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serotonin (5-hydroxytryptamine, 5-HT)
monoamine, indoleamine
cannot cross BBB, neurons must synthesize it
dietary tryptophan and 5-HT synthesis
tryptophan competes with large neutral a.a. for transport across BBB
ratio between amount of tryptophan and a.a determines whether 5-HT synthesis is stimulated in the brain
serotonin autoreceptors
terminal: 1B and 1D
somatodendritic: 1A in raphe nuclei
para-chloroamphetamine (PCA)
indirect 5-HT agonist
depletion of brain serotonin and neurotoxicity
not in clinical use
fenfluramine
indirect 5-HT agonist
reverses SERT and disrupts vesicular storage
4-methylenedioxymethamphetamine (MDMA)
indirect 5-HT agonist (ecstasy, molly)
high affinity ligand for SERT, 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 stimulate 5-HT release
serotonin syndrome in humans
severe toxicity associated with combinations of agents that act through different mechanisms
clinical triad of abnormalities:
cognitive effects
autonomic effects
somatic effects
dorsal and median raphe nuclei
almost all 5-HT cell bodies in the CNS found along midline of the brainstem
nearly all forebrain regions receive 5-HT innervation
5-HT1A (Gi)
in the forebrain, mostly hippocampus: postsynaptic receptors
in the raphe nuclei (brainstem): somatodendritic autoreceptors
reduce cAMP by inhibiting adenylyl cyclase
increase opening of K+ channels » hyperpolarization
5-HT2A receptors (Gq)
highly expressed in cortex, striatum, and NA
activate the phosphinositide second-messenger system (PLC)
lysergic acid diethylamide (LSD) and psilocybin
hallucinogenic effects
stimulation of 5-HT2A receptors
5-HT2A receptor antagonists
clozapine and risperidone
antagonize 5-HT2A receptors and D1 and D2 receptors
more pronounced 5HT antagonisms than DA
fewer movement-related side effects than D2 receptors
5-HT and aggression
brain areas involved in aggression receive substantial serotonergic innervation and express several 5-HT receptor subtypes
5-HT and Anxiety
SSRIs are most common treatment for anxiety disorders
efficacy can be prevented by tryptophan depletion
5-HT and Pain
descending modulatory system originating in the PAG
PAG synapses on raphe magnus » dorsal horn
inhibits ascending pain info going to cortex by synapsing onto dorsal horn neurons
serotonin hypothesis of depression
low 5-HIAA
