Serotoninergic neurotransmission

Question 1

Localization of serotoninergic neurons

Answer 1

• 90% in enterochromaffin cells in gut - regulate intestinal movements
• 10% synthesized by raphe nuclei - regulation of mood, petite, sleep, memory and learning

Question 2

Raphe nuclei

Answer 2

• 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

Question 3

Caudal raphe nuclei

Answer 3

• nucleus raphes magnus, pallidus and obscurus
• project to spinal cord and brainstem
• terminatein dorsal horn of grey matter
• regulate release of enkephalins

Question 4

Rostral raphe nuclei

Answer 4

• nucleus raphes pontis, centralis superior, dorsalis
• project to brain areas of higher function - basal ganglia, thalamus, hypothalamus, SCN
• feedback to SCN - circadian rhythm

Question 5

Synthesis of serotonin

Answer 5

L-tryptophan - TRYPTOPHAN HYDROXYLASE - 5-HTP - AA DECARBOXYLASE - serotonin

Question 6

Tryptophan hydroxylase

Answer 6

• located only in cytosol of serotoninergic neurons
• Km: 30-60uM
• phosphorylation increases activity
• rate limiting step
• serotonin cannot cross blood-brain barrier

Question 7

Fenclonine

Answer 7

• para-chlorophenylalaninen (PCPA)
• selective and irreversible inhibitor of TPH
• depletes serotonin in body + reduces its action

Question 8

Large neutral amino acid transporter (LAT1)

Answer 8

• transports tryptophan into brain
• heterodimeric membrane transport protein
• preferentially transports branched-chain and aromatic AAs
• highly expressed in capillaries in brain

Question 9

Tetrabenazine and Reserpine

Answer 9

• acts in cytosol

- irreversibly blocks VMAT

Question 10

Methysergide

Answer 10

• drug for prophylaxis of migraine

- antagonist of 5-HT receptor

Question 11

Synthesis of Melatonin from serotonin

Answer 11

• 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

Question 12

Fate of serotonin

Answer 12

• used in synapse
• synthesis of melatonin
• metabolism by MAO-A and aldehyde DH

Question 13

Iproniazid

Answer 13

• antidepressant

- irreversible and nonselective MAO inhibitor

Question 14

Fluoxetine (Prozac)

Answer 14

• acts in synapse
• selective serotonin reuptake inhibitor SSRi
• blocks SERT
• leads to increased extracellular serotonin conc. - increases serotoninergic neurotransmission

Question 15

VMAT 1 or 2

Answer 15

• serotonin uptake into vesicles
• low pH - maintained by H+ATPase
• secondary active transport
• facilitated via proton gradient
• 1 monoamine in, 2 protons out

Question 16

SERT

Answer 16

• repute of serotonin at presynaptic nerve terminal
• couples transport of 5HT with influx of Na+ and Cl-
• 50% homology to NET and DAT

Question 17

Fenfluramine

Answer 17

• 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

Question 18

MDMA (ecstasy)

Answer 18

• 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

Question 19

Serotonin receptors

Answer 19

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

Question 20

Antidepressant drugs

Answer 20

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

Question 21

Antipsuchotics and hallucinogenic drugs

Answer 21

• obtain by antagonistically blocking 5HT2 receptor
• used to manage psychosis, schizophrenia, bipolar disorder
  Olanzapine:
• atypical antipsychotic
• for schizophrenia and bipolar disorder

Question 22

Drugs agains nausea

Answer 22

• 5HT3 receptor antagonist against nausea
• chemotherapy 5HT release from GI enterochromaffin cells - 5HT3 receptor depol. - chemoreceptor activation - nausea
  e. g. Ondansetron

Question 23

Migraine headache medication

Answer 23

- arrives from decreased serotoninergic activity which causes vasoconstriction of brain vessels
Sumatriptan:
- synthetic drug
- structurally similar to serotonin
- 5HT1d and 5HT1b agonist