Chapter 6: Serotonin Flashcards
Serotonin is synthesized from amino acid […]
Serotonin is synthesized from amino acid tryptophan
- is obtained form the diet (protein)
Tryptophan —>
L- 5- Hydroxytryptophan (5-HTP)
Enzyme: Tryptophan hydroxylase (TPH2)
Cofactors: Fe2+, O2, BH4
5-HTP—>
Serotonin
Aka 5- hydroxytryptamine (5-HT)
Enzyme: amino acid decarboxylase (AADC)
Cofactor: pyrodixal phosphate (vitamin B6)
Two forms of TPH genes
TPH2: expressed by serotonergic neurons
TPH1: expressed by certain types of non-neuronal cells
- Enterochromaffin cells in gut
- Melatonin- secreting cells in pineal gland
Tryptophan and large neutral amino acids (LNAA) compete for […]
Tryptophan and large neutral amino acids (LNAA) compete for transport across BBB
- High-protein, low- carbohydrate meal
- High-carbohydrate, low- protein meal
High-protein, low- carbohydrate meal
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
High-carbohydrate, low- protein meal
- 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
TPH is a critical control point in […]
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
Administration of many AA except Trp =
Decreased Trp
- Surge of AA in bloodstream stimulates protein synthesis by liver (reduces Trp levels below starting level)
- LNAA inhibit entry of Trp into brain
5-HT is loaded into vesicles by […]
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
Release or 5-HT is decreased by […]
Release or 5-HT is decreased by autoreceptor activation
- 5-HT 1B/1D terminal autoreceptors
- 5-HT 1A somatodendritic autoreceptors
5-HT 1B/1D terminal autoreceptors
- Inhibit 5-HT release (direct inhibition)
- Decreased Ca2+ influx; decreased cAMP
5-HT 1A somatodendritic autoreceptors
- Decrease neural activity (indirect inhibition)
- Open K+ channels, hyperpolarizes Vm
- Important in psychopharmacology of SSRI’s
[…] act to […] 5-HT release
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
MDMA […] across widespread areas of cortex
MDMA reduces 5-HT fiber density across widespread areas of cortex
- MDMA assisted psychotherapy for PTSD
5-HT inactivation: Reuptake
- 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)
5-HT inactivation: Enzymatic Degradation
- 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)
Para- chlorophenylalanine
Depletes 5-HT by inhibiting tryptophan hydroxylase
Reserpine (5-HT)
Depletes 5-HT by inhibiting vesicular uptake
Para- chloroamphetamine, fenfluramine, and MDMA
Release 5-HT from nerve terminals
- MDMA and para- chloroamphetamine also have neurotoxic effects
Fluoxetine, paroxetine
Inhibit 5-HT reuptake
5,7- dihydroxytryptamine
5-HT neurotoxin
Almost all 5-HT neurons in the CNS are found along the midline of the midbrain
Raphe nuclei
- Dorsal raphe (B7)
- DRN - Medial raphe (B8)
- MRN
All forebrain regions receive serotonergic innervation
Neocortex, striatum, nucleus accumbens, thalamus, hypothalamus, limbic system structures (hippocampus, amygdala, septal area)
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
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
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
5-HT1A Agonists and Antagonists
Agonist: 8-OH-DPAT
Partial Agonist: buspirone, ipsapirone
Antagonist: WAY 100, 635
5-HT2A Agonists and Antagonists
Agonists: hallucinogens DOI, LSD
Antagonists: ketanserin, ritanserin, atypical antipsychotics
Iontophoresis
Patch designed to where drug molecules are driven from patch into skin and into bloodstream
Buspirone, ipsapirone, 8-OH-DPAT
Stimulate 5-HT1A receptors (agonists)
WAY100635
Blocks 5-HT1A receptors (antagonists)
Sumatriptan and zolmitriptan
Stimulates 5-HT1B/1D receptors (agonists)
*causes vesicles constrictions and provide relief from migraine symptoms
DOI
Stimulate 5-HT2A receptors (agonists)
Ketanserin and ritanserin
Block 5-HT2A receptors (antagonists)
Locaserin
Stimulates 5-HT2C receptors (agonist)
Ondansetron, granisetron, palonosetron, and alosetron
Block 5-HT3 receptors (antagonists)
5-HT neurotransmission controls […]
5-HT neurotransmission controls behavioral inhibition
- aggression
- anxiety
Aggression is a […]
Aggression is a multivariate construct
- Definitions rely on”intent” of organism
- There are many different classification systems
Human aggression can be classified as
Premeditated:
- Instrumental - Planned in advance
Impulsive
- Reactive
- Provoked
- “Hair trigger”
- lots of psychopathology
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
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
Physiological deficits TPH2 knockout mice
- Poor thermoregulation leading to inadequate maintenance of core body temperature
- 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
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
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
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
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)
Neuropathic pain
Reduced with 5-HT1A/1B/2C agonists
Exacerbated by 5-HT2A/4 agonists
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
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
