Catecholamines Flashcards
The catecholamines
Amine transmitters
Larger than amino acid transmitters (GABA, glutamate, glycine)
- synthesised from amino acids
- chemical structure: an ethylamine group is attached to a catechol nucleus at the 1 position
“Cheese effect”
Cheese contains a substantial amount of tyramine
Monoamine oxidase inhibitors (MAOI) inhibit the breakdown of amines —> people taking antidepressants are advised to avoid foods ric in tyramine
Leads to hypertensive crisis
Symptoms: headache, heart pounding/palpitations
Can leads to: subarachnoid hemorrhage, cardiac arrhythmias, cardia failure, pulmonary edema and death
Catecholamines transmitters get synthesised from tyrosine
Mammals synthesize tyrosine from the essential amino acid phenylalanine
(Phe), which is derived from food.
The conversion of Phe to Tyr is catalyzed by the enzyme phenylalanine hydroxylase, a monooxygenase. This enzyme catalyzes the reaction causing the addition of a hydroxyl group to the end of
the 6-carbon aromatic ring of phenylalanine —> becomes tyrosine.
Process of making dopamine
(1) Synthesis begins from
dietary tyrosine, which is
actively transported into the brain.
(2) The enzyme tyrosine
hydroxylase (TH) adds a
hydroxyl group to tyrosine
and turns it into dopa (L-
dopa).
(3) The removal of a
carboxyl group from dopa
by dopa decarboxylase
turns dopa into dopamine.
What is the first step in the production of all Catecholamine transmitters?
Tyrosine hydroxylase enzyme
L - dopa
Precursor for dopamine
Treatment for Parkinson’s disease
Catecholamine groups
Although these neurotransmitters perform
different functions, they each consist of a catechol nucleus and an amine group.
The synthesis of all catecholamine transmitters begins with the synthesis of dopamine. The catecholamine neurotransmitters, DA, NA and A, are sequential products of a single biosynthetic pathway.
The location of dopaminergic nuclei
Cell bodies are located in
the substantia nigra or
ventral tegmental area
(VTA) of the midbrain.
Dopamine neurons in the
substantia nigra give rise
to the nigrostriatal
pathway (important for
motor control).
Dopamine neurons in the
VTA give rise to the
mesocorticolimbic
pathway and are involved
in reward, reinforcement,
and appetitive behaviour.
Parkinon’s disease
Due to loss of dopaminergic (DA) neurons in substantia nigra
Healthy substantia nigra appears dark due to high neuromelanin content that forms from the L-DOPA precursor in dopamine synthesis.
Tyrosine hydroxylase in catecholamine synthesis
TH is the rate-limiting enzyme in catecholamine synthesis
(1) The ability of tyrosine to penetrate the
blood–brain barrier depends on an active
transport process. With normal dietary
consumption of tyrosine, both active transport
and TH activity are fully saturated.
(2) TH activity can be increased by
catecholamine release through transcriptional,
translational, and post-translational regulation.
Stimuli that up-regulate TH expression
include chronic environmental stress and
drugs such as caffeine, nicotine, and
morphine; drugs that down-regulate TH
expression include many antidepressants.
(3) Increased synthesis for treatment of PD
can be achieved by peripheral administration
of L-dopa, which bypasses the TH rate-limiting
step and penetrates the blood-brain barrier, so
long as its peripheral metabolism is blocked.
( 4 ) Dopamine and other monoamines are loaded into vesicles by VMAT.
Terminating the actions of dopamine
(1) Dopamine is taken back up into the terminal (via the DAT)
(2) Enzymes (MAO and COMT) break down dopamine.
MAO
Monoamine oxidase
both intra- and extracellular forms, it metabolises all catecholamines and also 5HT.
Two isoforms: MAOA expressed in DA neurons and and NA neurons. MAOB in 5HT neurons,
with their axons containing MAOA.
MAOA AND MAOB affinity
MAOA=B in terms of DA affinity.
MAOA>B, affinity to NA & 5HT.
MAOB might be needed to maintain amine fidelity.
COMPT and DAT
Catechol-O-methyltransferase (enzymatic degradation)
Dopamine transporter (Involved in reuptake)
MAO inhibitors in Parkinson’s disease
MAOIs are used to treat PD. They were initially tested for this purpose
after discovering that the dopamine neurotoxin MPTP, which can cause Parkinson disease, must be
converted to MPP+ by MAOB before it can exert its toxic effects.
MPTP was discovered when an illicit drug
laboratory, attempting to make the opiate meperidine, left MPTP as a
contaminant.
The individuals who
injected it became acutely and severely Parkinsonian and were found to have destroyed their SN
DA neurons, likely by extreme oxidative damage. To reduce the oxidative stress, selective MAOB
inhibitor selegiline (aka deprenyl) was used and found effective.
Catecholamines are also catabolised by COMT
Peripherally the major COMT isoform is soluble, but in the brain a membrane-bound predominates, found in catecholamine synapses
COMT inhibitors, e.g. entacapone, tolcapone, tropolone increase
levels of DA & NA in synapses and prolong receptor activation. In
general, COMT appears to play a far smaller role in terminating the synaptic action of catecholamines
than their membrane transporters.
In the prefrontal cortex DAT is expressed at relatively low levels
and COMT may have more
significant role. Mutations in COMT may be associated with cognitive phenotypes, and perhaps
with risk of psychiatric disorders.
What is COMPT a risk lotus for?
schizophrenia, bipolar
disorder, and schizoaffective disorder and has been examined in attention deficit hyperactivity disorder (ADHD) and addictive disorders.
Expression of DA receptors
D1:
Agonists: SK82958, SK81297
Antagonists: SCH223390*, SKF83566, haloperidal
G5 protein coupling
Localisation: Neostriatum, cerebral cortex, olfactory tubercle, nucleus accumbens
D2
Agonist: bromocriptine*
Antagonists: raclopride, sulpiride, haloperidol
G1/0 protein coupling
Localisation: Neostriatum, olfactory tubercle, nucleus accumbens
D3
Agonists: quinpirole*, 7-OH-DPAT
Antagonists: raclopride
G1/0 protein coupling
Localisation: nucleus accumbens, islands of calleja
D4
Antagonist: clozapine
G1/0 protein coupling
Localisation: midbrain, amygdala
D5
Agonist: SKF38393
Antagonist: SCH23390
G5 protein coupling
Localisation: hippocampus, hypothalamus