Serotonin, histamine, GABA, glycine Flashcards Preview

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Flashcards in Serotonin, histamine, GABA, glycine Deck (12):
1

Biosynthesis/catabolism of serotonin

-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

Melatonin

-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

Serotonin receptors

-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

Neuropharmacology of 5HT receptors

-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

5HIAA levels and aggression and MDMA

-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

Histamine

-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

Histamine pharmacology

-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

GABA

-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

GABA receptors

-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

GABA and etoh and GHB

-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

Glycine

-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

Human startle disease

-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

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