Serotoninergic neurotransmission Flashcards
Localization of serotoninergic neurons
- 90% in enterochromaffin cells in gut - regulate intestinal movements
- 10% synthesized by raphe nuclei - regulation of mood, petite, sleep, memory and learning
Raphe nuclei
- cluster in brainstem
- function: release serotonin
- 7-8 nuclei in midline around reticular formation
- axons from caudal raphe nucleus terminate in spinal cord and cerebellum
Caudal raphe nuclei
- nucleus raphes magnus, pallidus and obscurus
- project to spinal cord and brainstem
- terminatein dorsal horn of grey matter
- regulate release of enkephalins
Rostral raphe nuclei
- nucleus raphes pontis, centralis superior, dorsalis
- project to brain areas of higher function - basal ganglia, thalamus, hypothalamus, SCN
- feedback to SCN - circadian rhythm
Synthesis of serotonin
L-tryptophan - TRYPTOPHAN HYDROXYLASE - 5-HTP - AA DECARBOXYLASE - serotonin
Tryptophan hydroxylase
- located only in cytosol of serotoninergic neurons
- Km: 30-60uM
- phosphorylation increases activity
- rate limiting step
- serotonin cannot cross blood-brain barrier
Fenclonine
- para-chlorophenylalaninen (PCPA)
- selective and irreversible inhibitor of TPH
- depletes serotonin in body + reduces its action
Large neutral amino acid transporter (LAT1)
- transports tryptophan into brain
- heterodimeric membrane transport protein
- preferentially transports branched-chain and aromatic AAs
- highly expressed in capillaries in brain
Tetrabenazine and Reserpine
- acts in cytosol
- irreversibly blocks VMAT
Methysergide
- drug for prophylaxis of migraine
- antagonist of 5-HT receptor
Synthesis of Melatonin from serotonin
- light inhibits pineal gland to produce melatonin
- at night - photoreceptors not stimulated - sympathetic activity of B-receptor in pineal gland increases - increase cAMP - activation of 5HT N acetyl transferase - conversion of N acetyl serotonin to melatonin by 5 hydroxyindole o methyltransferase
Fate of serotonin
- used in synapse
- synthesis of melatonin
- metabolism by MAO-A and aldehyde DH
Iproniazid
- antidepressant
- irreversible and nonselective MAO inhibitor
Fluoxetine (Prozac)
- acts in synapse
- selective serotonin reuptake inhibitor SSRi
- blocks SERT
- leads to increased extracellular serotonin conc. - increases serotoninergic neurotransmission
VMAT 1 or 2
- serotonin uptake into vesicles
- low pH - maintained by H+ATPase
- secondary active transport
- facilitated via proton gradient
- 1 monoamine in, 2 protons out
SERT
- repute of serotonin at presynaptic nerve terminal
- couples transport of 5HT with influx of Na+ and Cl-
- 50% homology to NET and DAT
Fenfluramine
- part of fen-phen anti obesity medication
- increases level of serotonin
- inhibits VMAT and SERT
- reverses the reaction - 1 serotonin released into synapse
- leads to feeling of fullness and loss of appetite
MDMA (ecstasy)
- releasing agent of serotonin, NE and dopamine
- enters neuron via SERT
- inside neuron inhibits VMAT
- reverses reaction of SERT, NET, DAT through phosphorylation
- can induce euphoria, sense of intimacy, diminished anxiety
- acute effects:
1. psychotic effects: relaxation, euphoria, losing inhibitions, loss of negative thoughts
2. neurochemical effects: binds to NA, DA and 5HT transporters, release and depletion, inhibition of TPH and MAO, neurodegeneration, tachycardia, arrhythmia, vasoconstriction, increased body temp., hyperactivity
Serotonin receptors
5HT1: Gi pathway, in CNS and blood vessels, agonist: sumatriptan
5HT2: Gq pathway, in smooth m., platelets, PNS, CNS, GI tract, agonist: LSD/acid
5HT3: in PNS, CNS, ligand-gated non specific cation channels
5HT4/7: Gs pathway, 4 only in brain, 7 in brain, GI tract, blood vessels
5HT5/6: only in brain
Antidepressant drugs
MAO inhibitors (Selegiline):
- treatment of depression
- potentially lethal dietary and drug interactions
- act in cytosol
Buspirone and Flesinoxan:
- 5HT1a agonist
- efficacy in relieving anxiety and depression
Antipsuchotics and hallucinogenic drugs
- obtain by antagonistically blocking 5HT2 receptor
- used to manage psychosis, schizophrenia, bipolar disorder
Olanzapine: - atypical antipsychotic
- for schizophrenia and bipolar disorder
Drugs agains nausea
- 5HT3 receptor antagonist against nausea
- chemotherapy 5HT release from GI enterochromaffin cells - 5HT3 receptor depol. - chemoreceptor activation - nausea
e. g. Ondansetron
Migraine headache medication
- arrives from decreased serotoninergic activity which causes vasoconstriction of brain vessels Sumatriptan: - synthetic drug - structurally similar to serotonin - 5HT1d and 5HT1b agonist
