Serotonergic Systems and Receptors Flashcards by Cambell Meier

Seratonergic neurons project from a number of locations in the brainstem and innervate the entire forebrain. Most interesting are located in the

raphe nuclei (~165,000 seratonergic cells

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Caudal raphe nuclei Seratonergic projections to

the cerebellum and descending projections to the spinal cord.

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Seratonergic projections to the cerebellum and descending projections to the spinal cord. mediate

sensory, motor, and autonomic functions of 5-HT

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Rostral raphe nuclei Ventral projections to

basal ganglia, substantia nigra, VTA, limbic system and cortex.

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Rostral raphe nuclei Dorsal projections to

midbrain (tegmentum and tectum).

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Rostral raphe nuclei Cerebellar projections to

cerebellar cortex and deep cerebellar nuclei

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para-chloroamphetamine, MDMA both have

neurotoxic effects selectively on seratonergic pathways

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MDMA is

neurotoxic at high doses or via microinjection

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5,7-dihydroxytryptamine (5,7-DHT) is a

BBB impermeable selective toxin that can induce robust serotonergic injury

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Seratonergic lesions produce

deficits in food intake, reproductive behaviour, pain sensitivity, anxiety, learning, memory, and motor function

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Microelectrodes implanted into the dorsal raphe nuclei in free moving cats

While awake a steady firing pattern is observed Sudden sensory stimulus causes an abrupt cessation of output from the dorsal raphe nuclei

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Seratonergic firing patterns in the dorsal raphe suggests

activity during repetitive movement, Proposed to suppress sensory processing and facilitate repetitive tasks

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5-HT is colloquially thought to contribute to

happiness, Antidepressants target 5-HT reuptake and improve mood

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5-HT binding capacity has been suggested to correlate with tendency towards

spirituality

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5-HT1 – GPCR – Gi

(↓ cAMP, GIRK)

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5-HT2 – GPCR – Gq/11

(PLC, ↑ Ca2+)

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5-HT3

Ligand gated Na+ and K+ channel

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5-HT4 – GPCR – Gs

(↑ cAMP)

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5-HT5 – GPCR – Gi

(↓ cAMP , GIRK)

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5-HT6 – GPCR – Gs

(↑ cAMP)

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5-HT7 – GPCR – Gs

(↑ cAMP)

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5-HT1A Agonists

Buspirone, Cannabidiol - partial agonist)

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Agonists at 5-HT1A cause

hyperphagia

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Agonists decrease 5-HT release
Prevents

attenuation of appetite

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5-HT1A Concentrated in

hippocampus, amygdala, and septum

Agonists at 5-Inhibitory neurotransmitter

Signals through Giα to inhibit adenylate cyclase Signals through Gβγ to specialized inhibitory K+-channels (GIRK – G-protein coupled inward rectifying K+-channel)

WAY-100,635

Experimental selective 5HT1A receptor agonist

WAY-100,635 used as

as a PET ligand to identify 5HT1A receptors in the human brain

Spirituality

Proposed 5-HT system was the source of individual variation in spiritual zeal

5-HT1B and 1D

Inhibitory through cAMP and GIRK

1B not expressed in

humans, instead there are two 1D variants (1Dα and 1Dβ)

5-HT1B and 1D are found

on intracranial blood vessels

5-HT1B and 1D Agonists include

anti-migraine medicationq

anti-migraine medication

Sumatripan (Imitrex) agonized 1B and 1D receptors

Migraine pathogenesis

Cortical spreading depression Expanding pulse of activity followed by hypoactivity

migraines often originate

originates in occipital cortex (causing perception of auras)

Migraine pathogenesis - Cortical spreading depression accompanied by

constrictions in blood flow

Reactive vasodilation causes

pain

Reactive vasodilation causes pain

Sensory fibers release vasodilating peptides Peptides promote a sterile inflammatory response Inflammation causes sensitization of sensory fibers of the dura mater and meningeal blood vessels which are well innervated by pain fibers

5-HT modulates

neuropeptide release

5HT1D receptors are

inhibitory

Agonists of 5HT1D inhibit release of

vasodilating peptides

Agonists of 5HT1D inhibit release of vasodilating peptides

Promotes vasoconstriction rather than vasodilation

Agonists of 5HT1D inhibit release of vasodilating peptides Promotes vasoconstriction rather than vasodilation Leads to

decreased excitation of trigeminal nerve and decreased effect on nausea centres

5-HT2 receptor family

Gqα signal to PLC resulting in increased Ca2+ and PKC activation

5-HT2 receptor family Mostly function as

postsynaptic receptors

5-HT2 receptor family High densities in

nucleus accumbens, striatum, cortex (esp. frontal)

5HT2A Experimental agonists DOI

DOI administration to rodents leads to a characteristic head twitch (brief and periodic)

Antagonists of 5HT2A

ketanserin, clozapine (Cozaril) and risperadone (Risperdal)

ketanserin

antihypertensive and useful as a PET radioligand for 5HT2A receptors

Atypical antipsychotics

clozapine (Cozaril) and risperadone (Risperdal)

Psychedelics affecting 5HT2 receptors

LSD, mescaline, psilocybin are all agonists at 5HT2 receptors (particularly 5HT2A)

5HT2A agonists are considered

potent hallucinogens

5-HT2B and 2C receptors affect appetite

fenfluramine (norfenfluramine) is an agonist for 5-HT2B and 5HT2C (and 2A at sufficient dose)

Lorcaserin (Belviq)

is a specific agonist for 5-HT2C and anorectic drug in limited use to treat obesity

5-HT2C is also expressed in the

choroid plexus and regulates CSF composition and volume in response to 5-HT in the CSF

5-HT2C in the amygdala is

anxiogenic and proposed to be the cause of acute side effects of SSRIs

5-HT3 receptors

only 5-HT ligand-gated ion channel

5HT3 receptors are expressed in the

chemoreceptor trigger zone and in the gut

Agonists of 5-HT3 receptors are

vomit inducing

Agonists of 5-HT3

2-methyl-5-HT

Antagonists of 5-HT3 receptors are

anti-emetic

Ondasetron (Zofran)

is a prescription anti-emetic used to treat chemotherapy-related nausea

Subdivisions of the DRN have been implicated in

anxiety, panic, and mood disorders

anxiety in the Dorsal Raphe nucleus

DRN, dorsal part (DRD) DRN, caudal part (DRC)

Panic in the Dorsal Raphe nucleus

DRN, ventrolateral (DRVL) ventrolateral periaqueductal gray (VLPAG)

Serotonergic neurons in the DRN are active in response to

anxiogenic stimuli

Serotonergic neurons in the DRN are active in response to anxiogenic stimuli Anxiogenic agents

(caffeine) increase activity

Social defeat paradigms increase

DRN activity

DRD activated in

fear-potentiated startle

DRC activated by

unpredictable noise stress

Antidepressants targeting serotonergic neurotransmission are effective

anxiolytics

Antidepressants targeting serotonergic neurotransmission are effective anxiolytics

MAOI, TCA antidepressants are highly effective but with severe side effects

Antidepressants targeting serotonergic neurotransmission are effective anxiolytics ones with fewer side effects

SSRI and SNRI are effective and well tolerated

5-HT depletion (via tryptophan depletion)

increases depressive symptoms

5-HT1A receptors function primarily as

autoreceptors

Autoreceptors

drive negative feedback to inhibit 5HT release

5-HT1A agonists are effective

anxiolytics

5-HT1A agonists are effective anxiolytics

Cannabidiol (5-HT1A partial agonist) Buspirone (5-HT1A partial agonist)

Polymorphisms of the 5-HT1A receptor gene

are implicated in risk of depression and anxiety Predicts poor response to SSRI therapy

In the presence of SSRI antidepressants 5-HT is

broadly increased

In the basolateral amygdala

5-HT activates 5-HT2C receptors

5-HT2C activation is

anxiogenic

5-HT2C receptors are

downregulated slowly with SSRI use

In the basolateral amygdala 5-HT activates 5-HT2C receptors Proposed to play a role in the

early anxiety and depression in initial SSRI use