Ch 6 serotonin Flashcards
what is serotonin and pathway, forms of enzyme, rate limiting step?
5-HT
monoamine, can’t cross BBB
Tryp/5-HTP can cross BBB
Tryptophan -> 5-HTP (using TPH) -> 5-HT (using AADC)
TPH1 in gut, TPH2 in brain
TPH is rate limiting step, slowest enzyme
tryptophan and 5HT synthesis
tryp competes with other amino acids to transport across BBB
ratio between tryp and other acids determines whether 5-HT happens in brain
how serotonin vesicles and autoreceptors
transported into vesicles with VMAT2
Terminal auto = 1B/D
Somatodendricit auto = 1A in raphe nuclei
how serotonin removes from cleft/metabolized
removed via reuptake with SERT (5-HT transporter)
catalyzed by MAO into 5-HIAA, levels of this metabolite as indirect measure of serotonergic neurons
5HT release via indirect agonists
PCD empties terminals of 5HT
Fenflurmaine reverse SERT (5ht spills out)
MDMA releases 5HT
MDMA how work with 5HT, what do SSRIs do to it
Schedule 1 drug (no research), produces empathy
affinity for SERT stimulates 5HT efflux via reverse SERT and blocks VMAT
SSRIs block MDMA’s binding to SERT/its 5HT release
MDMA for PTSD
Breakthrough therapy designation - treatment can be good for PTSD
MDMA as DA/5HT neurotoxin
report showed lower motor/reward, and lower DOPA/DAT/VMAT, but retracted report, no replication of parkinsonism/DA dysfunction
5HT neurotoxin yes
- MDMA reduces 5HT fibers, even 7 yrs later (some regrowth)
SERT KO mice
SERT KO mice exhibit beh’r abnormalities
- gut hypermobile and underaggression
- mysertiously anxiety and depression (wouldnt expect bc high 5HT)
Serotonin syndrome
toxicity associated with multiple agents in diff mechanisms (MAOi and cocaine)
Triad of abnormalities
- cog (headache/confusion), autonomic (hyperthermia,vasoconstriction), somatic (tremors/twitch)
can replicate it in mice too
Organization of serotinergic
dorsal and median raphe nuclei in midline brainstem
innervate nearly all forebrain
firing rate = beh’r state wake/asleep
14 receptor subtypes 7 families, most metabotropic
5HT 1A
Gi
forebrain hippocampus are postsynaptic receptors
raphe nuclei are somatodendritic autoreceptors
Reduce cAMP by inhibit adenyl cyclase
increase open K channels = hyperpol
5HT 2A
Gq
straitum/NA
activates PLC leads to increase Ca2+
post synaptic receptor
hallucinogens stimulate 5HT 2A receptors
5HT 2A and Schizo
5HT 2A antagonists are good antipsychotics (antgaonize both 5HT and D1/2, but stronger 5HT antagonism
treat schizo with fewer EPS side effects than drugs that only block D2
5HT and vasoconstriction drugs
treat migraines (abnormal dilation)
Triptans are 5HT 1B/D agonists that constrict vessels
reduce central 5HT release by stimulating terminal autorec.
5HT and aggression
aggro areas have a lot fo 5HT innervation
TPH2 KO = aggro
5HT 1B KO = aggro
Intermittent Explosive Disorder = mutated 5HT 2B gene = impulsive and novelty seeking, in humans and 5HT 2B KO mice
5HT and SIDS
Lmx1b KO = no 5HT neurons
no themroregulation and apnea (sids has serotniergic lesions)
treat with 2A/B agonists restore breathing
5HT and Anxiety
SSRIs for anxiety
reduced efficacy if trytophan depletion
or if 5HT 1A KO mice = higher anxiety
Treat with partial 5HT 1A agonist
5HT in development
deficient 5HT 1A receptor during crit period = anxiety later
deficient in adult doesnt matter
5HT and Pain
PAG descends and modulates raphe in dorsal horn
Inhibits ascending pain info/inhibits pain synapses on dorsal neurons
TPH2 KO effects
aggro
higher anxiety (marbles compulsion)
can be treated by injecting 5HTP (skip enzyme step)
no depression tho!
Sertonin hypothesis of depression
hard to treat bc heterogeneity (many people dont respond to SSRIs, diff ones)
Supporting evidence
- low 5-HIAA in suicide
- tryptophan depletion = relpase depression, but not if no family history
- increased density of postsyn. 5HT2 receptors (upregulation bc no 5HT)
BUT, many papers say this theory isn’t exhaustive and need other research
acute/chronic antidepressant effect
Acute - antidepr. increase 5HT by blocking reuptake or inhibiting MAO (SSRI/MAOi). SERT blocked = autorec. inhibit further release = no net effect (more/less 5HT)
Chronic - SERT still blocked = autorec. downregulated so less inhibition = more 5HT on postsyn.. induce hippocampal neurogensis and rmeodel limbic circuits
Serotonin and BDNF
Chronic antidepresants increases BDNF = repair/protect neurons
Stress causes lower BDNF = neuron atrophy
