Serotonergic neurotransmision Flashcards
Where is 5-Ht produced?
90% of serotonin is produced in the GIT by enterochromaffin cells.
8% is located in platelets
only 2% is produced in the CNS
Hallucinogens
The structure of serotonin is similar to hallucinogenic or psychedelic drugs.
Psilocybin has a similar structure to serotonin. It is converted to Psilocin in vivo, which can act on serotonergic neurons to have hallucinogenic effects.
Lysergic acid diethylamide (LSD) is a psychedelic drug → intensified thoughts and emotions, altered sensory perception, and visual and auditory hallucinations.
N, N-Dimethyltryptamine (DMT) is a substituted 5-HT that occurs in many plants and animals and is a derivative and structural analogue of tryptamine. It is used as a recreational psychedelic drug.
All of these drugs act at 5-HT2A/C receptors. These are Gq-coupled, so activation causes an increase in IP3 and DAG.
Hallucinogens are selective agonists that stabilise a subset of receptor conformations and selectively activate some, but not all, signalling pathways. Biased agonism is involved in the psychoactive differences between hallucinogen and closely related non-hallucinogen 5-HT2A receptor agonists.
Neurons and synthesis
Serotonergic neurons in the rostral and median raphe nuclei project to the forebrain, thalamus and cerebellum.
Neurons in the caudal raphe nucleus project to the raphe obscurus, pallidus and magnus, as well as to the spinal cord and cerebellum.
Tryptophan hydroxylase (TH) adds a hydroxyl group to tryptophan. This requires tetrahydrobiopterin (BH4), NADPH and a metal ion (iron or copper).
5-hydroxytryptophan is then decarboxylated by L-aromatic amino acid decarboxylase (AADC) to form 5-HT.
Brain serotonin biosynthesis depends on the amount of tryptophan crossing the BBB. Only free plasma tryptophan, unbound to albumin, can do this.
Plasma cortisol, which is increased in depression, decreases free tryptophan concentrations.
Melatonin
Serotonin is transformed into melatonin in the pineal gland.
First, 5-HT N-acetyltransferase (AANAT) forms N-acetyl serotonin. This is converted to melatonin by 5-hydroxyindole-O-methyltransferase (HIOMT).
Melatonin levels show circadian variations, following changes in HIOMT expression, increasing during the night.
N-acetyl transferase activity also follows the same trend, increasing 7-150 fold during the night.
Light inhibits melatonin biosynthesis.
MT1/2 melatonin receptors are found in the entire body including the hypothalamus, hippocampus and other parts of the CNS. These are GPCRs.
MT1 is Gi-coupled, reducing cAMP levels. It also induces expression of the per and c-Fos proteins, involved in control of the circadian rhythm.
MT2 is Gq-coupled, activating PLC and DAG signalling.
Melatonin function and dysfunction
Melatonin controls sleep patterns and hormone rhythms.
Melatonin acts as an anti-ageing, senescence-delaying and antioxidant molecule in the brain.
Inappropriate light exposure causes degradation of pineal N-acetyltransferase, leading to suppression of melatonin synthesis and circadian dysfunction. This can cause amyloid plaque formation, tau pathology and oxidative stress, leading to Alzheimer’s.
Melatonin suppresses the expression of BACE1 and PSEN1, which are enzymes involved in the buildup of Amyloid plaques in the brain.
-BACE1 - beta-site amyloid precursor protein cleaving enzyme 1 → amyloidogenic pathway
-PSEN1 - presenilin 1 → associated with the 𝛾-secretase complex, increase likelihood of forming the longer Aꞵ42, which is pathogenic.
Melatonin supplementation enhances lifespan in Drosophila melanogaster and increased the survival chances of mice.
5-HT metabolism
Metabolised to 5-hydroxyindole acetic acid (5-HIAA) in a two step process by enzymes in neurones and glial cells: oxidation by MAO-A in the outer mitochondrial membrane followed by a second oxidation by aldehyde dehydrogenase.
5-HIAA is excreted by the kidneys.
Clorgyline is a selective MAO-A inhibitor, used for the treatment of panic disorder and last line treatment for depression.
SERT (SLC6A4)
12 TM symporter
Binds a Na+, then 5-HT, then a Cl-, and due to the membrane potential flips inside the cell freeing 5-HT into the cytoplasm.
SERT then binds a K+ ion to flip back outside the cell membrane and return to its active state ready for more 5-HT reuptake → net loss of positive charge.
The promoter region of the SLC6A4 gene contains a polymorphism and can have short (14) or long (16) repeats.
The short 14 repeats variant leads to less transcription and is associated with anxiety-related traits.
Receptors
14 distinct receptors in 7 different families, 5HT1-7.
1A-F receptors are Gi coupled, leading to a decrease in cAMP.
4, 5A, 5B, 6, 7 receptors are Gs coupled, leading to an increase in cAMP levels.
2A-C receptors are coupled to Gq PLC signalling, increasing IP3 and DAG levels.
3A-C receptors are ion channels, causing a rapid depolarisation due to an influx of Na+ and Ca2+.
1A receptors are found on presynaptic dendrites, the cell body and axons → activation causes a decrease in neuronal firing.
1B receptors are found at the presynaptic terminal → activation causes a decrease in NT release.
Pathophysiology
5-HT receptors are found pre- and post-synaptically, but also on astrocytes, microglia and oligodendrocytes.
5-HT released from raphe neurons in the brain regulate sleep, body temperature, food intake, cognition, mood, vomiting and pain perception.
Hypothalamic neurons with neuroendocrine function are regulated by 5-HT - e.g. cortisol release is regulated by 5-HT2 receptors.
In migraines, there’s a chronically low 5-HT disposition due to disturbances in synthesis.
In epilepsy, there are alterations in 1A, 2C, 3 and 7 subtypes. The binding capacity of 1A is also lower.
In depression, there are reduced levels in the CNS.
SERT mutations are associated with anxiety disorders.
Memory disorders
5-HT4 receptors (Gs) are found in the hippocampus.
5-HT4 activation can alter plasticity in mice brains. This can either lead to an enhancement or suppression of LTP.
Receptor activation strongly impacts plasticity and therefore learning and memory.
Imaging the mouse brain shows that 5-HT4 activation causes changes in brain connectivity, increasing budding and causing new spine formations.
Optogenetic activation of serotonergic terminals in the CA1 area of the hippocampus showed an increase in water maze memory formation in mice.
