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Chapter 6: Serotonin, 90-95% of all 5-HT in the body is in the GUT -…

- - - - in forebrain (hippocampus mostly, septum and cortex): postsynaptic receptors
      - in raphe nuclei (brainstem): somatodendritic autoreceptors
      - reduce cAMP by inhibiting AC --> increase opening of K+ channels --> hyperpolarization
    - - activates PLC 2nd messenger system
        
        leads to increase in Ca++ levels in postsynaptic cells and activates protein kinase C (PKC) (INCREASE INTRACELLULAR CALCIUM)
      - mostly in cortex, striatum, NA
      - HALLUCINOGENIC EFFECTS of LSD and psilocybin are due to STIMULATION of 5-HT2A receptors
    - - migraines are because of abnormal dilation of blood vessels in the brain
        
        Triptans: 5-HT 1B/1D agonists --> constriction of blood vessels
        
        may also reduce central 5-HT release by stimulating autoreceptors
  - - - significant problems with thermoregulation - cannot maintain body temp in cold conditions
      - frequent, long-lasting episodes of apnea in very young mice
      - 2A and 2B agonists RESCUES mutant phenotype
  - - - 5-HT1A KO mice are more anxious
      - 5-HT in development: deficient 5-HT1A receptor activity during a critical developmental period may give rise to anxiety as adults
- - - - MDMA for PTSD: reduce fear & defensiveness, enhance communication & introspect, increase empathy & compassion
    - - may also have direct effects on several 5-HT receptors
      - Via SERT, MDMA stimulates 5-HT efflux from synaptic terminals via a REVERSE-TRANSPORT MECHANISM and BLOCKING of VMAT2
        
        SSRIs BLOCK MDMA's ability to bind SERT and to stimulate 5-HT release
    - - MDMA as a DA neurotoxin? NO
        
        "MDMA cause brains similar to Parkinson's (kills dopaminergic cells)"
        
        NO OTHER LAB COULD REPLICATE THESE RESULTS: later found out scientists were giving monkeys METHAMPHETAMINE, NOT MDMA
      - MDMA as a 5-HT neurotoxin?
        
        high dosage, repeated for several days --> REDUCED DENSITY of 5-HT forebrain fibers
        
        BUT, fibers recover (indicates plasticity)
- - - - terminal: 1B and 1D (can also function postsynaptically)
      - Somatodendritic (in raphe nuclei): 1A (also postsynaptic in cortex)
    - - 5-HT is catalyzed by MAO to 5-HIAA (metabolite of 5-HT)
  - - - L-tryptophan acted on by tryptophan hydroxylase
        
        gives 5-HTP which is acted on by AADC
        
        serotonin
    - - increase in tryptophan ---> enhanced serotonin synthesis in blood
        
        more 5-HTP --> increase in GI contractability
    - - TPH1: gut and elsewhere
      - TPH2: brain
    - - RATIO between amount of tryptophan and its aa competitors determines whether 5-HT synthesis is stimulated in brain
        
        Increased plasma serotonin levels can be achieved with a HIGH-CARB, LOW-PROTEIN diet to push ratio toward increased tryptophan
        
        because insulin can stimulate UPTAKE of aa from the bloodstream, not tryptophan
- - - - anxiety - lacks SERT (blocks 5-HT reuptake) but still has anxiety
        
        remember LOW LEVELS of 5-HT are supposed to cause anxiety
      - depression - remember LOW LEVELS of 5-HT are supposed to contribute to depression
  - - - cognitive effects: headaches, agitation, hypomania, mental confusion, hallucinations, coma
      - Autonomic effects: shivering, sweating, hyperthermia, vasoconstriction, tachycardia (fast heart rate), nausea, diarrhea
      - Somatic effects: myoclonous (muscle twitching), hyperreflexia, tremor
- - - - depressed mood in healthy subjects who have a family history of depression, not in healthy subjects WITHOUT familiy history
        
        Indicates merely having low levels of serotonin DOES NOT CAUSE DEPRESSION, except in vulnerable individuals