Topic 9: Serotonergic Systems and Receptors

Question 1

Where are serotonergic receptors located in the brain?

Answer 1

serotonergic 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)

Question 2

What is the caudal raphe nuclei?

Answer 2

seratonergic projections to the cerebellum and descending projections to the spinal cord

mediate sensory, motor, and autonomic functions

Question 3

What is the rostral raphe nuclei?

Answer 3

comprises dorsal and medial raphe nuclei

ventral projections to basal ganglia, substantia nigra, VTA, limbic system and cortex

dorsal projections to midbrain (tegmentum and tectum)

cerebellar projections to cerebellar cortex and deep cerebellar nuclei

Question 4

What are seratonergic lesions?

Answer 4

seratonergic neurotoxins can be used to probe pathway functions

para-chloroamphetamine, MDMA both have neurotoxic effects selectively on seratonergic pathways

MDMA is neurotoxic at high doses or via microinjection

5,7-dihydroxytryptamine (5,7-DHT) is a BBB impermeable selective toxin that can induce robust serotonergic injury

seratonergic lesions produce deficits in food intake, reproductive behavior, pain sensitivity, anxiety, learning, memory, and motor function

Question 5

How does the dorsal raphe nuclei fire during behavior-dependent activity?

Answer 5

microelectrodes implanted into the dorsal raphe nuclei in free moving cats

while awake a steady firing pattern is observed

frequency increases with motor activity: especially repetitive activities like grooming, walking on a treadmill, chewing

sudden sensory stimulus causes an abrupt cessation of output from the dorsal raphe nuclei

Question 6

What are the motor effects of seratonergic neurons?

Answer 6

seratonergic firing patterns in the dorsal raphe suggests activity during repetitive movements: facilitation of motor control, proposed to suppress sensory processing and facilitate repetitive tasks

seratonergic firing patterns are stopped during sensory processing

presentation of novel stimuli disrupts tonic firing of the DRN

Question 7

What are the broad behavioral effects of seratonergic neurons?

Answer 7

diverse effects on behavior make it difficult to ascribe an overall function to seratonergic systems

5-HT is colloquially thought to contribute to happiness: antidepressants target 5-HT reuptake and improve mood

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

Question 8

What are the different types of 5-HT receptors?

Answer 8

5-HT1: GPCR-Gi (1A, B, D)

5-HT2: GPCR-Gq (2A, B, C)

5-HT3: ligand gated Na+ and K+ channel

Question 9

What are 5-HT 1A receptors?

Answer 9

agonists: Buspirone (partial agonist), Cannabidiol (partial agonist)

functions as somatodendritic autoreceptors

agonists at 5-HT 1A cause hyperphagia: agonists decrease 5-HT release, prevents attenuation of appetite

concentrated in hippocampus, amygdala, and septim

inhibitory neurotransmitter: signals through Gi to inhibit adenylate cyclase, signals through G beta-gamma to specialized inhibitory K+-channels (GIRK)

Question 10

What is WAY-100,635?

Answer 10

numbered compound developed by Wyeth-Ayerst

experimental selective 5-HT1A receptor agonist

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

Question 11

How is the 5-HT1A receptor connected to spirituality?

Answer 11

2003 study from a Swedish group correlated 5-HT1A binding capacity with components of the Temperament and Character Inventory self-report questionnaire in 15 male volunteers (age 20-45)

found a significant correlation with spiritual acceptance (component of self-transcendence metric)

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

Question 12

What are 5-HT 1B and 1D?

Answer 12

inhibitory through cAMP and GIRK

1B not expressed in humans, instead there are two 1D variants (1Dalpha and 1Dbeta)

found on intracranial blood vessels

agonists include anti-migraine medication

sumatriptan (Imitrex) agonized 1B and 1D receptors

Question 13

What is migraine pathogenesis?

Answer 13

cortical spreading depression: expanding pulse of activity followed by hypoactivity, often originates in occipital cortex (causing perception auras)

accompanied by constrictions in blood flow

reactive vasodilation causes pain

no pain fibers in the brain parenchyma but dura mater and meningeal blood vessels are well innervated by pain fibers

sensory fibers release vasodilating peptides

peptides promote a sterile inflammatory response

inflammation cause sensitization of sensory fibers

Question 14

How does 5-HT modulate neuropeptide release in migraine treatment?

Answer 14

5HT1D receptors are inhibitory

agonists of 5-HT1D inhibit release of vasodilating peptides

promotes vasoconstriction rather than vasodilation

leads to decreased excitation of trigeminal nerve and decreased effect on nausea centers

Question 15

What is the 5-HT2 receptor family?

Answer 15

Gq alpha to PLC resulting in increased Ca2+ and PKC activation

mostly function as postsynaptic receptors

many agonists affect all three receptors: soem antagonists show specificity

high densities in nucleus accumbens, striatum, cortex (especially frontal)

Question 16

What is the 5-HT2A receptor?

Answer 16

“classic” 5-HT2 receptor, best characterized

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

antagonists: ketanserin: antihypertensive and useful as a PET radioligand for 5-HT2A receptors, atypical antipsychotics clozapine and risperadone

Question 17

How do psychedelics affect 5-HT2A receptor?

Answer 17

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

5HT2A agonists are consider potent hallucinogens

Question 18

How do 5-HT2B and 2C receptor affect appetite?

Answer 18

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

Lorcaserin (Belviq) is a specific agonist for 5-HT2C and anorectic drug in limited use to treat obesity: agonists of 5-HT2C are thought to promote satiety through effects on the hypothalamus

5-HT2C is also expressed in the choroid plexus and regulates CSF composition and volume in response to 5-HT in the CSF

Question 19

Why are 5-HT2C receptors in the amygdala proposed to be the cause of acute side effects of SSRIs?

Answer 19

5-HT2C in the amygdala is anxiogenic and proposed to be the cause of acute side effects of SSRIs

early period of use of SSRIs often accompanied by anxiety and depression

5-HT2C expression decreases slowly with SSRI use - compensatory downregulation

5-HT2C expression correlates with the onset of clinical effectiveness

Question 20

What are 5-HT3 receptors?

Answer 20

5-HT3 is the only 5-HT ligand-gated ion channel

structured and functional relationship to nAChR

5-HT3 receptors are expressed in the chemoreceptor trigger zone and in the gut

agonists are emetic (nausea inducing)

antagonists are anti-emetic: ondasetron is a prescription anti-emetic used to treat chemotherapy-related nausea

Question 21

How does the dorsal raphe nuclei impact anxiety and mood?

Answer 21

subdivisions of the DRN have been implicated in anxiety, panic and mood disorders

anxiety: DRN, dorsal part (DRD) and DRN, caudal part (DRC)

panic: DRN, ventrolateral (DRVL) and ventrolateral periaqueductal gray (VLPAG)

Question 22

How does the DRN impact anxiety and stress?

Answer 22

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

Question 23

How are 5-HT 1A receptors involved in anxiety?

Answer 23

antidepressants targeting serotonergic neurotransmission are effective anxiolytics

MAOI, TCA antidepressants are highly effective but with severe 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: cannabidiol, buspirone

polymorphisms of the 5-HT1A receptor gene are implicated in risk of depression and anxiety: predicts poor response to SSRI therapy

Question 24

How are 5-HT receptors involved in anxiety and mood?

Answer 24

in the presence of SSRI antidepressants 5-HT is broadly increased

early phase of AD treatment has mixed effects

may increase anxiety and mood symptoms, increase suicidal thoughts

in the basolateral amygdala 5-HT activates 5-HT2C receptors

5-HT2C activation is anxiogenic

5-HT2C receptors are downregulated slowly with SSRI use

proposed to play a role in the early anxiety and depression in initial SSRI use