Dopamine,

Serotonine,
Epinephrine, and
Norephinephrine

Hafshah - 1610211062
Dopamine
Dopamine

– Neurotransmitter of the catecholamine and phenethylamine families

– Important in the brain and body
– Major role in the increase of reward-motivated behavior as well as
motor control and the release of hormones
– C8H11NO2
Dopamine Related Disorders

– Parkinson’s
– Loss of dopamine secreting neurons in substantia nigra
– Other disorders:
– Schizophrenia
– ADHD
– RLS
Dopamine in the Body

– Paracrine function– Synthesized locally and exerts its effects on cells that are located near the cells
that release it
– Blood vessels
– Inhibits norepinephrine release and acts as a vasodilator at [normal]
– Kidneys
– Increases Na excretion and urine output
– Pancreas
– Reduces insulin production
– Digestive system
– Reduces gastrointestinal motility and protects intestinal mucosa
– Immune system
– Reduces activity of lymphocytes
Physiological Effects in Brain

– Dopaminergic systems– responsible for motor control, motivation, arousal, cognitive

control, reinforcement and reward, lactation, sexual gratification, and nausea
– Dopaminergic neurons– Few in # ( about 400,000 in brain)
– Confined to small areas but have many projections all over brain areas with powerful effects
– Dopaminergic areas
– Substantia nigra– Significant in motor function and learning new motor programs
– Ventral tegmental area(VTA) – Role in reward and motivation
– Posterior hypothalamus– Unclear function, possibly involved in RLS
– Arcuate and Periventricular nuclei of hypothalamus– Influence secretion of prolactin from
pituitary gland
– Zona incerta– Controls gonadotropin releasing hormone involved in puberty
– Amacrine cells– increase sensitivity to color during bright light conditions
Cellular Effects
Dopamine receptors

– There are five subtypes of dopamine receptors D1-D5

– D1 and D5 increase the intracellular levels of cAMP by activating
adenylate cyclase.
– D2, D3, D4 decrease the intracellular levels of cAMP by inhibiting
adenylate cyclase.
– The effect the dopamine on a neuron depends on the receptor that is
one the particular neroun.
Disease and disorders

– Parkinson’s- stiffness of the body, slow movements, and trembling of

the limbs. It is caused by massive loss of dopamine cells.
– L-Dopa is used to treat this disease.
– Dopamine drugs help treat ADHD by increasing the levels of
dopamine in the brain.
– Pain and nausea can be increased with decreased dopamine levels in
the brain.
Biosynthesis

– Synthesized in a specific cell type seen in neurons and in the medulla

of the Adrenal Glands.
– Pathway
– L-Phenylalanine-> L-Tyrosine-> L-DOPA-> Dopamine
Receptors

– There are five subtypes of dopamine receptors, D1 , D2 , D3 , D4 , and

D5 , which are members of the large G-protein coupled receptor super
family
– The dopamine receptor subtypes are divided into two major
subclasses: types 1 and 5 are similar in structure and drug sensitivity,
and these two receptors are referred to as the "D1like" group or class
of receptors. Dopamine receptor types 2, 3, and 4 are also similar in
structure and are, therefore, grouped together as the "D2like" group
– Dopamine receptors are typically couple to Gs and Gi mediated
transduction systems
Serotonin
 Serotonin or
5-hydroxytryptamine
– Widely distributed amine (animals + plants)
– In humans, present in GI enterochromaffin cells (90%),
platelets and brain.
– Synthesized from tryptophan (in diet) in two steps.
– Platelets do not synthesize but take up from blood (active
uptake process in platelets and nerve terminals).
– Cell storage in granules similar to catecholamines.
 (Rate limiting)
COOH OH COOH
Tryptophan
hydroxylase
C NH2 C NH2

N N
In diet. Active
Tryptophan CNS transport
5-Hydroxytryptophan

5-OH Tryptophan
decarboxylase
C COOH
OH H
N

C NH2
5-Hydroxy Indole N
Acetic Acid 5-OH Indole
Acetaldehyde 5-Hydroxytryptamine
Synthesis and Metabolism

– Competition at the level of brain and neuronal uptake

– Rate limiting enzyme not saturated usually
– No end-product negative feedback
– 5-OHTr decarboxylase same as DOPA decarboxylase
– 5-OHIAA actively extruded from CNS (probenecid-sensitive) and
excreted in urine.
Interference with the system

– Inhibit uptake into CNS (other AA’s)

– Inhibit synthesis: p-chlorophenylalanine (irreversible)
– Inhibit neuronal re-uptake: cocaine, SSRA (e.g. fluoxetine), TCA (e.g.
imipramine)
– Inhibit storage-deplete: reserpine
– Inhibit metabolism: MAO inhibitors Non-selective
– Promote release: p-chloroamphetamine - then depletes (e.g.
fenfluramine to ↓ appetite)
Serotonin Receptors

– At least 15 types and subtypes

– Multiple transduction mechanisms
– 5HT-1A: role in anxiety/depression
– 5HT-1D: role in migraine
– 5HT-2: role in CNS various behaviors, and in cardiovascular system
– 5-HT3: role in nausea and vomiting esp. due to Chemotherapy.
Serotonin in the
Central Nervous System
– Pain perception
– Sleep/Wakefulness
– Various behaviors normal/abnormal: depression, schizophrenia,
obsessive compulsive behavior, etc.
– Neuroendocrine regulation – controls hypothalamic cells involved in
release of several anterior pituitary hormones.
 Serotonin Agonists

– Sumatriptan: 5-HT1D agonist; contraindicated in patients with

angina
– Fluoxetine: Selective serotonin uptake inhibitors for
depression and other indications
– Buspirone: 5-HT1A agonist for anxiety
– Cisapride: 5-HT4 agonist to ↑ GI motility and decrease G-E
reflux (Removed from US market due to fatal arrhythmias)
– LSD: 5HT1A – hallucinogen
– Ergot alkaloids: 5-HT1 and 2 and other receptors
Serotonin Antagonists

– Methysergide and Cyproheptadine. 5HT2 antagonists. In carcinoid,

migraine.
– Ketanserin: 5HT2 and Alpha antagonist – used as antihypertensive.
– Ondansetron: 5-HT3 antagonist for chemotherapy induced nausea and
vomiting
– Clozapine: 5HT2A/2C antagonist: for schizophrenia.
Epinephrine and
Norepinephrine
 Epinephrine (EPI) and Norepinephrine (NE)

– What are the sources of EPI and NE?

– EPI and NE are produced in cells in the adrenal medulla, but EPI is
more prevalent from this source. Sympathetic neurons activate the
adrenal medulla. Both EPI and NE are secreted into blood during
activation, and will act as hormones binding to adrenergic receptors
in targets.

– NE is released directly on target cells by efferent fibers of

sympathetic neurons. Here NE is acting as a neurotransmitter that
binds to adrenergic receptors.

– There are major NE neurons in the brain that play a role in the
integration of sleep-wake cycles and responses to stress.
Epinephrine (EPI) and Norepinephrine (NE)

– What will stimulate their secretion from sources?

– Many stimuli can activate sympathetic neural pathways, but they are generally
associated with stress and the “flight or fight” response where the organism is
trying to generate a coordinated response to a perceived or actual threat.

– They are also activated under milder forms of stress like exercise, in which the
organism is also generating a coordinated and energetic physiological
response.

– Hypoglycemic conditions will also increase NE/EPI levels.

Epinephrine (EPI) and Norepinephrine (NE)

– What are the actions of EPI/NE on the various targets with adrenergic receptors?
– Cardiovascular: increase blood pressure via increased heart rate and vasoconstriction in most
arterioles
– Lungs: open airways via bronchodilation to increase airflow
– Play role in cooling body during thermoregulation
– Sweat glands: increase activity
– Cutaneous arterioles: lead to vasodilation and increase flow to skin
– GI tract: in general NE and EPI inhibit activity
– Will lead to higher levels of fuel in plasma
– Adipocytes: lipolysis that leads to higher fatty acids in blood
– Liver: increase glycogenolysis and higher plasma glucose
– Pancreas: inhibits beta cells (lowers insulin) and activates alpha cells (elevated glucagon)– leads to higher
plasma glucose
Epinephrine (EPI) and Norepinephrine (NE)

– What are the endocrine connections?

– Direct effects listed above that occur during sympathetic activation of
adrenal medulla during a stress response
– Thyroid hormone is permissive on the actions of EPI/NE by increasing #
of adrenergic receptors in targets, increasing the effect of circulating
EPI/NE.
– Cortisol will increase levels of EPI synthesis in cells of the adrenal medulla,
thus increasing the above responses. Cortisol also has a permissive effect
on the smooth muscles around blood vessels that respond to circulating
levels of EPI/NE, increasing vasoconstriction and thus blood pressure.
 Stress that affects EPI/NE pathways

Increases of NE from sympathetic neurons.

Increases of EPI/NE in plasma from adrenal
medulla.

Maintain high plasma oxygen.

Increase fuels in plasma.
Increase in blood flow for delivery of fuel and
oxygen.
Increase removal of thermal energy gains.
 Sources

– https://www.omicsonline.org/open-access/dopamine-receptors-functions-synthesis-pathways-locations-
andmental-disorders-review-of-literatures-2471-271X-1000120.pdf
Journal of Mental Disorders and Treatment
Dopamine: Receptors, Functions, Synthesis, Pathways, Locations and Mental Disorders: Review of Literatures
Getinet Ayano* Chief Psychiatry Professional and mhGap Coordinator at Research and Training
Department, Amanuel Mental Specialized Hospital, Addis Ababa, PO box: 1971, Addis Ababa, Ethiopia
– https://www.researchgate.net/publication/26693775_The_Expanded_Biology_of_Serotonin
Literature Review in Annual review of medicine February 2009
By Miles Berger Duke University Medical Center, Bryan Roth University of North Carolina at Chapel Hill John
Alan Gray University of California, Davis
– https://www.annualreviews.org/doi/abs/10.1146/annurev.med.60.042307.110802?journalCode=med
– https://onlinelibrary.wiley.com/doi/pdf/10.1002/0471238961.0516091416210719.a01
– Silverthorn Physiology