Serotonin

5-HT (serotonin)

neurotransmitter produced in midline raphe nuclei of the brainstem, functioning in sleep-wake, mood, motor function, cognition, nausea, appetite, etc

dorsal raphe nucleus

main serotonergic nucleus of the brain

steps of monoaminergic neurotransmission

1) synthesis

2) packaging into vesicles

3) release from terminal into synapse

4) bind to receptors

5) reuptake by transporter

6) recycling into vesicles or breakdown by MAO

5-HT synthesis

-tryptophan → hydroxytryptophan by tryptophan hydroxylase (rate-limiting step)

-Hydroxytryptophan → 5-HT by AADC

5-HT metabolism

-5-HT → 5-hydroxyindole acetaldehyde by MAO

-5-hydroxyindole acetaldehyde → 5-HIAA by aldehyde dehydrogenase

SERT

sodium symporter that couples transport of Na+ down concentration gradient with transport of 5-HT

SERT binding sites

S1: high affinity substrate binding site

S2: low affinity allosteric binding site

SERT-targeting drugs

SSRIs, SNRIs, TCAs, MDMA, cocaine

SERT KO phenotype

decreased 5-HT clearance and increased 5-HT in synapse, causing receptor alterations that produce anxiety-like and depressive-like symptoms and social deficits

Gs-coupled 5-HT receptors

5-HT4, 5-HT6, and 5-HT7

Gi-coupled 5-HT receptors

5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT5

Gq-coupled 5-HT receptors

5-HT2A, 5-HT2B, and 5-HT2C

LGIC 5-HT receptor

5-HT3

brain 5-HT receptor distribution

cortex: 5-HT1A and 5-HT2A

hippocampus: 5-HT1A

striatum: 5-HT1B, 5-HT2A, 5-HT4, 5-HT6

basal ganglia/SN: 5-HT1B, 5-HT1D, 5-HT2C

raphe: 5-HT1A

somatodendritic 5-HT autoreceptors

presynaptic 5-HT1A receptors located on soma or dendrites that decrease signaling by opening GIRK K+ channels to cause K+ efflux

axonal 5-HT autoreceptors

presynaptic 5-HT1B receptors located on nerve terminals that decrease signaling by inhibiting Ca2+ influx

serotonin syndrome

potentially life-threatening condition caused by excess serotonergic signaling resulting in anxiety, agitation, tremors, restlessness, incoordination, tachycardia, and altered blood pressure

triptans

class of drugs used to treat migraines that activate 5-HT1B and 5-HT1D receptors in meningeal and cerebral arteries and in trigeminal nerve endings, which inhibits the release of proinflammatory neuropeptides such as CGRP to relieve pain

CGRP (calcitonin gene-related peptide)

proinflammatory neuropeptide that is released in response to activation of the sensory trigeminovascular system, causing sensitization of nerves in the face/head to produce migraines

5-HT2A receptor agonists

drugs that produce psychedelic effects via disruption of thalamic gating which produces sensory overload in the cortex; may be effective in treating depression and some SUDs; ex: LSD, psilocybin, mescaline, etc.

5-HT3 receptor antagonists

drugs that can be used to treat nausea and emesis by inhibiting activation of the chemoreceptor trigger zone mediated by 5-HT released from enterochromaffin cells, which stops signaling to the vomiting center

CTZ (chemoreceptor trigger zone)

area of the medulla activated by 5-HT that signals to the vomiting center in the lateral reticular formation to induce emesis

MAOIs (monoamine oxidase inhibitors)

drugs that were used as antidepressants that inhibit metabolism of monoamines with different levels of reversibility and selectivity for MAO-A or MAO-B

side effects include hypertension and serotonin syndrome

TCAs (tricyclic antidepressants)

drugs used as antidepressants that inhibit SERT and NET to enhance synaptic 5-HT and NE; ex: imipramine

off target side effects include sedation via histamine receptors and anticholinergic effects via mAChRs

NDRIs (norepinephrine-dopamine reuptake inhibitors)

drugs used for depression and smoking cessation that inhibit NET and DAT and act as a nAChR NAM; ex: bupropion

SSRIs (selective serotonin reuptake inhibitors)

drugs used to treat depression that inhibit SERT to enhance 5-HT in synapse, particularly in the DRN and other raphe nuclei, but takes weeks to produce their effect (suggesting that a biological adaption of the system contributes to therapeutic effects)

acute SSRI effects

inhibit 5-HT reuptake which activates DRN 5-HT1A autoreceptors to inhibit further 5-HT release

SSRI therapeutic mechanism of action

sustained inhibition of 5-HT reuptake downregulates and desensitizes 5-HT1A autoreceptors, limiting normal feedback inhibition and increasing 5-HT release from terminal to synapse -> associated with increased BDNF transcription, spinogenesis and hippocampal neurogenesis

limitations of SSRIs

-delayed onset of action

-side effects

enhancing therapeutic actions, targeting specific receptors

SSRI side effects can be reduced by _____ or by _____ that mediate off-target effects

SNRIs (serotonin-norepinephrine reuptake inhibitors)

drugs used to treat depression that inhibit SERT and NET, eventually resulting in downregulation and desensitization of somatodendritic 5-HT1A and α2 adrenergic autoreceptors, limiting normal negative feedback and increasing 5-HT and NE release from terminals into synapse; ex: venlafaxine

activity dependent, spatially and temporally specific

SSRIs/SNRIs/TCAs mechanism of action are _____ (requires release of endogenous NT to produce effect) and _____ (effect occurs when and where the endogenous NT is released); they are more similar to modulators than agonists

buspirone

drug used to treat anxiety disorders that acts as a partial 5-HT1A agonist, thus eventually producing downregulation and desensitization of 5-HT1A autoreceptors and activating postsynaptic receptors without requiring endogenous 5-HT release or SERT activity

SARIs (serotonin antagonist and reuptake inhibitors)

drugs used to treat depression that act as SSRIs and 5-HT2A/2C antagonists, which is believed to be synergistic and also reduces side effects such as insomnia, sexual dysfunction, and anxiety; ex: trazadone

SPARIs (serotonin partial agonist-reuptake inhibitors)

drugs used to treat depression that act as SSRIs and 5-HT1A partial agonists to enhance therapeutic adaptation and offset side effects; ex: vilazodone

Vortioxetine

multi-modal drug used to treat depression that acts as an SSRI, 5-HT1A agonist (enhances therapeutic effects), and 5-HT7 antagonist (inhibits GABAergic interneurons to disinhibit 5-HT release), among other effects

atypical (second generation) antipsychotics

drugs used to treat psychosis, such as in schizophrenia, that act primarily through D2 and 5-HT2A antagonism, producing less motor side effects (extrapyramidal side effects and tardive dyskinesia) but producing more metabolic effects that may involve histamine, serotonin, and adrenergic, and muscarinic receptors

extrapyramidal symptoms

side effects of antipsychotic medications, such as dystonia and parkinsonism, related to motor control that occur when D2 receptor occupancy is greater than 78%

D2 receptor

_____ occupancy between 60% and 75% produces antipsychotic effects, but occupancy higher than 78% produces extrapyramidal side effects

third generation antipsychotics

drugs used to treat psychosis, such as in schizophrenia, that act as D2 and 5-HT1A receptor partial agonists and 5-HT2A receptor antagonists therefore targeting hyperdopamine in mesolimbic system by antagonizing endogenous DA and targeting hypodopamine in the mesocortical system by direct agonism; ex: aripiprazole