Drugs Brain and Mind - Chapter 6: Serotonin

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:

1. cognitive effects

2. autonomic effects

3. 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-HT_1A (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-HT_2A 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-HT_2A receptors

5-HT_2A receptor antagonists

clozapine and risperidone

antagonize 5-HT_2A 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