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
5-HTP
decarboxylase
tryptophan
hydroxylase
tryptophan
5-HT
5-HTP

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,

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:

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, )
sertraline v placebo: p < .05 at weeks 12, 20 & 24
citalopram v placebo: p < .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,

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,
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 doesn’t 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-methylenedioxymethamphetamine

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 (<10 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,
W Merens et al (2007) The effects of serotonin manipulations on emotional information processing and mood. Journal of Affective Disorders 103, (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,
SN Young & M Leyton (2002) The role of serotonin in human mood and social interaction. Pharmacology, Biochemistry & Behavior 71,