogenic amoebas, and its effect on the gut causes diarrhea. Its
widespread presence in many seeds and fruits may serve to stimulate the digestive tract into
expelling the seeds.
In humans, defective signaling of serotonin in the brain may be the root cause of sudden infant
death syndrome (SIDS). Scientists in Italy genetically modified lab mice to produce low levels of
the neurotransmitter serotonin. The results showed the mice suffered drops in heart rate and other
symptoms of SIDS, and many of the animals died at an early age. Researchers now believe that
low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may
have caused sudden death.

Several classes of drugs target the 5-HT system including some antidepressants,
antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs
and empathogens.
Modulation of serotonin at synapses is thought to be a major action of several classes of
pharmacological antidepressants. Prozac is a selective serotonin reuptake inhibitor (SSRI), which
blocks re-uptake of serotonin by the presynaptic cell. This increases the amount of serotonin
present at the synapse and allows it to remain there longer, hence potentiating the effect of
naturally released serotonin.
The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD are agonists. MDMA
(ecstasy) releases serotonin from synaptic vesicles of neurons.
The most prescribed drugs in many parts of the world are drugs which alter serotonin levels.
They are used in depression, Generalized anxiety disorder and social phobia. The MAOIs prevent
the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase
concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many
adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with
high tyramine content and certain drugs. Some drugs inhibit the re-uptake of serotonin, making it
stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both
serotonin and norepinephrine.
The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer side-effects and fewer
interactions with other drugs. The side effects that have become apparent in recent times include a
decrease in bone mass in elderly and increased risk for osteoporosis. However, it is not yet clear
whether it is due to SSRI action on peripheral serotonin production and or action in the gut or in
the brain.
Certain SSRI medications have been shown to lower serotonin levels below the baseline after
chronic use, despite initial increases in serotonin. This has been connected to the observation that
the benefit of SSRI's may decrease in selected patients after a long-term treatment. A switch in
medication will usually resolve this issue (up to 70% of the time). The novel antidepressant
tianeptine, a selective serotonin reuptake enhancer, has mood-elevating effects. This provides
evidence for the theory that serotonin is most likely used to regulate the extent or intensity of
moods.
Although phobias and depression might be attenuated by serotonin-altering-drugs this does
not mean that the individual's situation has been improved, but only the individual's perception of
the environment. Sometimes a lower serotonin level might be beneficial, for example in the

ultimatum game, where players with normal serotonin levels are more prone to accept unfair
offers than participants whose serotonin levels have been artificially lowered.
Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a
condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible
to reach through an overdose of a single anti-depressant drug, but require a combination of
serotonergic agents, such as an SSRI with an MAOI. The intensity of the symptoms of serotonin
syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.
Norepinephrine is a catecholamine
with multiple roles including as a
hormone and a neurotransmitter. As a
stress hormone, norepinephrine affects
parts of the brain where attention and
responding actions are controlled. Along
with epinephrine, norepinephrine also
underlies the fight-or-flight response,
directly increasing heart rate, triggering
the release of glucose from energy stores, and increasing blood flow to skeletal muscle.
Norepinephrine also has a neurotransmitter role when released diffusely in the brain as an antiinflammatory agent.
Norepinephrine is released from the adrenal medulla into the blood as a hormone, and is also a
neurotransmitter in the central nervous system and sympathetic nervous system. Norepinephrine
is released when a host of physiological changes are activated by a stressful event.
The noradrenergic neurons in the brain form a neurotransmitter system, that, when activated,
exerts effects on large areas of the brain. The effects are alertness and arousal, and influences on
the reward system.
In the brain, this is caused in part by activation of an area of the brain stem called the locus
ceruleus. This nucleus is the origin of most norepinephrine pathways in the brain. Noradrenergic
neurons project bilaterally (send signals to both sides of the brain) along distinct pathways to
many locations, including the cerebral cortex, limbic system, and the spinal cord, forming a
neurotransmitter system.
Norepinephrine may be used for the indications attention-deficit/hyperactivity disorder,
depression and hypotension. Norepinephrine, as with other catecholamines, itself cannot cross the
blood-brain barrier, so drugs such as amphetamines are necessary to increase brain levels.

Norepinephrine, along with dopamine, has come to be recognized as playing a large role in
attention and focus. For people with ADHD, psychostimulant medications such as
methylphenidate (Ritalin/Concerta), dextroamphetamine (Dexedrine), and Adderall (a mixture of
dextroamphetamine and racemic amphetamine salts) are prescribed to help increase levels of
norepinephrine and dopamine. Atomoxetine (Strattera) is a selective norepinephrine reuptake
inhibitor, and is a unique ADHD medication, as it affects only norepinephrine, rather than
dopamine. As a result, Strattera has a lower abuse potential. However, it may not be as effective
as the psychostimulants are with many people who have ADHD. Consulting with a physician,
physician assistant or nurse practitioner is needed to find the appropriate medication and dosage.
(Other SNRIs, currently approved as antidepressants, have also been used off-label for treatment
of ADHD.)
Norepinephrine, along with dopamine, has come to be recognized as playing a large role in
attention and focus. For people with ADHD, psychostimulant medications such as
methylphenidate (Ritalin/Concerta), dextroamphetamine (Dexedrine), and Adderall (a mixture of
dextroamphetamine and racemic amphetamine salts) are prescribed to help increase levels of
norepinephrine and dopamine. Atomoxetine (Strattera) is a selective norepinephrine reuptake
inhibitor, and is a unique ADHD medication, as it affects only norepinephrine, rather than
dopamine. As a result, Strattera has a lower abuse potential. However, it may not be as effective
as the psychostimulants are with many people who have ADHD. Consulting with a physician,
physician assistant or nurse practitioner is needed to find the appropriate medication and dosage.
(Other SNRIs, currently approved as antidepressants, have also been used off-label for treatment
of ADHD.)

Differences in the norepinephrine system are implicated in depression. Serotoninnorepinephrine reuptake inhibitors are antidepressants that treat depression by increasing the
amount of serotonin and norepinephrine available to postsynaptic cells in the brain. There is some
recent evidence implying that SNRIs may also increase dopamine transmission. This is because
SNRIs work by inhibiting reuptake, i.e. preventing the serotonin and norepinephrine transporters
from taking their respective neurotransmitters back to their storage vesicles for later use. If the
norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance
dopaminergic transmission. Therefore, the antidepressant effects associated with increasing
norepinephrine levels may also be partly or largely due to the concurrent increase in dopamine
(particularly in the prefrontal cortex of the brain).
Tricyclic antidepressants (TCAs) increase norepinephrine activity as well. Most of them also
increase serotonin activity, but tend to produce unwanted side effects due to the nonspecific
inactivation of histamine, acetylcholine and alpha-1 adrenergic receptors. Common side effects
include sedation, dry mouth, constipation, sinus tachycardia, memory impairment, orthostatic
hypotension, blurred vision and weight gain. For this reason, they have largely been replaced by
newer selective reuptake drugs. These include the SSRIs, e.g. fluoxetine (Prozac), which however
have little or no effect on norepinephrine, and the newer SNRIs described above, such as
venlafaxine (Effexor) and duloxetine (Cymbalta).
Up to 70% of norepinephrine projecting cells are lost in Alzheimers Disease. It has been
shown that norepinephrine stimulates mouse microglia to suppress A-induced production of
cytokines and their phagocytosis of A suggesting this loss might have a role in causing this
disease.
Banana peels contain significant amounts of norepinephrine and dopamine.
Epinephrine (also known as adrenaline) is a hormone and neurotransmitter. It increases heart
rate, contracts blood vessels, dilates air passages and participates in the fight-or-flight response of
the sympathetic nervous system. Chemically, epinephrine is a catecholamine, a monoamine
produced only by the adrenal glands.
Epinephrine (also known as adrenaline) is a hormone and neurotransmitter. It increases heart
rate, contracts blood vessels, dilates air passages and participates in the fight-or-flight response of
the sympathetic nervous system. Chemically, epinephrine is a catecholamine, a monoamine
produced only by the adrenal glands.
As a hormone, epinephrine acts on nearly all body tissues. Its actions vary by tissue type and
tissue expression of Adrenaline junkie is a term used to describe somebody who appears to be

addicted to epinephrine (endogenous) and such a person is sometimes described as getting a

"high" from life. The term adrenaline junkie was popularly used in the 1991 movie Point Break to
describe individuals who enjoyed dangerous activities (such as extreme sports e.g. BASE
jumping) for the adrenaline "rush". Adrenaline junkies appear to favour stressful activities for the
release of epinephrine as a stress response. Doing this may result in physical harm because of the
potential danger. Whether or not the positive response is caused specifically by epinephrine is
difficult to determine, as endorphins are also released during the fight-or-flight response to such
activities.
Adrenaline is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in
diminished or absent cardiac output. Its actions are to increase peripheral resistance via
receptor-dependent vasoconstriction and to increase cardiac output via its binding to receptors.
Due to its vasoconstrictive effects, adrenaline is the drug of choice for treating anaphylaxis. It
is also useful in treating sepsis. Allergy patients undergoing immunotherapy may receive an
adrenaline rinse before the allergen extract is administered, thus reducing the immune response to
the administered allergen. It is also used as a bronchodilator for asthma.
Adverse reactions to epinephrine include palpitations, tachycardia, arrhythmia, anxiety,
headache, tremor, hypertension, and acute pulmonary edema.
Adrenaline junkie is a term used to describe somebody who appears to be addicted to
epinephrine (endogenous) and such a person is sometimes described as getting a "high" from life.
The term adrenaline junkie was popularly used in the 1991 movie Point Break to describe
individuals who enjoyed dangerous activities (such as extreme sports e.g. BASE jumping) for the
adrenaline "rush". Adrenaline junkies appear to favour stressful activities for the release of
epinephrine as a stress response. Doing this may result in physical harm because of the potential
danger. Whether or not the positive response is caused specifically by epinephrine is difficult to
determine, as endorphins are also released during the fight-or-flight response to such activities.

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