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Lecture_13-Catecholamines

Vesicles are small and clear vesicles are docked

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-Vesicles are small and clear - Vesicles are docked close to the active zone (i.e., require lower calcium input compared to neuropeptide-containing large, dense core vesicles) - Release occurs from varicosities along terminal = non-directional/modulatory release
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Re-uptake - Plasma Membrane Transporters NET: gene found only in noradrenergic neurons DAT: gene found only in dopaminergic neurons BUT substrate specificity is lacking esp. in areas with low DAT (like PFC) where DA can be taken up by NET - 12 TM domains - Many regulatory sites - Responsible for removing 80-90% of released NT
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Pharmacology of Re-uptake Non-selective re-uptake inhibitors - Bind DAT, NET and SERT - Example: cocaine Selective re-uptake inhibitors - ”tri-cyclic antidepressants” can be NET only but many inhibit SERT also - Desipramine is prototypical selective NET inhibitor - Nomifensine is prototypical selective DAT inhibitor Wellbutrin/Zyban (buproprione) is antidepressant/anti-smoking drug Amphetamines (AMPHs): - Because they look like a catecholamine, AMPHs enter cell through DAT/NET - Enter through VMAT, disrupt pH of vesicle àฏ drives DA/NE out into cytosol - Increased [DA/NE] cytosol àฏ creates a concentration gradient that drives DA and NE out of the cell through DAT/NET
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1. MAO: - Monoamine oxidase oxidative deamination of catecholamines - Enzyme localized in synapse as well as in terminal (in mitochondria); cytosolic MAO responsible for majority of break-down after re- uptake DA àฏ HVA & DOPAC NE àฏ MHPG (glycol) and VMA (acid) Catecholamine metabolism 2 processes: 1. deamination 2. O-methylation 2. COMT: - Catechol-O-methyl transferase O-methylation - Breaks down small fraction of NTs in cleft - Extracellular - Principle mechanism in periphery (high MHPG in urine)
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Pharmacology of MAO Metabolism MAO-inhibitors (MAOI’s) “suicide substrates”; irreversible until recently - Increase NT in tissue and synapse àฏ treat OCD, depression MAO-A - Expressed almost exclusively in NE neurons - Preferential enzyme for NE, Epi and 5-HT - Binds DA with lowest affinity MAO-B - Expressed almost exclusively in 5-HT neurons, but also other monoamine neurons - May be involved in DA metabolism Genes located on X chromosome
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Genetics of Metabolism: Variations in COMT A variation in the COMT gene's sequence results in two common versions: val and met — one version produces an enzyme that has the amino acid valine in the same position as the other has a methionine. The val version results in stronger COMT enzyme activity. For example, people who inherit
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