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Lecture 5 - Serotonin

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Title: Lecture 5 - Serotonin


1
Lecture 5 - Serotonin
2
The serotonergic neuron
3
Serotonin
  • serotonin 5-HT (5-hydroxytryptamine)
  • an indoleamine has an indole ring structure
  • this structure is also found in hallucinogenic
    or psychedelic drugs

4
Indole ring structure
5
Serotonergic systems
6
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

7
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

8
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

9
Serotonin (5-HT) synthesis
tryptophan
10
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

11
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)

12
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)

13
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

14
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

15
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

16
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

17
Action of an SSRI (fluoxetine Prozac)
18
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

19
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

20
Effects of 20mg/day SSRI (paroxetine) in normal
volunteers Knutson et al 1998, American
Journal of Psychiatry 155, 373-379
21
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.
22
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)

23
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)

24
Serotonin the Stroop task
  • ATD may reduce interference in the Stroop task

25
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

26
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)

27
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)

28
Hallucinogens/ Psychedelics
  • LSD, psilocybin, mescaline -
  • share indole ring structure with serotonin
  • hallucinogen causing hallucinations, but
    frank hallucinations are actually rare
  • psychedelic mind revealing

29
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)

30
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

31
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

32
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

33
MDMA (ecstasy) 3,4-methylenedioxymethampheta
mine
34
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)

35
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

36
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)

37
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

38
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)

39
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.

40
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
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