serotonin (finish updating later)

behavioral impact of serotonin in CNS

• mood and emo

  • linked to dep, anxiety, well-being

• sleep-wake cycle

• appetite and satiety

• pain modulation

• impulse control and social behavior

  • low serotonin assoc. with aggression and impulsivity

behavioral impact of serotonin in PNS

• gut motility and nausea/vomiting

  • activated brainstem vomiting centers

• bone metabolism

• organ repair

  • 5-ht stim. cellular repair of liver

• cardiovascular tone

  • vasoconstrictor or dilator depending on receptor

• skin and epithelial cells of the lungs

what do 5-ht neurotoxins do

• changes in hunger, eating, pain sensitivity, anxiety, learning and memory

• most compulsive, impulsive

• poor social skills including maternal

• poor thermoregulation and respiration

• inc in aggression

what was the most persistent finding

• inc in aggression

  • serotonin deficiency hypothesis of aggression

  • both reactive (provoked) and proactive (planning)

  • aggression decreaases with SSRIs

what is an example of a 5-ht neurotoxin

MDMA

what are indolamines — types, structure, synthesis

• types

  • 5-ht

  • melatonin

• structure

  • indole ring + amine group

• synthesized from AA tryptophan (essential!)

serotonin synthesis

what is 5-ht — loc of synthesis

• classic/amine NT

• synthesized in terminal buttons

what are the genes for tryptophan hydroxylase

• TPH1 — 5-HT gut cells and melatonin cells in pineal gland

• TPH2 — 5-ht neurons

what happens when you knockout TPH2

complete loss of 5-ht in brain

what happens when you have tph1 variants

linked to gut motility disorders, IBS, possible immune disregulation

does TPH cross bbb

nope

where is most 5-ht

90% in gut

what is rate limiting step?

• tryptophan hydroxylase as only 5-ht neurons contain it

what ratio is IMP?

• ratio bn LNAAs and tryptophan as they compete to cross the BBB

compare proteins vs carbs and why

• proteins

  • LNAA > tryptophan

• carbs

  • LNAA < tryptophan

• why?

  • insulin inc uptake of AA into cells, leaving TPH in the bloodstream

what does most tryptophan turn into?

• 95% is metabolized into Kynurenine

what is kynurenine involved in

• regulating the immune response

what disorders inc or dec it

• production inc in alzheimers and cardiovascular disease

• production dec in bipolar disorder

what is the kynurenine pathway implicated in?

MDD, Bipolar, Schizophrenia, anxiety disorders, tics, Huntington’s, MS, Tourette’s, Vitamin B6 deficiency, etc…

what are included as monoamines

• catecholamines (DA,NE,epi)

• indolamines (5-ht and melatonin)

what is involved in 5-ht inactivation?

• VMAT2 and MAO

  • not comt

• reuptake via SERT

what is the 5-ht metabolite

• 5-HIAA

  • 5-hydroxyindoleacetic acid

serotonin full pathway

SERT knockout in mice

SERT KO vs SSRI treatment vs normal

long term SSRI treatment

• downregulation of autoreceptors

• upregulation of some receptor subtypes in the cortex and hippocampus

5-ht — amount, loc, what regulates it

• 200,000 neurons

• 9 raphe nucleu

• DA, NE, Orexin, GABA, and acetylcholine all regulate it?

how many receptors and description of them

• 14 dif receptors

  • inhibitory and excitatory

  • metabotropic and ionotropic

  • postsynaptic and autoreceptors

what receptors are most imp for drugs of abuse

• 5-HT1 and 5-HT2

5-HT_1A vs 5-HT_2A

what are the types of antidepressant drugs? when did they come out?

• SSRIs (late 1980s)

• SNRIs (late 1990s)

• tricyclic antidepressants (TCAs) (second-line drugs, 1950s)

• MAOIs (1950s)

• atypical antidepressants

TCA

• multiple action

• (SNRI, SSRI, Weak at DAT, also 5-HT2A/C antagonists, some block histamine, some block alpha1, some block muscarinic)

MAOI-s

largely no longer used, except in Parkinson’s Disease

what are atypical antidepressants

• act in a different way

• wellbutrin, remeron, trazodone, seroquel

serotonin syndrome

• too much 5-ht

  • can cause fast heart rate, high blood pressure, death

• symptoms occur within a day

  • fever, tremor, muscle twitches, nausea

• typically due to two or more 5-ht drugs

• st. johns wort, nutmeg, grapefruit, cough syrup