Catecholamines

• Rate limiting enzyme for serotonin

  Try H
• Where does 5-HT synthesis occur

  the terminal
• Tryptophan


  essential amino acid derived from the diet
• How is tryptophan transported to the brain

  by a special transport system that also targets other amino acids
• What leads to higher tryptophan levels

  - the ratio between tryptophan and the sum of all competing LNAA

  - low protein, high carb meal
• Used experimentally to deplete brain 5-HT levels

  LNAAs
• Reserpine

  - MAO

  - inhibits monoamine transporter + 5-HT
• Small functional pool of 5-HT


  - 10-25%

  - Contains newly synthesized and released 5 HT
• Other functional pool of 5-HT vesicles

  large reserve pool
• somadendritic autoreceptors


  cause an increase in membrane K+ suppressing cell firing
• Pre-synaptic/terminal autoreceptors


  reduce Ca2+ inhibiting exocytosis
• the reuptake of 5-HT displays

  - high affinity

  - requirement for metabolic energy (primary active transport)
• Most 5-HT cell groups are associated with

  the raphe nuclei and lower brain stem
• Largest cluster of 5-HT neurons is found

  in the dorsal raphe nucleus
• B1-B4


  - medial region of the medulla

  - projects to the spinal cord + cerebellum

  - sensory, motor, and autonomic functions

  - inhibition of pain signals from spinal cord
• B5-B9


  80% of all forebrain 5-HT originates from dorsal (B6/7) and median (B5/8) raphe
• Almost all 5-HT receptor subtypes are

  - G protein-coupled receptors

  - Metabotropic
• 5-HT1A


  agonists induce: hyperphagia, hypothermia, anxiolytic, and 5-HT syndrome
• 5-HT2A


  - classic 5-HT2 receptor

  - hallucinogenic effects of LSD

  - Antagonism effective in treating schizophrenia

  - stimulates phospho. second messenger system
• 5-HT3


  - ligand gated

  - excitatory

  - PNS

  - induces vomiting

  - antagonists are anti-nausea
• Tyrosine


  amino acid derived from dietary proteins
• Rate-limiting enzyme in catecholamine synthesis

  tyrosine hydroxylase
• Formation of dopamine


  from L-DOPA by enzyme AADC
• NE and EPI neurons and chromaffin cells of the ______ contain the enzyme ______

  - adrenal medulla

  - dopamine β-hydroxylase (DBH)
• In NE cells, DBH is found

  inside the vesicles
• Synthesizes EPI from NE


  enzyme PNMT
• Vesicular exocytosis is initiated by

  Ca2+ in both DA and NE neurons
• Chromaffin cells use exocytosis to

  release NE or EPI as hormones into the blood stream
• Catecholamine reuptake


  - requires ATP

  - some molecules are re-packaged into vesicles

  - some metabolized
• are uptake transporters for DA and NE selective

  Not really for their respective NT
• Catechol-O-methyltransferase (COMT)


  - found in the brain, liver, kidney & heart

  - found in post-synaptic membrane
• Monoamine Oxidase Mitochondrial Isoenzymes A & B


  - found in brain (neurons & glia), liver, and kidney

  - outer membrane of mitochondria
• MAO-A


  for DA, NE, EPI, and 5-HT
• Metabolism of DA yields

  DOPAC & HVA

  - can be measured in the brain, CSF, and urine
• Metabolism of NE yields

  MHPG in CSF

  VMA in urine

  - both in plasma
• Most commonly used to produce experimental lesions of dopamine pathways (Experimentally produced Parkinsons)


  6-Hydroxydopamine (6-OHDA)
• Ascending DA systems


  - Mesostriatal

  - Mesolimbocortical

  - Mesolimbic

  - Mesocortical
• Mesostriatal DA System


  - vital for motor control

  - degeneration is a key feature of Parkinsons
• Mesolimbic System


  - learning, memory, motivation

  - Implicated in addictive behaviours
• Mesocortical


  - learning, memory, motivation-central role in addictive behaviours- schizophrenia