Lecture 11: Dopamine and Psychosis

Question 1

Psychosis Experiences and Phenomenology

Psychosis Treatment: 2

Answer 1

• Imaging dopamine D2 receptors in vivo
• Dopamine circuits

Question 2

Psychosis and Dopamine Neurophysiology

Answer 2

Elevated presynaptic dopamine capacity

Question 3

Amphetamine psychosis

Answer 3

• Mechanism of action is to release presynaptic dopamine

Question 4

dopamine roles

Answer 4

• Reward prediction errors
• Incentive salience

Linking psychosis to dopamine’s role in incentive salience

Contrasting delusions and hallucinations

Question 5

John Perceval - Early experiences and context

Answer 5

• Born 1803
• Father was Prime Minister
• Religious, anti-Catholic assassinated when John was 9
• Perceval entered the army, then went to Oxford in 1830, eventually visiting religious sects
• Perceval’s behaviour apparently too erratic for a group that spoke in
  tongues
• In Dublin, contracted syphilis
• Reports a rapid recovery attributed to combined medical and divine intervention
• Problem: Trust in God? Or take the medicine?

Question 6

John Perceval: Developing psychosis

Answer 6

• Growing
• Religious preoccupation and guilt
• Anxiety and disconnection aided by society’s denigration of religion
  and indifference to spiritual truths
• Describes “Fancies”/“Imaginations”
• “Fancying” that his food was poisoned, people plotting against him
• Seeing shadows, hearing whispers
• Believed he was on a special spiritual mission, and had direct communication with God
• Euphoria and heightened meaning
• Persecution by unseen forces and being controlled by external entities

‘I was also strongly persuaded that the time of the end was at hand, and that God was about to visit the nations with His plagues, His promises having been rejected; and finding in Scripture an exhortation to His people to come out in those days from the profane, and to flee to the mountains.’

Question 7

Psychosis symptoms:

Positive Symptoms = 2

Answer 7

1. Delusions
   * False beliefs, held despite evidence to the contrary
2. Hallucinations
   * False perceptions, attributed to an external
   source

Question 8

Psychosis symptoms

Negative Symptoms = 4

Answer 8

1. Apathy
2. Lethargy
3. Avolition/Anhedonia
4. Withdrawal

Question 9

John Perceval - Treatment 9

Answer 9

• 1800s
• Perceval was sure he would have recovered sooner if not for the “lunatic doctors”
• Treatments included various methods we use to
  induce a psychosis

-like phenotype in animal
models
* Restraint
* Isolation
* Cold showers
* Spinning contraptions

• Drove his mission as one of the founders of the “Alleged Lunatics’ Friend Society”

Question 10

Antipsychotic = Dopamine D2 receptor antagonists

• 6

Answer 10

Dopamine D2
receptor antagonists

1. Chlorpromazine discovered in 1950s
2. • Looking for sedative/relaxant drug for surgery, boost anaesthesia

3 * “Tranquiliser”

4 * Noted it dramatically improved psychosis

5. Evidence for dopamine antagonism around 1974
6. • Radiotracer studies
     Clinical studies showed that the effective concentration of antipsychotics was related
     specifically to D2 potency

Question 11

What the 2 Families of DOPAMINE RECEPTORS?

Answer 11

1. D1 RECEPTORS
   - D1 AND D5
2. D2 RECEPTORS
   - D2, D3, D4

Question 12

What is the feature of D1 RECEPTOR? = 3

Answer 12

1. D1 AND D5
2. EXCITATORY Gs COUPLED RECEPTOR
3. INCREASES ADENYLYL CYCLASE and cAMP/PKA

Question 13

What is the feature of D2 RECEPTOR? = 3

Answer 13

1. D2, D3, AND D4
2. INHIBITORY Gi COUPLED RECEPTOR
3. REDUCE ADENYLYL AND cAMP/PKA

Question 14

Where are both Dopamine receptors located?

Answer 14

1. BOTH LOCATED ON ‘GABAergic neurons’
2. D1 ACTIVATION INCREASES INHIBITION
3. D2 ACTIVATION REDDUCED INHIBITION

Question 15

Understanding DOPAMINE 2 RECEPTOR LOCALISATION: 2

Answer 15

1. PET tracer with 11C RACLOPRIDE
2. ADDITION OF TYHE ANTIPSYCHOTIC DOPAMINE D2 ANTAGONIST HALOPERIDOL

Question 16

LIST THE 2 PATHWAYS OF DOPAMINE NEURONS

Answer 16

1. Substantia Nigra Pars Compacta projecting to Striatum
2. ‘Ventral tegmental’ area projecting to ventral STRIATUM/NUCLEUS ACCUMBENS AND PREFRONTAL CORTEX

Question 17

EXPLAIN - ‘Substantia nigra pars compacta projecting to striatum’ : 2

Answer 17

1. BASAL GANGLIA (DIRECT AND INDIRECT PATHWAY)
2. PARKINSON’S AND MOVEMENT (TREMORS)

Question 18

EXPLAIN ‘Ventral tegmental area projecting to ventral striatum/nucleus accumbens and prefrontal cortex’ = 2

Answer 18

1. SCHIZOPHRENIA AND MOTIVATION AND INCENTIVE
2. EXECUTIVE AND OTHER COGNITIVE FUNCTION

Question 19

Dopamine also located in: 5

Answer 19

1. hippocampus
2. hypothalamus
3. olfactory bulb
4. retina
5. enteric system

Question 20

dopamine: understanding schizophrenia/ psychosis physiology = 10

Answer 20

1. SZ and PRE-SYNAPTIC DOPAMINE:
2. IN SZ, ‘failed to find clear changes in’:
3. • D2 RECEPTORS (maybe a mild elevation
4. • D1 RECEPTORS
5. • DOPAMINE TRANSPORTERS (DAT)
6. BUT, have found ELEVATED PRE-SYNAPTIC DOPAMINE (18F-DOPA TRACER STUDIES)
7. LARGE EFFECT SIZE FOR STRIATUM
   —8. INCREASED DOPAMINE RELEASE
   —9. INCREASED AMPHETAMINE-STIMULATED DOPAMINE RELEASE AND PSYCHOTIC SYMPTOMS
8. PRESENT PRIOR TO ‘FRANK PSYCHOSIS’

Question 21

Dopamine Terminal - process- 8

Answer 21

1. L-Tyrosine (L-Tyr) Uptake:
   
   • L-Tyr enters the neuron through the L-AAT transporter.
     - L-AAT: Large-amino acid transporter
2. L-Tyrosine to L-DOPA:
   
   • (Tyrosine Hydroxylase) TH enzyme converts L-Tyr into L-DOPA.
     — L-DOPA = = L-3,4-DihydrOxyPhenylAlanine
3. L-DOPA to Dopamine (DA):
   
   • AAADC enzyme converts L-DOPA into DA.
     AAADC = decarboxylase or Aromatic Amino Acid Decarboxylase
4. Dopamine Storage:
   
   • DA is stored in vesicles by VMAT.
     VMAT = Vesicular Monoamine Transporter
5. Dopamine Release:
   
   • DA is released into the synaptic cleft when an action potential arrives.
6. Dopamine Receptors:
   
   • DA binds to D2 receptors on the postsynaptic neuron.
7. Dopamine Reuptake:
   
   • DA is taken back into the presynaptic neuron by DAT.
     DAT = DopAmine Transporter
8. Dopamine Breakdown:
   
   • DA is broken down by MAO and COMT into HVA, which is excreted.
     - MAO = MonoAmine Oxidase
     - COMT = CatechOlamine Methyl Transferase
     - HVA = HomoVanillic Acid

Question 22

Psychotomimetics - Amphetamines

UNDERSTANDING ITS PHARMACOLOGY = 4

Answer 22

1. Release pre-formed (pre-synaptic) stores of ‘dopamine, noradrenaline and serotonin’
2. DA == NA&raquo_space; 5-HT
3. Acts to REVERSE THE TRANSPORTER
4. 45MIN ORAL ONSET AND AN 8-12 HR HALF LIFE

Question 23

Psychotomimetics - Amphetamines

UNDERSTANDING ITS COGNITIVE AND BEHAVIOURAL EFFECTS = 8

Answer 23

1. ACUTE DOSES
   - 2. Euphoria
   - 3. increase psychomotor activity
   - 4. reduce fatigue
   - 5. increase motivation
   - 6. makes really dull things interesting
   
   7. at the expense of everybody else having to listen to you
      - 8. enhanced capacity for fun

Question 24

Amphetamine Psychosis case study 1 = 8

Answer 24

1. Case report by Young and Scoville 1938
2. • 34-year old male
3. • Prescribed Benzedrine for narcolepsy
4. • Increased dose above recommended
5. • Became anxious, tense, fearful
6. • Sought police protection thinking his house was
     wired
7. • Upon being admitted to hospital, became paranoid
     that he was being poisoned
8. • Believed there were alligators and snakes in his bed
9. • Upon withdrawal of amphetamine, improved
     rapidly

Question 25

What is it that dopamine does exactly? = 10

Answer 25

1. need a way to get from cellular actions of dopamine 2. at minimum, try to explain 3. delusions 4. hallucinations 5. drug dependence 6. probability should also consider (but won't really here) --- 7. THOUGHT DISORDER --- 8. THINKING, LANGUAGE, AND COMMUNICATION --- 9. 'CLANGING', NEOLOGISMS, ASSOCIATIVE LOOSENING, BLOCKING 10. NEGATIVE SYMPTOMS

Question 26

Dopamine and prediction errors = EXPLAIN DOPAMINE SIGNALS UNEXPECTED REWARD = 4

Answer 26

1. Dopamine neurons fire in response to an UNEXPECTED REWARD - 2. SUPPRESSION DURING REWARD WITHDRAWAL - 3. INCREASE DURING SALIENT PUNISHERS ( approx 10%) - 4. transfers to predictor of reward

Question 27

Dopamine Maths -Reward prediction error =

Answer 27

Magnitude of the phasic dopamine neuron bursts quantitatively represent positive prediction errors * Dopamine response = reward occurred – reward predicted * RPE = r - EV * RPE = reward prediction error * EV = expected value * r = reward * Many other PEs also exist * Brain is a hierarchical PE organ Use maths to build a relationship between state and feeling So that r = * +1 = reward = :) * -1 = punishment = :( * 0 = neutral = :| ∆ dopamine is proportional to the RPE * If RPE is > 0, then increase Dopamine firing * If RPE is < 0, then reduce Dopamine firing

Question 28

Dopamine and reward learning? 'ASSOCIATIVE LEARNING' = 5

Answer 28

1. Dopamine is unlikely to be the signal that directs learning about rewards 2. * E.g., hyperdopaminergic mice do not show excessive learning or habit formation 3. - * S-R perseveration not present 4. * Learning likely happens elsewhere 5. * The dopamine signal is the outcome of that learning

Question 29

Dopamine and reward learning? =Analogy to Pavlov’s dogs = 4

Answer 29

1. An electrophysiologist studied how learning alters firing in a brainstem neuron projecting to the salivary nerve 2. * Initially, the nerve only fires to the food 3. * Gradually the nerve ‘learns’ to fire to the bell 4. * Is the salivary nerve the cause of the learning?

Question 30

Incentive Salience = Dopamine is “tagging” stimuli = 8

Answer 30

1. Important stimuli cause dopamine neurons to fire 2. * Attributes incentive salience to the stimuli 3. * Stimuli become important 4. * Stimuli are “wanted” 5. * Dissociable from “liking” the stimuli 6. * Stimuli should have resources allocated to (e.g., energy expenditure) 7. Role in drug dependence 8. * Drug-related stimuli take on a high “wanted” value

Question 31

Incentive Salience =Drug dependence = 6

Answer 31

1. Classic example is drug dependence 2. Drugs of “addiction” increase dopamine release 3. Amphetamine increases dopamine release 4. * Repeated amphetamine administration leads to increasing incentive salience towards amphetamine-related stimuli 5. * Become important, wanted, should direct energy towards 6. * At the expense of other things?

Question 32

Dopamine, incentives, & psychosis - How does dopamine cause psychosis? = 3

Answer 32

1. Primary physiological alteration in schizophrenia/psychosis is elevated presynaptic dopamine 2. Dopamine’s role is to attribute stimuli with incentive salience 3. Argument – Aberrant dopamine leads to inappropriate attribution of incentive salience to otherwise innocuous stimuli, and then filtered through cognitive and sociocultural experience

Question 33

Dopamine, incentives, & psychosis = E.g. Perceval’s delusional experiences =

Answer 33

1 * “Heightened meaning” 2 * Global increase in incentive salience would manifest as everything having more meaning than it probably should 3 * Believing his food was poisoned 4 * Father was assassinated 5 * The food in front of him would take on extra incentive salience 6 * But why is the food so important? What is it about the food? 7 * Confusion/cognitive dissonance leads to a cognitive rationalisation to account for why something is strangely so important. Once that is solved, there is almost relief.

Question 34

Delusions vs Hallucinations = Hallucinations more complex to explain? = 5

Answer 34

1. Aberrant attribution of incentive salience to internal stimuli/representations 2. * Loosely contrasted to the external stimuli of delusions 3. Interaction with other abnormalities in sensory processing 4. * Dopamine projections to auditory cortex 5. * We showed increases in 40 Hz activity to increased dopamine by dexamphetamine

Question 35

Dopamine’s role= 4

Answer 35

1. Primary role of ventral pathway is to attribute incentive salience to stimuli 2. * Motivationally relevant stimuli increase dopamine neural firing and release of dopamine into the ventral striatum/nucleus accumbens, increasing motivation for the target and dedication of resources 3. * Dissociable liking vs wanting roles 4. * Clever experiments show increased motivation to acquire aversive stimuli through stimulation of incentive circuits

Question 36

Dopamine’s explanation of psychosis = 5

Answer 36

1. Core positive symptoms of delusions and hallucination formation in schizophrenia and other psychoses 2. * Elevated pre-synaptic dopamine capacity in schizophrenia imbues innocuous stimuli with excessive “incentive salience” and is related to amphetamine-induced psychosis both physiologically and phenomenologically 3. * Dopamine D2 receptor antagonists are therapeutic for psychosis 4. * Especially for patients with elevated presynaptic dopamine 5. * Although, often limited to dampening of symptoms