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
Are DA receptors excitatory or inhibitory?
Dopamine can have an excitatory or inhibitory
effect depending on which receptor it binds to
D1-like and D2-like receptors
There are 5 types of dopamine receptors (D1 to D5) that
belong to 2 general categories: D1-like or D2-like.
* D1-like receptors (D1 and D5) typically stimulate the
activity of adenylyl cyclase (AC).
* D2-like receptors (D2, D3, and D4) typically inhibit the
activity of adenylyl cyclase (AC).
DA receptors and ADHD
DA involved in cognitive control of behaviour, attention and working memory
ADHD —> treated with psychostimulants (indirect dopamine agonists e.g methylphenidate and amphetamines)
DA receptors and antipsychotic drugs
Antipsychotic drugs produce their main therapeutic effects
(diminishing psychotic symptoms, eg, delusions and hallucinations) by blocking D2 receptors in subcortical structures in the limbic forebrain
Inhibiting D2 receptors in
the striatum produces side effects that are similar to the symptoms of Parkinson disease (treated by anticholinergics).
DA receptors and clozapine
Clozapine has less tendency to produce these side effects
due to a combination of receptor binding properties: a lower affinity for D2 receptors, antagonism of 5HT2A receptors, antagonism of muscarinic cholinergic receptors.
D2 agonists
E.g bromocriptine
- useful in the treatment
of Parkinson disease, whilst some D3-preferring agonists show also promise in PD (eg pramipexole and ropinirole)
Drugs affecting DA transmission
Reserpine —> inhibits V,AT and depleted dopamine stores
Cocaine —> inhibits DAT
Amphetamine —> increases dopamine release via transporter
Pramipexole —> partially selective D3 agonist
Tropoline —> inhibits COMPT
AMPT —> inhibits tyrosine hydroxylase and dopamine synthesis
Selegiline —> inhibits MAOB
Most antiphyschotic drugs —> block D2 receptors
Whereas
Ariprazole —> partial agonist
Bromocriptine —> D2 agonist
Noradrenaline function
Noradrenaline regulates
attention and impulsivity,
and also plays a central role in autonomic function.
How is noradrenaline made from Dopmaine?
- The addition of a
hydroxyl group to
dopamine by DBH
turns dopamine into
noradrenaline. - Terminating the actionof noradrenaline is the same as for dopamine.
The location of noradrenaline nuclei
Cell bodies of ~ 50% of
NA neurones are llocated
in the locus coeruleus
(about 12,000 neurons per hemisphere)
Projections are diffuse
(to the entire cortical
mantle, diencephalon and
cerebellum).
Each NA neuron can make
about 250,000 synapses!
N.B. The rest of NA
neurones in the brain are in loose collections of cells in the brainstem.
Adrenaline function
In the periphery, adrenaline increases heart-rate, constricts blood vessels, and relaxes airways
How is adrenaline made
- The addition of methane group to noradrenaline by PNMT (phentolamine N-methyltransferase) turns it into adrenaline
- Terminating the
actions of adrenaline
is the same as for
dopamine and
noradrenaline.
Production of noradrenaline and adrenaline
(1) Tyrosine -> Dopa -> Dopamine -> VMAT -> Vesicle
(2) NA is synthesised in synaptic vesicles. In NA
neurons dopamine-β-hydroxylase (DBH) catalyzes DA to NA.
(3) In neurons that produce adrenaline, NA gets
released from the vesicles.
(4) Phenylethanolamine-N-methyltransferase (PNMT),
converts NA to Adrenaline.
(5) Adrenaline is packed in vesicles by VMAT.
Tyrosine hydroxylase in production of Na and A
is the rate limiting enzyme in production of
NA and A (same as for DA).
Adrenaline location
Adrenaline occurs in only a small number of central neurons, all located in the medulla. It is also produced by the adrenal medulla.
Terminating the action od NA (and adrenaline)
(1) NA & A are taken back up into the terminal (NA via NAT)
(2) Enzymes (MAO and COMT) break down both NA & A (DA).
COMPT inhibitors in terminating actions of NA, A and DA
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 specific membrane transporters
Are all adrenal receptors Metabotropic?
Yes
All of the postsynaptic noradrenergic receptors are excitatory (β1, β2, β3, and α1) while the presynaptic α2 autoreceptor is inhibitory. However, the end result of
activation depends on second messenger substrates expressed in the particular
postsynaptic cell type, leading to either excitatory or inhibitory effects in neurons.
Adrenaline and noradrenaline use the same receptors. Each receptor subtype
responds in varying degrees to both NA and A with most adrenergic drugs targeting the autonomic nervous system.
Autoreceptors typically function to inhibit activity
Activation of α-adrenergic receptors (α- ARs) in a noradrenergic cell body, leads to a decrease in
the firing rate of the cell, which can be recorded experimentally with an extracellular electrode.
In the synaptic terminal, release of NA into the synaptic cleft allows for the diffusion of transmitter and the activation of presynaptic α-ARs. Such activation can inhibit further synthesis of NA and block the release of more transmitter.
Thus autoreceptors function in negative
feedback loops to modulate signaling
between neurons.
(Tyr, tyrosine; TH, tyrosine hydroxylase).
Adrenergic functions in the sleep-wake cycle
NA, along with 5HT, ACh, and a number of other singling molecules, is a critical regulator of the sleep–wake cycle and of
levels of arousal. Locus ceruleus (LC) receives input from other systems involved in sleep and arousal.
Adrenergic functions in attention and vigilance
the LC influences diverse aspects of attention and vigilance. In response to threat, LC firing may also increase anxiety, by releasing NA in the amygdala and other regions of the limbic forebrain
Adrenergic functions - Stimulation of β-adrenergic receptors
Stimulation of β-adrenergic receptors in the amygdala results in enhanced memory for stimuli encoded under strong
negative emotion, facilitating the recall of
stimuli that predict danger. This mechanism may contribute to post-
traumatic stress disorder (PTSD) in humans.
β-adrenergic receptor antagonists (eg,
propranolol) are being investigated as
interventions to decrease the intensity of
traumatic memories in PTSD.
Adrenergic functions - ADHD
Drugs that increase synaptic NA by blocking the NA transporter (NAT), such
as the antidepressant despiramine or
atomoxetine, exhibit some efficacy in treating ADHD.
Adrenergic functions and opiates
With chronic administration of opiates,
adaptations within LC neurons lead to tolerance and dependence and with
cessation to the opiate physical withdrawal syndrome
Psychostimulants
Psychostimulants have greater efficacy in most patients, probably because they increase DA as well as NA. Indeed they
act not only on DAT and NAT, but also on the serotonin transporter (SERT).
Drugs affecting NA transmission
Reserpine —> inhibits VMAT and depletes noradrenaline stores
NRI and SNRI —> antidepressants inhibit the noradrenaline transporter
Troplone —> inhibits COMPT
Prazosin —> alpha 1 antagonist
AMPT —> inhibits tyrosine hydroxylase and noradrenaline synthesis
MAOI - antidrepessants inhibit MAOA
Yohimbine —> alpha 2 antagonist
Clonidine —> alpha 2 agonist
Propanol —> beta antagonist
“Cheese effect” explained
MAOA found in gut and liver catabolises biogenic amines present in food
When MAOA is inhibited biogenic amines in foods can enter the general circulation and get taken up into sympathetic nerve terminals by NA transporters
This can lead to the release of NA and A
Release causes a hyperadrenergic crisis
What causes the hyperadrenergic crisis, which is also known as the ‘cheese effect’?
Inhibition of monoamine oxidase (MAO)
