Serotonin (5HT) Flashcards
Serotonin syndrome
Potentially life-threatening adverse drug reaction that results from therapeutic drug use, intentional self-poisoning or inadvertent interactions between drugs
Serotonin syndrome is not an idiopathic drug reaction, it is a predictable consequence of excess serotonergic agonism of CNS receptors and peripheral serotonergic receptors
Excess serotonin produces a spectrum of clinical findings
Clinical manifestations of the serotonin syndrome range form barely perceprible to lethal
Symptoms: akathisia, altered metal status, clonus (sustained), hypothermia, tremor, clonus (inducible(, muscular hypertonicity
Serotonin (or 5-HT)
Serotonin and the catecholamine neurotransmitters have closely related functions, closely related mechanisms of clearance from synapses, some shared pathways of metabolism, and, perhaps most importantly, are jointly targeted by several important classes of drugs, including psychostimulants (DA, NA, and 5HT), tricyclic antidepressants (NA and 5HT), monoamine oxidase inhibitors (DA, NA, and 5HT), and serotonin-noradrenaline selective reuptake inhibitors (NA and 5HT).
Tryptophan
Tryptophan is an amino acid that we get solely from our diet
How is serotonin is synthesised from tryptophan?
- The removal of a hydroxyl group by tryptophan
hydroxylase turns tryptophan into 5-HTP. - 5-HTP is converted into
serotonin when 5-HTP
decarboxylase removes a
carboxyl group from 5-HTP. - Removal of serotonin from the synapse is by reuptake or degradation by MAO.
The location of serotonergic nuclei
Cell bodies are located in
midline raphe nuclei
throughout the brain stem.
Caudal raphe nuclei project
to the spinal cord and are
important for the modulation of afferent pain signals.
Rostral raphe nuclei project
just about everywhere
else
THP is the rate-limiting enzyme in 5HT synthesis
(1) Tryptophan is actively transported across
the blood-brain barrier.
(2) THP hydroxylates tryptophan and is the
rate-limiting enzyme for 5HT biosynthesis.
There are 2 genes, TPH1, predominantly expressed in the periphery, and TPH2, expressed preferentially in the brain. TPH can be regulated through neuronal activity. Levels of 5HT in the brain can be altered by several other means: (a) Drugs, such as PCPA, can irreversibly inhibit TPH to produce
a long-lasting depletion of 5HT. (b) Individuals who are asked to follow a low-tryptophan diet and subsequently are challenged with a beverage containing other amino acids but lacking tryptophan typically experience not only a dramatic reduction in blood tryptophan levels but also a substantial reduction of 5HT in the brain (N.B. relevance to depression).
(3) AADC (same as for the other chatecolamines) decarboxylases 5HTP into 5HT.
(4) 5HT, like other monoamines, is loaded into vesicles by VMAT
Terminating the actions of 5HT
(1) 5HT is taken back up into the terminal (via the SERT)
(2) MAO breaks down 5HT.
(NO COMPT)
MAO
it metabolises all
catecholamines and also
5HT.
The intracellular form is
associated with the outer
membrane of mitochondria. The extracellular form may also act to metabolise neurotransmitter
while in the synapse.
MAO inhibitors (MAOI) and depression
The first MAOI used in the clinic in the 1950s, iproniazid, was tested as treatment for tuberculosis. Although it was ineffective against mycobacteria, it
relieved the depression that was common among patients with TB
Most MAOIs, such as phenelzine,
tranylcypromine, isocarboxazid, which
can be used to treat depression and
anxiety disorders are nonselective MAOA
and MAOB inhibitors.
They are more effective than tricyclic antidepressants in the treatment of atypical
depression, which is characterised by a reversal of the usual neurovegetative symptoms of depression (eg, hypersomnia
instead of insomnia, and hyperphagia instead of anorexia).
Selegiline is also efficacious against depression, but only at high doses; becoming a nonselective MAOI and its use requires precautions against dietary
tyramine
Today, SSRIs are far more widely used for treating depression because of their superior tolerability.
Serotonin receptors
Serotonin receptors are the targets of numerous pharmacological
treatments for mood disorders.
5-HT1A, B and D are
presynaptic metabotropic receptors
5-HT1E-1F and 5-HT2A-2C are postsynaptic metabotropic receptors
5-HT3 receptors are
ionotropic receptors
5-HT autoreceptors
The 5HT1A receptor is a somatodendritic autoreceptor. It resides on cell bodies and dendrties —> regulates cell firing, release of serotonin and serotonin synthesis (by influencing secondary messenger systems that regulate tryptophan hydroxylase)
The 5HT1D receptor is localised in presynaptic terminals and also regulates the synthesis and release of serotonin
Serenity, tranquility and peace - hallucinogens and 5HT2A
Hallucinogens, sometimes also described as “psychedelic drugs,” are partial agonists at 5HT2A receptors.
The indolamine d-lysergic acid diethylamide (LSD, “acid”) —> nonselective serotonin receptor agonist
sensory distortions (eg, visual illusions), hallucinations (most commonly visual, in contrast with schizophrenia in which hallucinations are more commonly auditory), and emotional changes.
Its effects on sensory perception are mediated through partial agonist effects on 5HT2A receptors. This is a shared property of other psychedelic agents, including other indolamine hallucinogens (eg, N,N-dimethylamine [DMT] and psilocybin) and the phenethylamine psychodelics (eg, mescaline and dimethoxymethylamphetamine [DOM / STP]).
Distorting effects of LSD on sensory perception and their capacity to produce hallucinations
presumably reflect the dense innervation of the cerebral cortex by serotonin fibres.
5HT3 receptors
Anatgonists: ondansetron, granisetron
G protein: ligand-gated channel
Localisation: spinal cord, cortex, hippocampus, brainstem nuclei
70–80% of the 5-HT3 receptors in the brain locate presynaptically associated with
axons and nerve terminals except for the hippocampus where they locate mainly postsynaptically in somatodendritic
regions. The prevalent expression of 5-HT3 receptors on nerve endings is consistent with their physiological role in
neurotransmitter release such as dopamine, glutamate, acetylcholine and GABA.
5HT3 receptor primary binding site
Orthosteric ligand binding site:
Agonists/competitive antagonists —> ‘setrons’, local anaesthetics, morphine, methadone (5HT3A), mianserin, mitrazapine, clozapine, quinine (5HT3A), quercetine
Drugs affecting serotonergic transmission
Reserpine —> inhibits VMAT and depletes serotonin stores
SSRI and SNRI —> antidepressants inhibit the serotonin transporter
Many antipsychotic drugs —> inhibit 5HT2A receptors
Odansetron —> 5HT3 antagonist
PCPA —> inhibits tryptophan hydrolase ans serotonin synthesis
Antimigrane triptans —> 5HT1D antagonists
MAOI antidepressants —> inhibit MAOA
Busipiorine —> a partial agonist at 5HT1A receptors
