Catecholamine biosynthesis

-TH is rate-limiting (site of control of catecholamine synthesis)

-TH function is regulated by two mechanisms:

1) Enzyme activity
↑ TH activity by phosphorylation
End product inhibition ↓ TH activity
Also known as AADC

2) Amount of enzyme
↑ TH synthesis → ↑ TH activity

Not very specific: Can convert

tyramine into Octopamine:
False neurotransmitters

Enriched in the
adrenal medulla
Cartoon of catecholaminergic neuron

- Synthesis of catecholamine from tyrosine

- Taken into vesicles by VMATs (vesicular monoamine transporters)
- Neurotransmitter release - act on postsynaptic and presynaptic receptors
- Taken up by NET and DAT (transporters)
Biosynthesis of dopamine
 Catecholamine neuroanatomy

Norepinephrine – cell bodies in pons/medulla oblongata

locus coeruleus → ascending throughout neuraxis (cortex, thalamus,
hypothalamus, limbic areas)
medullary cells → hypothalamus and spinal cord (autonomic function,
blood pressure regulation)
Epinephrine – medulla → project to spinal cord
 CNS Norepinephrine
• Functions:
– Reward, mood
– Sleep / awake
– Autonomic control
– Endocrine function
• Location:
– Medullary nuclei (descending tracts)
– Locus coeruleus → forebrain
• Drug effects:
– NE uptake inhibitors, eg desipramine, are
antidepressants
α2 agonists → sedation, ↓ BP
 Dopamine neuroanatomy

Nigro-striatal:
– Nigrostriatal projection (motor control)
– cells degenerate in Parkinson’s Disease
Mesolimbic-mesocortical:
– VTA to mesolimbic areas (→ Limbic system: emotions, behavior, memory. Also
euphoria, hallucinations- positive psychotic symptoms)
– VTA to mesocortical (→ cortex:negative psychotic symptoms, cognition)
Tubero-infundibular:
–Hypothalamus →median eminence – control prolactin secretion (endocrine)
 Catecholamine receptors
All metabotropic receptors
Epinephrine and norepinephrine (adrenergic receptors α1, α2 and β)
-α receptors: α1A, α1B, α1C (coupled via Gq to PLC)
α2A (autoreceptors) , α2B, α2C (negatively coupled to adenylate cyclase via Gi)
-β receptors: β1A , β1B, β1C (positively coupled to adenylate cyclase via Gs)

-Brain: α1, α2 and β1

-Isoproterenol: agonist highly specific for βARs (asthma). β2 agonist: salbutamol (asthma)
Propranolol: antagonist of β receptors (Hypertension, tachicardia, essential tremor…).
-Phentolamine: antagonist of α receptors (used to treat hypertensive emergencies).

Dopamine (5 subtypes grouped into D1- or D2-like receptors)

D1-like: D1, D5 – positively coupled to adenylate cyclase via G-proteins
D2-like: D2short, D2long, D3, D4 – negatively coupled to adenylate cyclase via G-proteins
– many antipsychotic drugs are D2 antagonists (e.g. haloperidol)
• Functions:
CNS dopamine
– Motor system (nigro-striatal pathway)
– Reward system, pleasure and addiction (n. accumbens)
– Emotional reactions (limbic system)
– Endocrine (prolactin)
– Autonomic control (brain stem)
– Thermoregulation
– Emesis
– Appetite

D2 receptor blockers (neuroleptics, anti-psychotics)

Tranquilization
Anti-psychotic effect
Parkinsonism
Amphetamines (Amphetamine, methamphetamine, methylphenidate
(ritalin)) - norepinephrine and dopamine reuptake inhibitors
Behavioral stimulation
Improved concentration
Appetite suppression
Stereotyped behavior
– Side effects: Psychosis (abnormal thinking, hallucinations), difficulty sleeping, mood swings,
mood changes, nervousness, stomach aches, diarrhea, headaches, lack of hunger (leading
to weight loss), dry mouth. Also, palpitations and high blood pressure.
 Parkinson's Disease (PD)
• PD is the second most common neurodegenerative disorder, after Alzheimer's
disease

• It is characterized clinically by parkinsonism (resting tremor, bradykinesia,

rigidity, and postural instability). Common associated symptoms: depression,
expressionless face, hypophonia, fatigue, dementia…

• It is characterized pathologically by the loss of neurons in the substantia nigra

and presence of ubiquinated protein deposits in the cytoplasm of neurons
(Lewy bodies) and thread-like proteinaceous inclusions within neurites (Lewy
neurites).
PD substantia nigra

Control S. nigra PD S. nigra

 Parkinson’s disease (PD)
-Arvid Carlsson (2000 Nobel Laureate) is rewarded for his pioneering studies
showing that dopamine is an important neurotransmitter in the brain and that L-dopa
could be used to treat Parkinson’s disease.

-In contrast with dopamine, L-dopa crosses the blood-brain barrier. To avoid peripheral
degradation of L-dopa, peripheral decarboxylase inhibitor is administered to patients with
PD.
 Pathology of PD
• Degeneration of dopaminergic neurons of the Substantia Nigra Pars
Compacta
• Marked decrease in DA content in striatum
• Post-Mortem studies: do not get symptoms until 80% of DA neurons gone
• Abnormal depositions called Lewy Bodies prominent in Substantia Nigra
Pars Compacta
• Decrease in DA results in disrupted ‘DA/ACh Balance’

Ach DA
Normal
DA
Ach
In vivo imaging of dopaminergic activity in
striatum shown by [18F]fluorodopa PET Parkinson
 Metabolism of dopamine

L-Dopa Dopamine DOPAC HVA

DDC MAO COMT
COMT COMT

3-OMethyldopa 3-Methoxytiramine HVA

MAO
MPTP and Parkinsonism
Heroin derivate (used by heroin -
(addicted in the early 1980s

MPTP is converted to MPP+ by -

MAOb

MPP+ is selectively taken up -

by dopaminergic cells in substantia
nigra through DAT
+MPP
mithocondrial (-)
MMP+ inhibits mithocondrial complex I - complex I

- Pretreatment of animals with MAOb inhibitors (Selegiline) inhibits MPP+

formation and disease
 Treatment of Parkinson’s Disease
• Dopamine-based therapies
• L-Dopa + Dopa decarboxylase inhibitor (together with L-Dopa)
• Dopamine agonists
• MAOb inhibitors
• COMT inhibitors
• Amantadine (Dopamine releasing drug)
• Muscarinic antagonists
 Adverse Effects of L-Dopa
• Gastrointestinal effects
• anorexia
• Nausea (relieved if taken with meals)
• vomiting
• Cardiovascular effects
• cardiac arrythmias
• postural hypotension
• Dyskinesias
• On-Off effect
• Behavioral effects
• depression
• anxiety
• Insomnia
• Psychosis (high doses)

L-Dopa (as well as anticholinergics) should be discontinued slowly. Abrupt discontinuation

may cause total immobilization and sometimes neuroleptic syndrome
 Side effects of COMT inhibitors
• Interferes with metabolism of other chemicals by COMT
enzyme, such as brochodilators, dopamine agonists, and
antihypertensives
• Muscle cramps
• Dyskinesia
• Diarrhea
• Headache
• Nausea and vomiting
• Sleep disorders
• Confusion
• Anxiety
• Urine discoloration
• Liver damage (monitor patients who are taking this drug on a
regular basis to make sure their liver is functioning normally)
 Dopamine Agonists
Bromocriptine (D2)
Pergolide (D1and D2)

Ropinirole
Pramipexole
Gastrointestinal effects
anorexia
nausea
vomiting
Cardiovascular effects
postural hypotension
cardiac arrythmias
Neurological effects
Dyskinesias
Mental disturbances
confusion
Hallucinations (patients with dementia)
Unpredicted sleepiness

Retroperitoneal, pleural and pericardial fibrosis/dysfunction of cardiac valves

(Bromocriptine and pergolide)
 Muscarinic Antagonists
Benztropine (Cogentin)
Trihexylphenidyl (Artane)
Most used to relieve tremors that are not responsive to other drugs

Side Effects
Central Nervous System Effects
drowsiness
mood changes
hallucinations (not used for patients with dementia)
Gastrointesinal Effects
dryness of the mouth
constipation
nausea and vomiting
Cardiovascular Effects
tachycardia
palpitations

Urinary retention
Visual Effects
Mydriasis (blurred vision)
 Monoamine Oxidase A and B isoforms
Two types of MAO have been described
• MAOA (NE and 5-HT)
• MAOB (DA)

Inhibition of monoamine oxidase (A + B) and concomitant

ingestion of products containing high levels of tyramine
(aged cheese, chicken liver, broad-bean pods, or pickled
herring) can cause fatal increase in blood pressure.
Recommendation to treat initial stages of Parkinson’s disease
Mild symptoms do not necessarily require treatment. Patients who
do not require pharmacologic therapy might be encouraged to
enter trials of neuroprotective therapies.
When symptoms start to affect normal function, the pros and cons
of various therapies should be discussed. If the patient had no
preference, and given that he is younger than 70 years and his
cognitive ability is intact, therapy with a nonergot dopamine
agonist should be started because of the low risk of motor
complications during the first five years of treatment. Levodopa
would be a reasonable, and more potent, alternative. If there
were an inadequate response to the agonist at the maximal
tolerated dose, levodopa could be added to the regimen.

Nutt & Wooten N Engl J Med 2005;353:1021-7.

 Schizophrenia
Anti-psychotic drugs exert their effect by blocking dopamine
receptors, suggesting that imbalances in the dopaminergic
system may be associated with neuropsychiatric disorders
such as Schizophrenia.

Increased activity of the Mesolimbic system (Positive

symptoms)
-Delusions ‫מחשבות שווא‬
-Hallucnations ‫הזיות‬
-Aggresiveness

Decreased activity of the Mesocortical system (Negative

symptoms)
- Increase of negative symptoms like cognitive decline,
apatia, decrease of initiative
Chances to develop Schizophrenia
Receptor Binding Profiles of Typical and Atypical APDs

Haloperidol Clozapine
D1
D2
D4
5-HT2A
5-HT2C

Risperidone Olanzapine Alpha 1

H1
M1

J Pharmacol Exp Ther 1996;277:968;J Clin Pharmacol 1999;39:1S;

Psychopharmacology 1993;112:S60;Am J Psychiatry 1997;154:782.
DA pathways induced side effects of antipsychotics
 Side effects of APDs
• Clozapine: agranulocytosis – It should be reserved for patients who have
failed to respond to other standard medications or who are at risk for
recurring suicidal behavior.

• Olanzapine: Also used for Bipolar disorders. Drugs that decrease

concentrations of olanzapine: Carbamazepine, omeprazol, smoking.
Side effects: orthostatic hypotension, akathisia, constipation, drowsinees,
dizziness, tremor, increase blood sugar levels and weight gain. Can
develop extrapiramidal effects.

• Risperidone: extrapyramidal effects (sudden, often jerky, involuntary

motions of the head, neck, arms, body, or eyes), dizziness, hyperactivity,
tiredness, nausea, orthostatic hypotension and increase blood sugar levels.
 Cartoon of serotoninergic neuron

Many parallels with catecholamine neurons

-Smooth muscle contraction
-Present in many other tissues, such as platelets, chromaffin cells, etc.
-Brain accounts for only 1% of body stores of serotonin. Does not cross blood-brain barrier.
-Serotonin = 5-hydroxytryptamine (5-HT)
-LSD structure similar to serotonin
 Serotonin biosynthesis
TPOHase is rate-limiting
- Enzyme is not saturated, so changes in dietary tryptophan can
affect 5-HT levels
- ↑ TPOHase activity by phosphorylation
- NO end product inhibition (different from TH)
- ↑ TPOHase synthesis → ↑ TPOHase activity
add l-dopa
-In the pineal gland, 5-HT is further converted to melatonin
Hormone plays a role in circadian cycle

Storage by vesicular monoamine transporter (VMAT)

in vesicles
 Serotonin neuroanatomy

- In the raphe nuclei (distinct nuclei, widespread projections). Also in Locus coeruleus
-Dorsal raphe median raphe
project rostrally → dual ascending thick and thin fiber system (cortex, thalamus,
hypothalamus, limbic regions, and midbrain)
-Caudal raphe
project caudally → descending, autonomic function. Involved also in pain sensation.
 CNS 5-HT
• Functions:
– Mood
– Awake/sleep
– Sensory systems, pain
– Sexual drive (inhibitory)
– Emesis
– Endocrine, autonomic
– Thermoregulation
Serotonin (cont.)
Release modulating autoreceptors
5-HT1A-D receptors on serotonergic neurons
↓ firing activity → ↓ release

Inactivation
- uptake by SERT (≡ to NET/DAT)
Inhibited by antidepressants (tricyclic antidepressants, serotonin-
specific reuptake inhibitors (SSRIs) such as fluoxetine (Prozac)

- breakdown by MAO (preferentially by MAOA)

 Antidepressants

Selective serotonin reuptake inhibitors (SSRIs)

Fluoxetine (Prozac), Fluvoxamine (Luvox), Citalopram (Celexa,
Recital), Trazodone (Desyrel)

Selective norepinephrine reuptake inhibitors (NRIs)

Reboxetine (Edrox, Vestra),

Tricyclic antidepressants
Amitriptyline (Elavil), Imipramine (Tofranil), Clomipramine
(Anafranil)
Tertiary amines: Less specific, more side effects (Anti-muscaric)

Nortriptyline (Sensoval) ), Desipramine (Norpramin)

Vincent Van Gogh’s 1890
Secondary amines: More specific to NE and less side effects On the Threshold of Eternity

Monoamine oxidase inhibitors

Phenelzine, Tranylcypromine (irreversible)
Moclobemide (reversible)
Adverse effects of SSRI
• Nausea, vomiting
• Sexual dysfunction
• Agitation and restlesness
• Rash, vasculitis

Adverse effects of tricyclic antidepressants

• Antimuscarinic effects: dry mouth, blurred vision, sinus tachycardia, urinary
retention, myoclonic jerking, agitation and even hallucinations
• cardiac effects (hypotension, arrythmias), should be avoided after cardiac
stroke
• Weakness and fatigue (central antihistaminic effects)
• Weight gain
• Sexual dysfunction

Adverse effects of MAOA inhibitors

• Sedation or behavioral excitation
• Postural hypotension
• Increase in diastolic blood pressure
 Tricyclic antidepressants
Treatment of depression, neuropathic pain, nocturnal enuresis (anti-muscarinic
effects), ADHD, headaches (migrane), anxiety, bulimia, irritable bowel syndrome,
persistent hiccups, adjuvant in schizophrenia.

Amitriptyline (& butriptyline): Elavil, Endep, Tryptanol, Trepiline, Amyzol

Amoxapine: Asendin, Asendis, Defanyl, Demolox, Moxadil

Clomipramine: Anafranil

Desipramine: Norpramin, Pertofrane

Imipramine: Tofranil

Most tricyclic are norepinephrine and serotonine reuptake inhibitors. Some can also
be histamine antagonist (sedation).
 Serotonin receptors
5-HT1 receptors – 1A, 1B, 1D (negatively coupled to adenylate cyclase via Gi)
-Sumatriptan (Imitrex) is a 5-HT1B-D agonist. It is used to treat migrane. Serotonin
levels in the brain become extremely low before the onset of a migraine. Sumatriptan
helps aid in leveling the serotonin levels in the brain. It activates these receptors and
cause vasoconstriction.

5-HT2 receptors – 2A, 1B, 1C (coupled via Gq to PLC: DAG+IP3)

5-HT3 receptors – heterotetrameric ionotropic receptor (5-HT3A and 5-HT3B)

– 5-HT3 antagonists used to treat chimiotherapy-induced nausea (ondansetron; zofran:
acts on chemoreceptor trigger zone) and antipsychotics

5-HT4, 5-HT6, 5-HT7 – (positively coupled to adenylate cyclase via Gs)

LSD X 5-HT
Lysergic acid diethylamide
It is not so much physically addicting,
although tolerance to the drug can
develop in as few as three days but
disappears after week of abstinence

The psychotropic effects of LSD are

attributed to its strong partial agonist effects
at 5-HT2A receptors as specific 5-HT2A
agonist drugs are psychotropics and largely
5-HT2A specific antagonists (Trazodone-
Desyrel) block the psychotropic activity of
LSD.

Trazodone: Sedative, anxiolytic and

antidepressant properties
 LSD
Hallucinogenic agent, also called psychomimetic agent. It is capable of
producing hallucinations, euphoria, sensory illusions and bizarre thoughts.

It stimulates centers of the sympathetic nervous system in the midbrain, which

leads to pupillary dilation, increased blood pressure and increased heart rate.

During the first hour after ingestion, the user

may experience visual changes with extreme
changes in mood. The user may also suffer
impaired depth and time perception, with
distorted perception of the size and shape of
objects, movements, color, sound, touch and
the user's own body image.
 Ectasy
• MDMA (Ecstasy), blocks the reuptake of serotonin, thereby leaving
more serotonin in the synapse and prolonging activation. Prolonged
use of MDMA results in destruction of serotonergic neurons in the
brain. May have effects similar to LSD.

• Produces euphoria. Also produce a sense of intimacy with others

and diminished feelings of fear and anxiety. Increase “inner peace”,
intensification of sensory experience, decreased appetite, urinary
retention, mydriasis, increased physical energy, increased body
temperature and heart rate.

• Can be followed by several hours of restlessness.

• Wear off: Period of neurotransmitter recovery when low moods

predominate, which may exacerbate psychiatric diseases. May
cause neurotoxicity.
 Serius side effects of MDMA (Ectasy)
• Hyperthermia
• Dehydration
• Hyponatremia
• Serotonin Syndrome (believed to be due
to excess release of serotonin, sometimes
triggered by co-administration of other
serotonergic drugs)
Tachycardia, and shivering, excessive sweting, mydriasis (dilated
pupils), myoclonus (intermittent tremor or twitching). In addition
moderate intoxication includes abnormalities such as hyperactive
bowel sounds, hypertension and hyperthermia. Also, hypervigilance
and agitation.
 Cartoon of cholinergic neurons

- Acetylcholine (Ach) was the first neurotransmitter discovered (vagal substance discovered by Otto Loewi).
- Ach is the NT at the neuromuscular junction and superior cervical ganglion (easily studied due to its peripheral
localization)
- Choline acetyltransferase (ChAT) is the synthesizing enzyme (not rate limiting)
- Choline transporter inhibited by hemicholinium 3
- Stored in vesicles by a transporter that is ≅ to VMAT
- Release inhibited by muscarinic autoreceptors
- Inactivation largely by acetylcholinesterase (many isoforms) Also present in different tissues.
 found at very high concentrations in synaptic cleft
 extremely fast enzyme (10,000-100,000/s)
 Anatomy of cholinergic neurons
Projecting neurons
- Basal forebrain  cortex
- Pontine neurons

Local circuit (interneurons)

- Striatal (large aspiny neurons)
cholinergic receptor antagonists can
reduce motor symptoms of PD

ACh receptors – ionotropic and metabotropic

- Nicotinic receptors:
-Five subunits to form heteropentameric ionotropic receptors (neuromuscular junction and
throughout CNS)
-Two binding sites for ACh.
-Named because nicotine can bind to ACh-binding site and activate it (agonist). The snake venom
toxin α-bungarotoxin binds to nAChR.
-Permeable for most cations but monovalent cations are preferred. Na+, Ca2+ in and K+ out.
- Muscarinic receptors – metabotropic m1, m3, m5 (Gq  PLC); m2, m4 (Gi  ↓ AC and G 
↑
Na+ and K + channels). Brain: m1, m3 and m4. Antagonists: atropine and scopolamine.
Agonists: muscarine, pilocarpine.
 CNS neurotransmitters: ACh
•Function:
–Ach involved in: CNS control of autonomic function,
memory, motor system
–Receptors:
–M1, M3, M5: ↑ PLC, stimulatory, ↓ K conductance
–M2, M4: ↓adenylate cyclase, inhibitory, ↑ K conductance
–Nicotinic (small number relative to M)
•Drug effects:
–Cholinesterase inhibitor and muscarinic modulator
(tacrine): improve short term memory
–Scopolamine (hyoscine): antiemetic, amnesia, sedation
–Atropine: behavioral stimulation in high doses
 Cholinergic Stimulants

Carbacol Pilocarpine Nicotine Physostigmine Malathion

Bethanecol Muscarine Neostigmine DFP
Edrophonium Nerve gas
 Muscarinic receptor agonists
• Choline esters
- ACH
- bethanechol (urinary retention, reverse GI depression)
- carbachol

• Alkaloids:
- muscarine (mushrooms; muscarine poisoning). Contain also muscimol
(GABAA agonist)
- pilocarpine (used in glaucoma emergency)
- oxotremorine (synthetic) CNS action (basal ganglia)
 Anticholinesterases
I. Reversible
HO +
N (CH3)3
Short Acting
Edrophonium

H3C CH3
N C O
H Medium Acting
N N
CH3
Physostigmine
CH3
(Eserine)
H3C O
+
N C O N (CH3)3
H3C Neostigmine

O
H 3C +
N C O N CH3 Pyridostigmine
H 3C
 Anticholinesterases (cont.)
• Reversible: Medium - Longer-Acting (cont.)
– used in Alzheimer’s Disease

Tacrine

Donepezil

Rivastigmine
Tacrine – less specific for CNS-type ChE’s
medium-acting (3-4/d); highly
hepatotoxic
Donepezil and rivastigmine- more
specific for CNS-type ChE’s; longer-acting
(1/d); not hepatotoxic
 Alzheimer’s disease (AD)
-One of the most common causes of dementia in persons over 65 years of age (50%-60%)

- Presence of amyloid plaques and neurofibrillary tangles in post-mortem examination of AD

brains

- Degeneration of cholinergic neurons

- Acetylcholinesterase inhibitors (tacrine, donepezil and rivastigmine) seem to ameliorate

symptoms of AD (cognitive decline).
 Anticholinesterases

II. Irreversible

Organophosphates
R2 O Parathion
P DFP
R1 X Soman
Ecothiophate
 H3C CH3CH3
O
CH O O H3C C CH O
H3C P F P F
CH3 H3C
CH O
CH3
H3C H5C2 O O
Isoflurophate, DFP P S CH2 CH2
+
N CH3 Soman
H5C2 O CH3
Echothiophate

H5C2 O S O
O
P O NO2 P O
H5C2 O O
Paraoxon
Parathion

O O
H3C O S
P S CH C O C2H5 P S
H3C O O
CH2 C O C2H5 Malaoxon
Malathion

Structures of some organophosphate cholinesterase inhibitors.

 Major Therapeutic Uses
of Cholinergic Receptor Stimulants
• The eyes (glaucoma)

• The G.IT. and urinary tract (postoperative atony, neurogenic

bladder)

• The neuromuscular junction (myasthenia gravis, curare-

induced paralysis)

• Antimuscarinic drug intoxication (atropine intoxication in

children and adults; overdosage of tricyclic antidepressants)

• Central nervous system (Alzheimer’s disease)

 Acetylcholinesterase Inhibitors

Approximate
Uses Duration
of Action
Alcohols
Edrophonium (Tensilon) Myasthenia gravis, 5-15 minutes
ileus, arrhythmias
Carbamates and related agents
Neostigmine (Prostigmine, ) Myasthenia gravis, 1/2-2 hours
ileus
Pyridostigmine (Mestinon) Myasthenia gravis 3-6 hours
Physostigmine (Eserine) Glaucoma 1/2-2 hours
Ambenonium (Mytelase) Myasthenia gravis 4-8 hours
Demecarium (Humorsol) Glaucoma 4-6 hours
Organophosphates
Echothiophate , DFP Glaucoma 100 hours
(Phospholine), etc.)
 Adverse Reactions – Cholinergics

• Slugbam (muscarinic excess):

- Salivation, seizure
- Lacrimation
- Urination
- GI distress: diarrhea, vomiting
- Bronchoconstriction
- Abominal cramps
- Miosis
• MTWThF (nicotinic excess):
- Mydriasis
- Tachycardia
- Weakness (muscle paralysis)
- Th Hyperthermia
- Fasciculations
 Irreversible inhibitors

• Organophosphates
(highly lipid soluble, >50,000 compounds)

- Diisopropyl-fluorophosphate (DFP)

- Sarin, Suman (nerve gases)

- Malathion, Parathion (more toxic)

converted to active compounds
pesticides, very lipid soluble
US Military 2-PAM / Atropine Injector

2.5 mg Atropine, 600mg 2-PAM