Lecture 5 - Serotonin

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Lecture 5 - Serotonin
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The serotonergic neuron
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Serotonin

• serotonin 5-HT (5-hydroxytryptamine)
• an indoleamine has an indole ring structure
• this structure is also found in hallucinogenic
  or psychedelic drugs

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Indole ring structure
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Serotonergic systems
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Serotonergic systems

• the major serotonergic systems originate in the
  raphe nuclei (in the brain stem) and project to
  areas throughout the brain
• these projections appear to have a primarily
  inhibitory function, acting in opposition to
  cholinergic, noradrenergic dopaminergic
  projections

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Serotonergic systems

• increased serotonergic activity is associated
  with reduced levels of behavioural activation
  arousal
• serotonin plays an important role in sleep, mood,
  appetite, temperature regulation pain
  perception

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Serotonin cognition

• effects of manipulating serotonin are highly
  task-dependent
• increasing or decreasing serotonergic activity
  can improve or impair cognitive performance (or
  have no effect), depending on nature of task

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Serotonin (5-HT) synthesis
tryptophan
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Acute tryptophan depletion (ATD)

• ATD is used in experimental studies to reduce
  levels of 5-HT in the brain
• subjects ingest a drink containing a concentrated
  mixture of amino acids, but no tryptophan
• this induces protein synthesis (which requires
  tryptophan)
• therefore, available tryptophan in the body is
  used up
• this results in a decline in 5-HT synthesis in
  the brain

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Increasing serotonergic activity

• tryptophan supplementation
• buspirone - a mood enhancer used to treat
  anxiety depression
• SSRI antidepressants e.g. fluoxetine (
  Prozac), paroxetine ( Seroxat)
• psychedelic drugs - LSD, mescaline (peyote),
  psilocybin (magic mushrooms), MDMA (ecstasy)

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Serotonin mood

• ATD is associated with negative mood in normal
  subjects e.g. increased irritability
  aggressiveness
• ATD can cause a temporary recurrence of
  depressive symptoms in some subjects (50) who
  have a history of depression
• see Young Leyton (2002)

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Serotonin mood

• increasing serotonergic activity through
  tryptophan supplements, direct 5-HT agonists
  (e.g. buspirone), or selective serotonin reuptake
  inhibitors (SSRIs) is associated with more
  positive subjective mood reports in both normal
  subjects and those with a history of mood
  disorders

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Buspirone effects in normal subjects

• Effect of buspirone on self-report
  contentedness after 2 hrs cognitive performance
  testing (drug had no significant effect on any
  performance measure) Chamberlain et al (2007)
  Journal of Psychopharmacology 21, 210-215

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Depression

• intense feelings of persistent sadness,
  helplessness hopelessness
• inability to experience pleasure in activities
  that are normally pleasurable (anhedonia)
• tiredness lack of energy
• abnormal sleep eating patterns (increased or
  decreased)
• cognitive impairments difficulty concentrating,
  deficits in memory executive functions
• affects 10-20 of people at some point in their
  lifetimes
• website www.DepressionAlliance.org

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SSRI antidepressants

• SSRI selective serotonin reuptake inhibitor
• blocks reuptake of 5-HT, so concentration
  increases and more receptors are activated
• SSRIs are the most common drug treatment for
  major depressive illnesses, and are also used to
  treat anxiety disorders

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Action of an SSRI (fluoxetine Prozac)
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Effects of two SSRIs on Hamilton Depression
Rating scores in a randomized, double-blind,
placebo-controlled study of 316 patients with
major depressive disorder (from Stahl 2000,
Biological Psychiatry 48, 894-901)

• sertraline v placebo p lt .05 at weeks 12, 20
  24
• citalopram v placebo p lt .01 at weeks 4 to 24

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Serotonin mood

• as with ATD, effects of SSRIs in non-depressed
  subjects are seen in changes in subjective
  feelings of hostility, aggression irritability
• increasing levels of 5-HT with SSRIs in
  non-depressed subjects reduces hostility
  irritability
• and increases social affiliation and
  co-operative behaviours

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Effects of 20mg/day SSRI (paroxetine) in normal
volunteers Knutson et al 1998, American
Journal of Psychiatry 155, 373-379
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Scores for co-operative behaviour in a 2 person
(1 SSRI 1 placebo) problem-solving task.
Behaviour was filmed using hidden camera and
scorers were blind to condition.
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Serotonin cognition

• serotonin appears to play an important role in
• memory (hippocampus is rich in 5-HT receptors)
• tasks that require response inhibition (e.g.
  Stroop tasks)
• processing emotional information (e.g. facial
  expressions)

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Serotonin memory

• ATD generally impairs memory performance
• however - impairment may be for emotionally
  neutral and positive stimuli only, with memory
  for negative emotional stimuli unaffected or even
  improved (mood-congruent memory bias)
• see Merens et al (2007)

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Serotonin the Stroop task

• ATD may reduce interference in the Stroop task

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Serotonin the Stroop task

• e.g. Evers et al (2006), NeuroImage 32, 248-255
• interference score extra time needed for
  colour-incongruent words compared to
  colour-congruent words

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Serotonin facial expression processing

• 5-HT manipulations affect recognition of emotions
  
• reducing levels of 5-HT with ATD impairs
  recognition of fear happiness in normal
  subjects
• increasing levels of 5-HT with SSRIs enhances
  recognition of fear happiness
• see Merens et al (2007)

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Mechanism of action of SSRIs

• some researchers have hypothesised that changes
  in cognition (memory biases, face processing,
  etc.) are basis for mood-enhancing effects of
  SSRI antidepressants
• could explain delay between physiological
  behavioural effects it may require several
  weeks for cognitive changes to build up to a
  clinical (i.e. mood) effect
• see Merens et al (2007)

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Hallucinogens/ Psychedelics

• LSD, psilocybin, mescaline -
• share indole ring structure with serotonin
• hallucinogen causing hallucinations, but
  frank hallucinations are actually rare
• psychedelic mind revealing

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Lysergic acid diethylamide (LSD)

• Objects appeared to gain in relief they
  assumed unusual dimensions and colours became
  more glowing. Even self-perception and the sense
  of time were changed. When the eyes were closed,
  there surged upon me an uninterrupted stream of
  fantastic images of extraordinary plasticity and
  vividness and accompanied by an intense,
  kaleidoscope-like play of colours. (Albert
  Hofmann, discoverer of LSD, 1943)

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Hallucinogens / Psychedelics

• structure suggests action at 5-HT receptors, but
• increasing serotonergic activity with buspirone
  or SSRIs doesnt produce hallucinogenic or
  psychedelic effects,
• and neither does reducing serotonin levels
  through acute tryptophan depletion

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Hallucinogens / Psychedelics

• research shows that these drugs produce their
  effects mainly by acting as serotonin agonists
• but only at some sub-types of 5-HT receptors (
  may act as antagonists at others)
• a sub-type of 5-HT receptor found in the
  prefrontal cortex (PFC) and thalamus is the main
  site of agonistic action

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Hallucinogens / Psychedelics

• PFC high level cognitive processes and
  subjective experience of self
• thalamus sensory relay station receiving
  inputs from sense organs, and projecting to
  cortex
• disruption of these systems could be basis for
  psychedelic and hallucinatory experiences

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MDMA (ecstasy) 3,4-methylenedioxymethampheta
mine
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MDMA acute effects

• MDMA is a modified amphetamine - it increases
  release of both DA NA, so has psychostimulant
  properties
• also increases release inhibits reuptake of
  5-HT, so has mood-enhancing psychedelic
  properties
• has additional subjective effects not seen in
  other drugs - increased emotional sensitivity
  empathy
• these led to MDMA and similar drugs (MDA, MDE)
  being classed as entactogens (Nichols, 1986) or
  empathogens (Metzner, 2001)

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MDMA sub-acute effects

• users often report midweek blues after taking
  MDMA at weekends
• low mood, lethargy, irritability, difficulty
  concentrating
• thought to be caused by depleted levels of
  monoamine NTs
• symptoms are similar to effects of acute
  tryptophan depletion (ATD) in lab studies

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MDMA effects of chronic use

• many (80) long-term, heavy users report an
  increased incidence of depression, anxiety
  sleep disorders
• cognitive impairments are seen in
  frontal-executive functions (planning, problem
  solving) memory tasks in studies of heavy users
• may be due to damage to 5-HT nerve axons in the
  cerebral cortex hippocampus (see Parrott, 2002)
  

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Free recall of word lists in MDMA users (Parrott
Lasky 1998, Psychopharmacology 139, 261-268)

• light grey non-user control group
• dark grey novice (lt10 times) MDMA users
• white regular MDMA users

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Serotonin (5-HT) - summary

• 5-HT has a primarily inhibitory function often
  acts in opposition to acetylcholine,
  noradrenaline dopamine
• important role in sleep, mood, pain temperature
  regulation
• also modulates cognitive function especially
  memory, response inhibition perception of
  emotional stimuli (e.g. faces)
• 5-HT levels can be manipulated by dietary
  interventions tryptophan supplements increase
  5-HT, tryptophan depletion reduces 5-HT
• acute tryptophan depletion (ATD) is associated
  with negative mood (irritability, aggression,
  depression)
• increased serotonergic neurotransmission is
  associated with positive mood pro-social
  behaviour, and is the basis for action of SSRI
  anti-depressants (e.g. Prozac) subjective
  effects of psychedelic drugs (LSD, Ecstasy)
• long-term, heavy use of Ecstasy is associated
  with increased incidence of mood sleep
  disorders, and with impaired cognitive function
  (especially in frontal executive memory tasks)
  

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Learning outcomes

• Understand how the manipulation of brain
  serotonin affects mood, cognition and social
  behaviour in humans.
• Understand how SSRI antidepressants work, both in
  terms of their acute effects and how these may
  lead to a clinically significant improvement in
  mood.
• Understand the acute, sub-acute and long-term
  effects of MDMA/Ecstasy use and their
  psychopharmacological basis.

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Recommended reading

• PJ Cowen (2008) Serotonin and depression. Trends
  in Pharmacological Sciences 29, 433-436
• W Merens et al (2007) The effects of serotonin
  manipulations on emotional information processing
  and mood. Journal of Affective Disorders 103,
  43-62 (read the introduction discussion)
• AC Parrott (2000) Human research on MDMA
  neurotoxicity. Neuropsychobiology 42, 17-24
• AC Parrott (2002) Recreational Ecstasy/MDMA, the
  serotonin syndrome, and serotonergic
  neurotoxicity. Pharmacology, Biochemistry
  Behavior 71, 837-844
• SN Young M Leyton (2002) The role of serotonin
  in human mood and social interaction.
  Pharmacology, Biochemistry Behavior 71, 857-865