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Starting with the precursor substance tyrosine, draw three diagrams showing how the various enzymes convert this substance to serotonin, dopamine and norepinephrine.

Identify and briefly describe each chemical step required to create each neurotransmitter.

Neurobiology and
Pharmacokinetics
NUR 520
P SYCHOP HARMACOLOGY
Receptor: configured so that precisely shaped
molecules fit and cause or prevent a response
Ligand: a transmitter substance that fits and evokes
a response from a receptor
Neurobiological
Definitions
Synapse: A structure that permits a neuron to pass
an electrical or chemical signal to another neuron
Neurotransmission: Communication between
neurons
Neurotransmitters: The electrochemical messengers
that send signals to from neuron to neuron. They
either excite or stimulate an action in the cells
(excitatory) or inhibit or stop an action (inhibitory).
BRAIN
FUNCTIONS
FOREBRAIN
MIDBRAIN
HINDGRAIN
The Forebrain:
Functions of the
Brain
â—¦ Controls all the higher mental
functions, such as learning, speech,
thought, and memory
Thalamus:
◦ “Relay station;” transmits nerve impulses
throughout brain
Hypothalamus:
â—¦ Regulates bodily drives and body conditions
Limbic system:
â—¦ Involves experiencing and expressing
emotions and motivation
The Midbrain:
Functions of
the Brain
• Involved in vision and hearing,
and along with the hindbrain,
controls sleep, alertness, and pain
• Manufactures serotonin,
norepinephrine, and dopamine
The Hindbrain:
• Controls motor movements, heart
rate, sleep, and respiration
• Manufactures norepinephrine and
serotonin
Pharmacokinetics
Absorption: getting the drug into the
bloodstream
Distribution: getting the drug from the
bloodstream to the tissues and organs
Metabolism: breaking the drug down into
inactive and typically water-soluble form
Excretion: getting the drug out of the
body
Affects 90% of all drugs, 25% of all psychotropic drugs by CYP2D6
Found primarily in the liver. Also in the intestine, lungs, brain, and kidney
Definitions
➢Substrate: Enzyme surfaces that receive inducers or inhibitor enzymes
➢Inducers: Increases the drug metabolism=decrease serum drug
concentration. Takes several days to weeks to develop.
➢Inhibitors: Decreases the drug metabolism=increases serum drug
concentration. Happens almost immediately.
CYP-450 System
Smoking and
CYP 450
Cigarette smoking causes
the induction of CYP-450
1A2, which causes more of
this enzyme to be
synthesized.
Maximum enzyme
induction occurs with 7 to
12 cigarettes per day for
some medications, such as
clozapine and olanzapine.
Leads to a 40% to 50%
reduction in serum level.
If a patient smokes half of a
pack or more, a higher dose
of medication is needed.
Same effects occur from
secondhand smoke.
The
CYP1A2
Enzyme
❖Amitriptyline
❖Propranolol
❖Theophylline
❖Olanzapine
❖Naproxen
❖Nortriptyline
❖Acetaminophen ❖Desipramine
❖ Carbamazepine ❖ Cigarette
smoking (PAH)
❖ Charbroiled
Food
❖ Echinacea
❖Clozapine
❖Fluvoxamine
❖Coumadin
❖Haloperidol
❖ Mirtazapine
❖Imipramine
❖ Phenobarbital ❖ St. John’s Wort
❖ Broccoli
❖ Cabbage
❖ Phenytoin
❖ Insulin
❖ Cauliflower
Retrieved from : https://apotential.wordpress.com/
2011/08/22/how-to-memorize-cyp450/
Normal metabolizers: persons with one or two functioning
copies of CYP2D6 or CYP2C19
Metabolism
and Genetics
Ultra-rapid metabolizers: multiple copies of CYP2D6 or
CYPC19. High risk for poor efficacy.
About 10% to 29% of people who are of East African or Middle
Eastern descent are ultra-rapid metabolizers of CYP2D6 drugs
Poor metabolizers: Patients with two inactivated copies of
either CYP2D6 or CYPC19. High risk for toxicity.
About 5% to 10% Caucasians higher likelihood to have lower
CYP2D6 activity, making them poor metabolizers of CYP2D6 drugs
Metabolism: Genetic
Considerations
Some Examples:
Cardiovascular effects of propranolol
â—¦ Asian descent – more sensitive
â—¦ African descent – less sensitive
Caucasians
â—¦ 5-10 % of Caucasians are poor metabolizers of CYP 2D6
Asian descent
â—¦ 20% people of Asian descent have educed activity CYP
2C19
â—¦ May require lower doses of certain psychotropics
Block metabolism: TCAs and drugs for Alzheimer’s
disease
Block reuptake: SSRI and other antidepressants
Block receptors: antagonists
Psychotropics,
Drugs and
Neurotransmitters
Stimulate or block auto-receptors
Stimulate receptors (agonists)
Stimulate receptor affinity (Benzodiazepines)
Stimulate release of neurotransmitter
(Amphetamines stimulate release of dopamine)
High concentration in brain
Point-to-point communication
Amino Acid
Neurotransmitters
Consistently
excitatory or
inhibitory
Fast acting, short
duration
Glutamate
Aspartate
GABA
Glycine
Glutamate
➢Principal excitatory NT
➢Biosynthesized as byproduct of
cell metabolism
➢Removed by reuptake
Major receptor types
â—¦ NMDA
â—¦ AMPA
â—¦ Kainate
➢ At high levels, can have major
neurotoxic effects.
➢ Implicated in the brain
damage caused by stroke,
hypoglycemia, sustained
hypoxia or ischemia, and
some degenerative diseases
such as Huntington’s or
Alzheimer’s.
Gamma Aminobutyric Acid (GABA)
➢ Principal Inhibitory NT
➢ Biosynthesis:
Glu
Glutamic Acid
Decarboxylase (GAD)
and B6
• Agonists
Benzodiazepines
Barbiturates
Ethyl alcohol (EToH)
GABA
➢ Found in the brain.
➢ Modulate other
neurotransmitter systems
rather than to provide a
direct stimulus.
➢ Prevents brain from
overstimulation
➢ Reduction in GABA results
in epilepsy
GABAa Binding Sites
Benzodiazepine (Agonist)
â—¦ Probably also site for alcohol
Barbiturate (indirect agonist)
Steroid (indirect agonist)
Picrotoxin (inverse agonist)
Kandel, 2013
Biogenic Amines
Medium concentration in brain
Modulatory functions
â—¦ Excitatory or inhibitory as a function of receptor
Slow acting, long duration
Examples:
â—¦Acetylcholine
â—¦Epinephrine
â—¦Norepinephrine
â—¦Dopamine
â—¦Serotonin
The role of histamine in mental
illness is under investigation.
Histamine
It is involved in peripheral allergic
responses, control of gastric
secretions, cardiac stimulation and
alertness.
Some psychotropic drugs block
histamine, resulting in weight gain,
sedation, and hypotension.
Acetylcholine (ACh)
Mostly excitatory effects
Removal
Synthesis
Acetyl CoA
+
Choline
CoA
+
Choline Acetyltransferase
ACh
(ChAT)
ACh
Acetylcholine
Esterase (AChE)
Acetate
+
Choline
• Synthesized from dietary choline found in red meat and vegetables
• 2 receptor types
• Nicotinic
• Muscarinic
Major ACh Pathways
Dorsolateral Pons → mid/hindbrain [REM sleep]
Basal Forebrain → cortex [Learning (esp. perceptual), Attention]
Medial Septum → Hippocampus [Memory]
➢ Found in the brain, spinal cord, and peripheral nervous system
➢ Involved in sleep/wake cycle and muscle stimulation.
➢ Alzheimer’s disease= decreased acetylcholine-secreting neurons
➢ Myasthenia gravis=reduced acetylcholine receptors
Major ACh Pathways
(Kandel, 2013)
Monoamines
Catecholamines
Indolamines
Dopamine- DA
â—¦ Dopaminergic
Serotonin- 5-HT
â—¦ Serotonergic
Norepinephrine- NE
â—¦ Noradrenergic
Epinephrine- E
â—¦ Adrenergic
Dopamine
Rewarding/motivating effects
Biosynthesis:
Tyrosine
L-DOPA
Tyrosine
Hydroxylase
DA
DOPA
Decarboxylase
• Dopamine reuptake transporter (DAT)
• 5 receptor types
Dopamine (DA)
➢ Located primarily in the brain stem
➢ Involved in the control of complex movements, motivation,
cognition, and regulation of emotional responses.
➢ Dopamine is generally excitatory and is synthesized from tyrosine, a
dietary amino acid.
➢ Implicated in schizophrenia, other psychoses, movement disorders
like Parkinson’s disease.
↑Dopamine
Schizophrenia
D1=Nigrostriatal (Substantia Nigra → Striatum) [Motor movement]
D2=Mesolimbic (VTA → limbic system) [Reinforcement and Addiction]
D3=Mesocortical (VTA → prefrontal cortex) [Working memory and
planning]
D4=Tuberoinfundibular tract (hypothalamus → pituitary)
[neuroendocrine regulation]
Major DA Pathways
Major DA Pathways
Kandel, 2013
Norepinephrine (NE)
Generally excitatory behavioral effects
Biosynthesis:
DA
NE
Dopamine
Beta-hydroxylase
• Many receptor types
Ø Norepinephrine (noradrenalin), the most prevalent neurotransmitter in the
nervous system
Ø Precursor to Epinephrine (adrenaline) has limited distribution in the brain
but controls the fight-or-flight response in the peripheral nervous system
Ø Involved in pulse, blood pressure, changes in attention, learning and memory,
sleep and wakefulness, and mood regulation.
Ø Excess norepinephrine: several anxiety disorders
Ø Deficits: memory loss, social withdrawal, and depression
Norepinephrine
Major NE Pathway
Locus Ceruleus → throughout brain [vigilance and attentiveness]
Primarily located in the brain stem
Kandel, 2013
Serotonin
Varying excitatory and primarily inhibitory behavioral effects
Biosynthesis:
Tryptophan
5-HTP
5-HT
Tryptophan
Hydroxylase
5-HT
Decarboxylase
• At least 14 receptor types, all metabotropic and
postsynaptic except:
• 5-HT1A,B,D (autoreceptors) – found in CNS
• 5-HT3 (inhibitory, ionotropic) – found in the intestines
Major 5-HT Pathways
Dorsal Raphe Nuclei → cortex, striatum
Medial Raphe Nuclei → cortex, hippocampus
➢ Produced in the brain and intestines
➢ Serotonin contributes to the delusions,
hallucinations, and withdrawn behavior
seen in schizophrenia.
➢ Some antidepressants block serotonin
reuptake causing longer availability of
5-HT in the synapse= improved mood.
5-HT Roles:
Mood regulation
Eating disorders
Sleep and
dreaming
Arousal
Sexual behavior
Pain
Aggression
Indirect Monoamine
Agonists
MAOIs
Reuptake blockers (SSRIs)
â—¦ Tricyclic antidepressants
â—¦ Imipramine
â—¦ Desipramine
â—¦ Cocaine & Amphetamine
Opioids Receptors-Neuropeptide
Receptor
High affinity ligands
mu
-endorphin, enkephalins (primarily analgesic)
delta
enkephalins (some analgesia)
kappa
dynorphins (negative side effects)
• Opioids act at all opioid receptors, but with different affinities
• Distributed throughout brain and spinal cord, especially in limbic areas
• Morphine and heroin are agonists that bind to receptor sites, thereby
increasing endorphin activity
• Some overlap but quite distinct localizations
• Co-localized with other transmitters
• Modulatory functions, mostly inhibitory
Muscarinic Blockage
Possible
Effects of
Receptor
Binding
• Blurred Vision
• Dry mouth
• Constipation
• Urinary difficulty
Alpha 1 Antagonism
• Orthostatic hypotension
• Ejaculatory failure
Antidepressants: Possible effects of
receptor binding
(Varcarolis, 2011)
Neurotransmitters and Related Disorders
Neurotransmitter
Mental Disorder
↑Dopamine
Schizophrenia
↓ Dopamine
Parkinson’s Disease
↓Norepinephrine
Depression
↓Serotonin
Depression
↓Acetylcholine
Alzheimer’s disease
↓ GABA
Anxiety
↑Glutamate
Excitotoxicity leading to neuronal
death, migraine
↓Glutamate
Concentration, mental exhaustion
References
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction
Table. Indiana University School of Medicine. Accessed July 23, 2019, via
the Web: http://medicine.iupui.edu/flockhart/table.htm.
Halter, M. & Varcarolis, E. (2014). Varcarolis’ foundations of psychiatric
mental health nursing : a clinical approach. St. Louis, Mo: Elsevier.
Kandel, E. (2013). Principles of neural science. New York: McGraw-Hill.
Stahl, S. M., & Muntner, N. (2017). Stahl’s essential
psychopharmacology: Neuroscientific basis and practical applications
(4th ed.). Cambridge: Cambridge University Press.

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