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Neuropharmacology > Chapter 6: Serotonin > Flashcards

Chapter 6: Serotonin Flashcards

1
Q

Serotonin is synthesized from amino acid […]

A

Serotonin is synthesized from amino acid tryptophan

  • is obtained form the diet (protein)
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2
Q

Tryptophan —>

A

L- 5- Hydroxytryptophan (5-HTP)

Enzyme: Tryptophan hydroxylase (TPH2)
Cofactors: Fe2+, O2, BH4

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3
Q

5-HTP—>

A

Serotonin

Aka 5- hydroxytryptamine (5-HT)

Enzyme: amino acid decarboxylase (AADC)
Cofactor: pyrodixal phosphate (vitamin B6)

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4
Q

Two forms of TPH genes

A

TPH2: expressed by serotonergic neurons

TPH1: expressed by certain types of non-neuronal cells

      - Enterochromaffin cells in gut
      - Melatonin- secreting cells in pineal gland
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5
Q

Tryptophan and large neutral amino acids (LNAA) compete for […]

A

Tryptophan and large neutral amino acids (LNAA) compete for transport across BBB

  • High-protein, low- carbohydrate meal
  • High-carbohydrate, low- protein meal
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6
Q

High-protein, low- carbohydrate meal

A

Doesn’t increase brain TRP levels or 5-HT synthesis

  • Trp competes with group of other AA (LNAA) for transport across BBB
    - Ratio between Trp in blood and amount of competitors is most important
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7
Q

High-carbohydrate, low- protein meal

A
  • increase ratio of Trp: LNAA
    - more Trp can cross BBB
  • enhances entry of Trp and stimulates 5-HT synthesis
  • carbs trigger insulin release
    - stimulates reuptake of many AA, but not Trp
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8
Q

TPH is a critical control point in […]

A

TPH is a critical control point in 5-HT synthesis

  • TPH is rate-limiting enzyme
  • Trp deletion
    - Trp-free, high LNA solution
    - induces symptoms in people with major depression
  • p- chlorophenylalanine (PCPA)
    - blocks 5-HT synthesis by irreversible inhibiting TPH
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9
Q

Administration of many AA except Trp =

A

Decreased Trp

  1. Surge of AA in bloodstream stimulates protein synthesis by liver (reduces Trp levels below starting level)
  2. LNAA inhibit entry of Trp into brain
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10
Q

5-HT is loaded into vesicles by […]

A

5-HT is loaded into vesicles by VMAT2

  • different from SERT located on nerve terminal
  • blocked by reserpine
  • energy provided by a proton gradient
    - ATP-driven H+ pump acidifies vesicles lumen
  • 5-HT storage in vesicles plays critical role in protecting transmitter from enzymatic breakdown in nerve terminal
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11
Q

Release or 5-HT is decreased by […]

A

Release or 5-HT is decreased by autoreceptor activation

  • 5-HT 1B/1D terminal autoreceptors
  • 5-HT 1A somatodendritic autoreceptors
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12
Q

5-HT 1B/1D terminal autoreceptors

A
  • Inhibit 5-HT release (direct inhibition)

- Decreased Ca2+ influx; decreased cAMP

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13
Q

5-HT 1A somatodendritic autoreceptors

A
  • Decrease neural activity (indirect inhibition)
  • Open K+ channels, hyperpolarizes Vm
  • Important in psychopharmacology of SSRI’s
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14
Q

[…] act to […] 5-HT release

A

Serotonin releasing agents (SRA’s) act to increase 5-HT release

Based on family of drugs based on structure of amphetamine

Para-chloroamphetamine (PCA, 4-CA)
      - Neurotoxic, similar to 6-OHDA
      - Mainly experimental 
Fenfluramine
      - in combo with phentermine (fen-phen)
      - appetite suppression
MDMA, ecstasy, X, Molly
      - recreational drug, dangerous neurotoxin, or medication
  • Can exert toxic effects on serotonergic system
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15
Q

MDMA […] across widespread areas of cortex

A

MDMA reduces 5-HT fiber density across widespread areas of cortex

  • MDMA assisted psychotherapy for PTSD
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16
Q

5-HT inactivation: Reuptake

A
  • 5-HT transporter (SERT)
    - Na+ -dependent ATPase
  • Target of SSRI antidepressants (ex. Fluoxetine/ Prozac), cocaine, and MDMA

*Cocaine and MDMA interact with SERT, but aren’t selective (also affects DA and NE transporters)

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17
Q

5-HT inactivation: Enzymatic Degradation

A
  • Monoamine oxidase A (MAO-A)
    - 5-HIAA is the major metabolite
    - used as a proxy for 5-HT activity
  • 5- hydroxyindoleacetic acid- levels in brain are used as measure of activity of serotonergic neurons
  • not affected by COMT (5-HT isn’t a catecholamine)
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18
Q

Para- chlorophenylalanine

A

Depletes 5-HT by inhibiting tryptophan hydroxylase

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19
Q

Reserpine (5-HT)

A

Depletes 5-HT by inhibiting vesicular uptake

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20
Q

Para- chloroamphetamine, fenfluramine, and MDMA

A

Release 5-HT from nerve terminals

  • MDMA and para- chloroamphetamine also have neurotoxic effects
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21
Q

Fluoxetine, paroxetine

A

Inhibit 5-HT reuptake

22
Q

5,7- dihydroxytryptamine

A

5-HT neurotoxin

23
Q

Almost all 5-HT neurons in the CNS are found along the midline of the midbrain

A

Raphe nuclei

  • Dorsal raphe (B7)
    - DRN
  • Medial raphe (B8)
    - MRN
24
Q

All forebrain regions receive serotonergic innervation

A

Neocortex, striatum, nucleus accumbens, thalamus, hypothalamus, limbic system structures (hippocampus, amygdala, septal area)

25
There are at least 15 different types of 5-HT receptors
5-HT1 - A, B, D, E, F 5-HT2- A,B,C Not expressed in humans- 5-HT3, 5-HT4, 5-HT5A, 5-HT5B In humans- 5-HT6, 5-HT7
26
5-HT1A vs 5-HT2A
5-HT1A - Inhibition adenylyl cyclase activity - Decreases cAMP - Increase gk (increased opening of K+ channels) - membrane hyperpolarization * function as somatodendritic autoreceptors in dorsal and median raphe nuclei * concentrated in hippocampus, septal area, amygdala, and dorsal raphe nuclei * decreased firing 5-HT2A - coupled to PLC - increased [Ca2+] - activates PKC * cerebral cortex, striatum, and nucleus accumbens
27
All 5-HT receptors are metabotropic except […]
5-HT3 * excitatory ionotropic receptor (ligand-gated) - peripheral terminals of vagus nerve (transmits sensory info from viscera (including GI) to brain) - release of 5-HT in gut induces vomiting
28
5-HT1A Agonists and Antagonists
Agonist: 8-OH-DPAT Partial Agonist: buspirone, ipsapirone Antagonist: WAY 100, 635
29
5-HT2A Agonists and Antagonists
Agonists: hallucinogens DOI, LSD Antagonists: ketanserin, ritanserin, atypical antipsychotics
30
Iontophoresis
Patch designed to where drug molecules are driven from patch into skin and into bloodstream
31
Buspirone, ipsapirone, 8-OH-DPAT
Stimulate 5-HT1A receptors (agonists)
32
WAY100635
Blocks 5-HT1A receptors (antagonists)
33
Sumatriptan and zolmitriptan
Stimulates 5-HT1B/1D receptors (agonists) *causes vesicles constrictions and provide relief from migraine symptoms
34
DOI
Stimulate 5-HT2A receptors (agonists)
35
Ketanserin and ritanserin
Block 5-HT2A receptors (antagonists)
36
Locaserin
Stimulates 5-HT2C receptors (agonist)
37
Ondansetron, granisetron, palonosetron, and alosetron
Block 5-HT3 receptors (antagonists)
38
5-HT neurotransmission controls […]
5-HT neurotransmission controls behavioral inhibition - aggression - anxiety
39
Aggression is a […]
Aggression is a multivariate construct - Definitions rely on”intent” of organism - There are many different classification systems
40
Human aggression can be classified as
Premeditated: - Instrumental - Planned in advance Impulsive - Reactive - Provoked - “Hair trigger” - lots of psychopathology
41
Animal aggression is inferred
Territorial- aggression that occurs in the context of defending one’s territory, commonly modeled in the laboratory by using the resident- intruder test in which a strange male is introduced into the home cage of a resident male Resident- intruder test- measured latency of attacks and number of attacks
42
TPH2 knockout mice
- are virtually devoid of 5-HT in the brain - are more aggressive - are more impulsive and compulsive - 5-HT helps regulated development of its fiber system - 5-HT can be restored by injecting 5-HTP, but only temporarily because of MAO-A
43
Physiological deficits TPH2 knockout mice
1. Poor thermoregulation leading to inadequate maintenance of core body temperature 2. Abnormal respiration - In early postnatal period: - Apnea: cessation of breathing - Related to lack of 5-HT2A receptor activation - Apnea- induced hypercapnia (elevated blood CO2 levels) is proposed cause of death in SIDS
44
Serotonin deficiency hypothesis
- Low CNS 5-HT is associated with greater aggressive behavior, impaired PFC function - The metabolite 5-HIAA is inversely related to aggression in people with personalities disorders (ASPD, BPD) - Alzheimer’s disease, alcohol abuse suicide - Non-human primates - Reductions in 5-HT increase aggression - 5,7-DHT lesions, OCOA, TPH2 KO mice - Increases in 5-HT decrease aggression - SSRI, SERT-KO - Both 5-HT1A and 5-HT1B KO mice are hyperaggressive
45
5-HT is also implicated in anxiety
5-HT1A partial agonists are anxiolytic - buspirone (BuSpar) and vilazodone (Viibryd) 5-HT1A KO mice are more anxious 5-HT2A/2C receptors are also involved - Agonist mCPP increases anxiety - KO reduces anxiety
46
5-HT in aggression, anxiety, and feeding
Aggression- manipulations that lower 5-HT signaling generally impair behavioral control Anxiety- Without 1A, 2A or 2C receptors, behavioral control is impaired Feeding- 5-HT1B and 5-HT2C agonists (lorcaserin/ Belviq) are anoretics (appetite- reducing), induce hypophagia
47
5-HT in pain
- 5-HT has been implicated in processing of pain signals at spinal cord - 5-HT neurons of raphe magnus influence transmission of incoming pain info to ascending systems - Nerve tissue damage can lead to neuropathic pain (associated with hyperalgesia and allodynia)
48
Neuropathic pain
Reduced with 5-HT1A/1B/2C agonists | Exacerbated by 5-HT2A/4 agonists
49
Learning and Memory
- 5-HT1A receptor activation improved performance in spatial learning and memory - Activation of hippocampal 5-HT1A receptors has been shown to impair memory encoding - 5-HT4 receptors expressed most highly in basal ganglia and hippocampus - Partial agonist retards development of Alzheimer’s- related pathology - 5-HT6 found in striatum, nucleus accumbens, and olfactory tubercles - Cognition is improved when treated with receptor antagonists
50
5-HT in gut
Enteric nervous system- large system of ganglia situated in muscle walls of intestine - Stimulated by entry of food to GI tract Gut 5-HT is synthesized by enterochromaffin cells using TPH1 - Taken up by SERT in membrane of enterocytes

Neuropharmacology (15 decks)

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