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Psych 478 > Serotonergic Systems and Receptors > Flashcards

Serotonergic Systems and Receptors Flashcards

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1
Q

Describe serotonergic neurons

A

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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2
Q

Describe caudal RAPHE NUCLEI

A

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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3
Q

Describe rostral raphe nuclei

A

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

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4
Q

Describe lesions

A
  • 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 behaviour, pain sensitivity, anxiety, learning, memory, and motor function
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5
Q

Describe behaviour dependent activity

A
  • Microelectrodesimplantedintothedorsal raphe nuclei in free moving cats
  • While awake a steady firing pattern is observed
  • Frequencyincreaseswithmotoractivity
  • Esp. repetitive activities like grooming, walking
    on a treadmill, chewing
  • Suddensensorystimuluscausesanabrupt cessation of output from the dorsal raphe nuclei
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6
Q

Describe motor effects of these neurons

A
  • Seratonergic firing patterns in the dorsal raphe suggests activity
    during repetitive movement
  • 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
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7
Q

Describe broad behavioural effects

A
  • Diverse effects on behaviour 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
    ….
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8
Q

Describe how serotonin receptors are a large family

A
  • 14 5-HT receptors identified to date in 7 families
  • 5-HT1 –GPCR–Gi (↓cAMP,GIRK)(1A,B,D,E,F)
    • 5-HT2 – GPCR – Gq/11 (PLC, ↑ Ca2+) (2A, B, C)
  • 5-HT3 – Ligand gated Na+ and K+ channel
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9
Q

Describe 5-HT1A

A
  • Agonists:
    Agonists at 5-HT1A cause hyperphagia
  • Agonists decrease 5-HT release
  • Prevents attenuation of appetite
  • Concentrated in hippocampus, amygdala, and septum

Inhibitory neurotransmitter

    1. Signals through Giα to inhibit adenylate cyclase
  2. Signals through Gβγ to specialized inhibitory K+- channels (GIRK – G-protein coupled inward rectifying K+-channel)
  • Agonists:
  • Buspirone (Buspar, anxiolytic,
    antidepressant – partial agonist)
  • Cannabidiol (CBD) – partial agonist
  • Functions as somatodendritic autoreceptors
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10
Q

Describe WAY-100,635

A
  • Numbered compound developed by Wyeth- Ayerst
  • Experimental selective 5HT1A receptor agonist
  • Used as a PET ligand to identify 5HT1A receptors in the human brain
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11
Q

Describe serotonin and spirituality

A
  • 2003 study from a Swedish group correlated 5HT1A 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
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12
Q

Describe 5-HT1B AND 1D

A
  • Inhibitory through cAMP and GIRK
  • 1B not expressed in humans, instead there are two 1D variants (1Dα and 1Dβ)
  • Found on intracranial blood vessels
  • Agonists include anti-migraine medication
  • Sumatripan (Imitrex) agonized 1B and 1D receptors
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13
Q

Describe MIGRAINE PATHOGENESIS

A
  • Cortical spreading depression
  • Expanding pulse of activity followed by hypoactivity
  • Often originates in occipital cortex (causing perception of 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 causes sensitization of sensory fibers
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14
Q

Describe how 5-HT MODULATES NEUROPEPTIDE RELE ASE

A

5HT1D receptors are inhibitory
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.

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15
Q

Describe 5-HT2 RECEPTOR FAMILY

A
  • Gqα signal to PLC resulting in increased Ca2+ and PKC activation
  • Mostly function as postsynaptic receptors
  • Many agonists affect all three receptors
  • Some antagonists show specificity
  • High densities in nucleus accumbens, striatum, cortex (esp. frontal)
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16
Q

Describe 5HT2A

A
  • ‘Classic’ 5-HT2 receptor – best characterized
  • Experimental agonists
  • 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)
  • DOI administration to rodents leads to a characteristic head twitch (brief and periodic)
  • Antagonists
  • ketanserin – antihypertensive and useful as a PET radioligand for 5HT2A receptors
  • Atypicalantipsychotics–clozapine(Cozaril)andrisperadone(Risperdal)
17
Q

Describe PSYCHEDELICS AFFECTING 5HT2 RECEPTORS

A
  • LSD, mescaline, psilocybin are all agonists at 5HT2 receptors (particularly 5HT2A)
  • 5HT2A agonists are consider potent hallucinogens
18
Q

Describe how 5-HT2B AND 2C RECEPTORS AFFECT APPETITE

A
  • An active metabolite of 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
  • Agonists of 5-HT2C are thought to promote satiety through effects on the hypothalamus
  • Reclassified as Schedule IV drug in USA due to effects on 5HT2A at high doses (hallucinations!)
  • 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
  • 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
19
Q

Describe 5-HT3 RECEPTORS

A
  • 5-HT3 is the only 5-HT ligand- gated ion channel
  • Structural and functional relationship to nAChR
  • 5HT3 receptors are expressed in the chemoreceptor trigger zone and in the gut
  • Agonists are emetic:
    • 2-methyl-5-HT
  • Antagonists are anti-emetic:
  • Ondasetron (Zofran) is a prescription anti-emetic used to treat chemotherapy-related nausea
20
Q

Describe DORSAL RAPHE NUCLEI IN ANXIETY AND MOOD

A

Subdivisions of the DRN have been implicated in anxiety, panic, and mood disorders
Anxiety
* DRN, dorsal part (DRD)
* DRN, caudal part (DRC) Panic
* DRN, ventrolateral (DRVL)
* ventrolateral periaqueductal gray (VLPAG)

21
Q

Describe DRN in anxiety and stress

A
  • 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
22
Q

Describe SEROTONIN 1A RECEPTORS IN ANXIETY

A
  • Antidepressants targeting serotonergic neurotransmission are effective anxiolytics
  • MAOI, TCA antidepressants are highly effective but with severe side effects
  • SSRIandSNRIareeffectiveandwell 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 (5-HT1A partial agonist)
  • Buspirone (5-HT1A partial agonist)
  • Polymorphisms of the 5-HT1A receptor gene (HTR1A – C1019G) are implicated in risk of depression and anxiety
  • Predicts poor response to SSRI therapy
23
Q

Describe 5-HT RECEPTORS IN ANXIETY AND MOOD

A
  • 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
24
Q

Describe serotonin in depression (conventional view)

A

Conventional view:
Drugs that increase 5HT are effective at improving mood in depression and relieving anxiety
◦ MAOI, TCA, SSRI, SNRI antidepressants have demonstrable efficacy
Tryptophan depletion induces rapid, transient sadness or depressed mood
◦ 5HT synthesis is depleted leading to deficient serotonergic function
Insufficient 5HT is causally involved in the pathogenesis of depression
◦ Fits the colloquial viewpoint that elevated 5HT is associated with positive mood

25
Q

Describe serotonin in depression (alternative view)

A

Normal firing of serotonergic neurons of the DRN is associated with anxiety and panic behaviours
◦ 5HT2C receptors in the amygdala are highly anxiogenic ◦ 5HT releasers (fenfluramine) dysregulate mood
5HT1A (autoreceptor) agonists are effective anxiolytics/antidepressants
◦ Buspirone, cannabidiol agonize 5HT1A and cause feedback inhibition of DRN activity
5HT1A mutations are predictive of poor response to SSRI therapy
◦ Implicates 5HT1A function in the efficacy of SSRI tx
Antidepressants may act by 5HT1A-mediated inhibition of 5HT signalling (particularly 5HT2C) to improve mood/anxiety
◦ Opposes the conventional view that 5HT is mood elevating

Psych 478 (28 decks)

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