Catecholamines

Question 1

Catecholamines

Answer 1

• Molecules w/ benzene rings containing 2 adjacent hydroxyl residues and a side chain amine
• Are synthesized from tyrosine
• Liver controls availability of tyrosine and its precursor phenylalanine
• Tyr can also be obtained from high-protein foods

Question 2

Biosynthesis of tyrosine

Answer 2

• Phe is converted to Tyr by phenylalanine hydroxylase
• Mutations in this nz can lead to accumulation of neurotoxic phenylketones (phenylketonuria, or PKU)
• Decarboxylation of phe leads to phenylethylamine, which is elevated in the crises of paranoid schizophrenics
• Tyrosine decarboxylation leads to tyramine (sympathomimetic), which has actions similar to epinephrine (is also present in cheese, beer, wine, chocolate)

Question 3

Biosynthesis of L-DOPA

Answer 3

• Tyr hydroxylase (TH) converts tyr into L-DOPA, this is the rate-limiting step in catecholamine (CA) synthesis
• TH is most important nz in CA synthesis
• TH is in all cells capable of synthesizing CAs
• TH inhibited by AA analogs (alpha-methyltyrosine), CA-derivatives, Fe chelators, and lead
• Short-term regulation of TH activity occurs thru phosphorylation (increasing activity)
• Long-term regulation of TH thru transcriptional regulation by NTs, hormones, caffeine, and nicotine

Question 4

Biosynthesis of dopamine (DA)

Answer 4

• Action of DOPA decarboxylase, aromatic acid or dihydroxyphenylalanine decarboxylase (AADC) converts L-DOPA into DA
• Vit B6 is cofactor
• Nzs are present in excess

Question 5

Biosynthesis of dopamine (DA)

Answer 5

• Action of DOPA decarboxylase, aromatic acid or dihydroxyphenylalanine decarboxylase (AADC) converts L-DOPA into DA
• Vit B6 is cofactor
• Nzs are present in excess

Question 6

Biosynthesis of norepinephrine (NE)

Answer 6

• Synthesized from dopamine beta-hydroxylase nz, requires vit C, Cu, O2
• NE plays important role in sleep, arousal, attention, vigilance, learning, and memory

Question 7

Catecholamine catabolism 1

Answer 7

• Monoamine oxidases (MAO) convert the amino group to aldehyde (two types: A and B)
• MAO is preceded by or followed by COMT, then followed by aldehyde reductase, to produce a hydroxyl group from the aldehyde, or by aldehyde dehydrogenase, to produce a carboxyl group
• 1-deprenyl is a MAO-B inhibitor and can increase the T1/2 of DA
• Smoking inhibits MAO-B activity, increasing the T1/2 of DA and could be relevant to addiction
• Nicotine also stimulates the cholinergic receptors on DA neurons causing them to fire APs and release DA

Question 8

MAO mutations

Answer 8

• Abnormal and violent behavior in a family is associated w/ a point mutation in the MAO-A gene
• Pts do not have detectable amounts of HVA (CA breakdown product) and low amounts of 5HIA (serotonin breakdown product)
• MAO-B does not compensate for loss of MAO-A
• MAO-B KO in mice lead to submissive behavior

Question 9

MAO mutations

Answer 9

• Abnormal and violent behavior in a family is associated w/ a point mutation in the MAO-A gene
• Pts do not have detectable amounts of HVA (CA breakdown product) and low amounts of 5HIA (serotonin breakdown product)

Question 10

DA and NE catabolism

Answer 10

• Principle metabolite of DA after action of MAO + COMT followed by aldehyde dehydrogenase is homovanillic acid (HVA)
• HVA is an indicator of DA activity in the CNS
• Principle metabolite of NE after the action of MAO + COMT + aldehyde dehydrogenase is 3-methyle-4-hydroxyphenol-glycol (MHPG)
• MHPG is an indicator of NE activity in the CNS

Question 11

DA and NE catabolism

Answer 11

-Principle metabolite of DA after action of MAO + COMT followed by aldehyde dehydrogenase is homovanillic acid (HVA)

Question 12

DA systems of the brain

Answer 12

• DA neurons that originate in substantia nigra project to the striatum
• Those that originate in VTA project to nucleus accumbens (NA), cerebral cortex, and hypothalamus
• DA in NA is where the DA rush occurs, associated w/ drugs, sex, and risk-taking

Question 13

DA storage and release

Answer 13

• DA release requires an influx of Ca ions and the fusion of synaptic vessels
• Membrane potentials and DA synthesis/release can be regulated by presynaptic receptors
• DAT (dopamine transporter) reuptakes DA into presynaptic cells
• DAT inhibited by cocaine

Question 14

DA receptors

Answer 14

• 5 major types and all are GPCRs
• D1 and D5: stimulate cAMP synthesis by AC
• D2-4: inhibit cAMP synthesis by AC
• Present in presynaptic cells to regulate NT release

Question 15

Other compounds affecting CA pathways

Answer 15

• Alpha-methyltyrosine: inhibits TH and prevents CA production
• Reserpine: blocks DA uptake (VMAT) and storage
• Amphetamine: stimulates release of DA and blocks its uptake
• Cocaine: inhibits DAT
• Pargyline: inhibitor of MAO

Question 16

Other compounds affecting CA pathways

Answer 16

• Alpha-methyltyrosine: inhibits TH and prevents CA production
• Reserpine: blocks DA uptake and storage
• Amphetamine: stimulates release of DA and blocks its uptake

Question 17

DA receptor and schizophrenia

Answer 17

-D4 receptor bp repeats lead to increased susceptibility to delusional disorder