Lecture 11: Dopamine and Psychosis Flashcards
Psychosis Experiences and Phenomenology
Psychosis Treatment: 2
- Imaging dopamine D2 receptors in vivo
- Dopamine circuits
Psychosis and Dopamine Neurophysiology
Elevated presynaptic dopamine capacity
Amphetamine psychosis
- Mechanism of action is to release presynaptic dopamine
dopamine roles
- Reward prediction errors
- Incentive salience
Linking psychosis to dopamine’s role in incentive salience
Contrasting delusions and hallucinations
John Perceval - Early experiences and context
- 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?
John Perceval: Developing psychosis
- 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.’
Psychosis symptoms:
Positive Symptoms = 2
- Delusions
* False beliefs, held despite evidence to the contrary - Hallucinations
* False perceptions, attributed to an external
source
Psychosis symptoms
Negative Symptoms = 4
- Apathy
- Lethargy
- Avolition/Anhedonia
- Withdrawal
John Perceval - Treatment 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”
Antipsychotic = Dopamine D2 receptor antagonists
- 6
Dopamine D2
receptor antagonists
- Chlorpromazine discovered in 1950s
- Looking for sedative/relaxant drug for surgery, boost anaesthesia
3 * “Tranquiliser”
4 * Noted it dramatically improved psychosis
- Evidence for dopamine antagonism around 1974
- Radiotracer studies
Clinical studies showed that the effective concentration of antipsychotics was related
specifically to D2 potency
- Radiotracer studies
What the 2 Families of DOPAMINE RECEPTORS?
- D1 RECEPTORS
- D1 AND D5 - D2 RECEPTORS
- D2, D3, D4
What is the feature of D1 RECEPTOR? = 3
- D1 AND D5
- EXCITATORY Gs COUPLED RECEPTOR
- INCREASES ADENYLYL CYCLASE and cAMP/PKA
What is the feature of D2 RECEPTOR? = 3
- D2, D3, AND D4
- INHIBITORY Gi COUPLED RECEPTOR
- REDUCE ADENYLYL AND cAMP/PKA
Where are both Dopamine receptors located?
- BOTH LOCATED ON ‘GABAergic neurons’
- D1 ACTIVATION INCREASES INHIBITION
- D2 ACTIVATION REDDUCED INHIBITION
Understanding DOPAMINE 2 RECEPTOR LOCALISATION: 2
- PET tracer with 11C RACLOPRIDE
- ADDITION OF TYHE ANTIPSYCHOTIC DOPAMINE D2 ANTAGONIST HALOPERIDOL
LIST THE 2 PATHWAYS OF DOPAMINE NEURONS
- Substantia Nigra Pars Compacta projecting to Striatum
- ‘Ventral tegmental’ area projecting to ventral STRIATUM/NUCLEUS ACCUMBENS AND PREFRONTAL CORTEX
EXPLAIN - ‘Substantia nigra pars compacta projecting to striatum’ : 2
- BASAL GANGLIA (DIRECT AND INDIRECT PATHWAY)
- PARKINSON’S AND MOVEMENT (TREMORS)
EXPLAIN ‘Ventral tegmental area projecting to ventral striatum/nucleus accumbens and prefrontal cortex’ = 2
- SCHIZOPHRENIA AND MOTIVATION AND INCENTIVE
- EXECUTIVE AND OTHER COGNITIVE FUNCTION
Dopamine also located in: 5
- hippocampus
- hypothalamus
- olfactory bulb
- retina
- enteric system
dopamine: understanding schizophrenia/ psychosis physiology = 10
- SZ and PRE-SYNAPTIC DOPAMINE:
- IN SZ, ‘failed to find clear changes in’:
- D2 RECEPTORS (maybe a mild elevation
- D1 RECEPTORS
- DOPAMINE TRANSPORTERS (DAT)
- BUT, have found ELEVATED PRE-SYNAPTIC DOPAMINE (18F-DOPA TRACER STUDIES)
- LARGE EFFECT SIZE FOR STRIATUM
—8. INCREASED DOPAMINE RELEASE
—9. INCREASED AMPHETAMINE-STIMULATED DOPAMINE RELEASE AND PSYCHOTIC SYMPTOMS - PRESENT PRIOR TO ‘FRANK PSYCHOSIS’
Dopamine Terminal - process- 8
-
L-Tyrosine (L-Tyr) Uptake:
- L-Tyr enters the neuron through the L-AAT transporter.
- L-AAT: Large-amino acid transporter
- L-Tyr enters the neuron through the L-AAT transporter.
-
L-Tyrosine to L-DOPA:
- (Tyrosine Hydroxylase) TH enzyme converts L-Tyr into L-DOPA.
— L-DOPA = = L-3,4-DihydrOxyPhenylAlanine
- (Tyrosine Hydroxylase) TH enzyme converts L-Tyr into L-DOPA.
-
L-DOPA to Dopamine (DA):
- AAADC enzyme converts L-DOPA into DA.
AAADC = decarboxylase or Aromatic Amino Acid Decarboxylase
- AAADC enzyme converts L-DOPA into DA.
-
Dopamine Storage:
- DA is stored in vesicles by VMAT.
VMAT = Vesicular Monoamine Transporter
- DA is stored in vesicles by VMAT.
-
Dopamine Release:
- DA is released into the synaptic cleft when an action potential arrives.
-
Dopamine Receptors:
- DA binds to D2 receptors on the postsynaptic neuron.
-
Dopamine Reuptake:
- DA is taken back into the presynaptic neuron by DAT.
DAT = DopAmine Transporter
- DA is taken back into the presynaptic neuron by DAT.
-
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
- DA is broken down by MAO and COMT into HVA, which is excreted.
Psychotomimetics - Amphetamines
UNDERSTANDING ITS PHARMACOLOGY = 4
- Release pre-formed (pre-synaptic) stores of ‘dopamine, noradrenaline and serotonin’
- DA == NA»_space; 5-HT
- Acts to REVERSE THE TRANSPORTER
- 45MIN ORAL ONSET AND AN 8-12 HR HALF LIFE
Psychotomimetics - Amphetamines
UNDERSTANDING ITS COGNITIVE AND BEHAVIOURAL EFFECTS = 8
- ACUTE DOSES
- 2. Euphoria
- 3. increase psychomotor activity
- 4. reduce fatigue
- 5. increase motivation
- 6. makes really dull things interesting- at the expense of everybody else having to listen to you
- 8. enhanced capacity for fun
- at the expense of everybody else having to listen to you
Amphetamine Psychosis case study 1 = 8
- Case report by Young and Scoville 1938
- 34-year old male
- Prescribed Benzedrine for narcolepsy
- Increased dose above recommended
- Became anxious, tense, fearful
- Sought police protection thinking his house was
wired
- Sought police protection thinking his house was
- Upon being admitted to hospital, became paranoid
that he was being poisoned
- Upon being admitted to hospital, became paranoid
- Believed there were alligators and snakes in his bed
- Upon withdrawal of amphetamine, improved
rapidly
- Upon withdrawal of amphetamine, improved
What is it that dopamine does exactly? = 10
- need a way to get from cellular actions of dopamine
- at minimum, try to explain
- delusions
- hallucinations
- drug dependence
- probability should also consider (but won’t really here)
— 7. THOUGHT DISORDER
— 8. THINKING, LANGUAGE, AND COMMUNICATION
— 9. ‘CLANGING’, NEOLOGISMS, ASSOCIATIVE LOOSENING, BLOCKING - NEGATIVE SYMPTOMS
Dopamine and prediction errors = EXPLAIN DOPAMINE SIGNALS UNEXPECTED REWARD = 4
- Dopamine neurons fire in response to an UNEXPECTED REWARD
- SUPPRESSION DURING REWARD WITHDRAWAL
- INCREASE DURING SALIENT PUNISHERS ( approx 10%)
- transfers to predictor of reward
Dopamine Maths -Reward prediction error =
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
Dopamine and reward learning?
‘ASSOCIATIVE LEARNING’ = 5
- Dopamine is unlikely to be the signal that directs learning about rewards
-
- E.g., hyperdopaminergic mice do not show
excessive learning or habit formation
- S-R perseveration not present
- E.g., hyperdopaminergic mice do not show
- Learning likely happens elsewhere
- The dopamine signal is the outcome of that learning
Dopamine and reward learning? =Analogy to Pavlov’s dogs
= 4
- An electrophysiologist studied how learning alters firing in a brainstem neuron projecting to the salivary nerve
- Initially, the nerve only fires to the food
- Gradually the nerve ‘learns’ to fire to the bell
- Is the salivary nerve the cause of the learning?
Incentive Salience = Dopamine is “tagging” stimuli = 8
- Important stimuli cause dopamine neurons to fire
- Attributes incentive salience to the stimuli
- Stimuli become important
- Stimuli are “wanted”
- Dissociable from “liking” the stimuli
- Stimuli should have resources allocated to
(e.g., energy expenditure)
- Stimuli should have resources allocated to
- Role in drug dependence
- Drug-related stimuli take on a high “wanted”
value
- Drug-related stimuli take on a high “wanted”
Incentive Salience =Drug dependence = 6
- Classic example is drug dependence
- Drugs of “addiction” increase dopamine release
- Amphetamine increases dopamine release
- Repeated amphetamine administration leads to
increasing incentive salience towards amphetamine-related stimuli
- Repeated amphetamine administration leads to
- Become important, wanted, should direct energy
towards
- Become important, wanted, should direct energy
- At the expense of other things?
Dopamine, incentives, & psychosis - How does dopamine cause psychosis? = 3
- Primary physiological alteration in schizophrenia/psychosis is elevated presynaptic dopamine
- Dopamine’s role is to attribute stimuli with
incentive salience - Argument
– Aberrant dopamine leads to inappropriate attribution of incentive salience to otherwise innocuous stimuli, and then filtered through cognitive and sociocultural experience
Dopamine, incentives, & psychosis = E.g. Perceval’s delusional experiences =
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.
Delusions vs Hallucinations = Hallucinations more complex to explain? = 5
- Aberrant attribution of incentive salience to
internal stimuli/representations - Loosely contrasted to the external stimuli of
delusions
- Loosely contrasted to the external stimuli of
- Interaction with other abnormalities in sensory
processing - Dopamine projections to auditory cortex
- We showed increases in 40 Hz activity to increased dopamine by dexamphetamine
Dopamine’s role= 4
- Primary role of ventral pathway is to attribute
incentive salience to stimuli - 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
- Motivationally relevant stimuli increase
- Dissociable liking vs wanting roles
- Clever experiments show increased motivation to acquire aversive stimuli
through stimulation of incentive circuits
- Clever experiments show increased motivation to acquire aversive stimuli
Dopamine’s explanation of psychosis = 5
- Core positive symptoms of delusions and hallucination formation in schizophrenia and other psychoses
- 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
- Elevated pre-synaptic dopamine capacity in
- Dopamine D2
receptor antagonists are
therapeutic for psychosis
- Dopamine D2
- Especially for patients with elevated presynaptic
dopamine
- Especially for patients with elevated presynaptic
- Although, often limited to dampening of
symptoms
- Although, often limited to dampening of