Serotonin, histamine, GABA, glycine Flashcards
1
Q
Biosynthesis/catabolism of serotonin
A
- Tryptophan is precursor (levels have daily rhythmic variation) and are converted to 5-hydroxytryptophan by tryptophan hydroxylase (rate limiting step in 5HT synthesis)
- 5-hydroxytryptophan is acted on by 5-HTP decarboxylase to produce serotonin (enz is similar to AADC)
- 5HT is broken down by MAO and aldehyde dehydrogenase to generate 5 hydroxy-indole acetic acid (5-HIAA)
2
Q
Melatonin
A
- 5HT can also be broken down to N-acetyl serotonin (by 5-HT N-acetylase), which then is converted to melatonin (by 5-hydroxyindole-0-methyltransferase)
- Levels of melatonin very as a function of daily light and dark cycles (released in the evening)
3
Q
Serotonin receptors
A
- Most are GPCRs that use a variety of 2nd messengers
- The 5HT3 receptor family is the exception, and it is an ionophore for Na
- 5HT receptors have multiple functions (can be excitatory or inhibitory)
- Mescaline and psilocybin are potent agonists of 2A and 2C groups
- LSD acts as a partial agonist on 5HT receptors
4
Q
Neuropharmacology of 5HT receptors
A
- Evidence that intron 7 polymorphisms of tryptophan hydroxylase has higher frequency in pts w/ manic-depressive illness
- Reserpine blocks vesicle uptake of 5HT and depletes serotonin from synapse
- SSRIs prevent reuptake and Rx depression and OCD
- Hallucinations linked to 5HT receptors
- Sleep regulation linked to serotonin metabolism
5
Q
5HIAA levels and aggression and MDMA
A
- Low levels of the 5HIAA metabolite have been found in some pts w/ aggressive behavior
- MDMA (ecstasy) is an indirect agonist that releases 5HT
- Using MDMA can reduce the availability of 5HT over months
- These consequences may show up only later in life
6
Q
Histamine
A
- Abundant outside the CNS (mast cells)
- Precursor is histidine which is decarboxylated by histidine decarboxylase to produce histamine
- H1-H4 receptor groups
- H1 stimulation causes bronchoconstriction, awakefulness
- H2 antagonists used to decrease gastric acid secretion
7
Q
Histamine pharmacology
A
- Effects similar to anaphylactic reaction: hypotension and bronchoconstriction
- Blocking H1 causes sedation
- Driving under influence of anti-histamines is just as dangerous as driving under influence of eton
- Prolonged use of antihistamines my contribute to AD
8
Q
GABA
A
- The main inhibitory NT, implicated in d/o such as epilepsy, schizophrenia, tardive dyskinesia, HD, and others
- GABA metabolism linked to krebs cycle (TCA)
- Decarboxylation of glutamic acid by glutamic acid decarboxylase (GAD) is regulatory step
- GAD is marker of GABAergic neurons
- Glial cells participate in GABA metabolism/recycling
9
Q
GABA receptors
A
- 2 main types: GABAA and GABAB
- GABAA: gated Cl channels (inhibitory), large variety
- BZDs activate them and bicuculline (convulsant) inhibits them
- Have barbiturate binding sites (pentobarbital)
- Picrotoxin is a non-competitive inhibitor used as an antidote for barbiturate poisoning
- GABAB: GPCRs using cAMP or phosphatidyl inositol as 2nd messenger
- Muscle relaxant baclofen is an agonist
10
Q
GABA and etoh and GHB
A
- Low levels of eton increase the affectivity of some GABA receptors
- GHB= gamma hydroxybutyrate
- Taking GHB can induce coma (esp w/ etoh), vomiting, seizures, respiratory depression and amnesia
11
Q
Glycine
A
- Major inhibitory NT in the brainstem and SC, predominantly used by short axon interneurons
- Gly is synthesized from serine
- Receptor is a Cl ion channel w/ 5 subunits
- Strychnine is an alkaloid that is a competitive antagonist of the receptor and a potent convulsant
12
Q
Human startle disease
A
- Hereditary hyperekplexia: overreaction to unexpected stimuli w/ myoclonic jerks and stiffness (can result in falling)
- Distinct over-excitability and diminished inhibition in pts w/ hyperekplexia
- Based on a point mutation in the a1 subunit of the Gly receptor results in a 100-fold decreased affinity to the Gly receptor
