Lecture 3 - Dopamine , salience and schizophrenia

Question 1

what are the main dopaminergic pathways
Dopaminergic (DA ergic) systems

Answer 1

• Nigrostriatal
• Mesocortical
• Mesolimbic

Question 2

explain the nigrostriatal system
-what can it affect

Answer 2

substantia nigra in brain (black stripe of cells) these cells produce dopamine - release dopamine to → (dorsal) striatum

• motor control (in Parkinson’s the substantia niagrs cells die)
• effects executive function (indirectly, via fronto-striatal circuitry) pfc and striatum linked

Question 3

mesocortical system
-what can it affect

Answer 3

ventral tegmental area.- they send axons to → PFC (prefrontal cortex) directly

• so can impact executive function

Question 4

Mesolimbic system

Answer 4

ventral tegmental area but goes elsewhere - cell bodies send axons that release dopamine to
→ nucleus accumbens (“ventral striatum”) in basal forebrain

• reward
• motivational ‘drive’
• salience

Question 5

What effect do drugs with high potential for abuse/addiction have on dopaminergic activity in the ventral striatum?

Answer 5

Drugs with high potential for abuse/addiction have been shown to increase DA-ergic activity in ventral striatum

Question 6

what concept describes how addictive drugs affect the brain

Answer 6

Addictive drugs are thought to “hijack” the brain’s reward system

Question 7

which drugs increase dopamine levels within the synapse

Answer 7

Some drugs (e.g. amphetamine, cocaine) rapidly and directly increase DA levels within the synapse

Question 8

How do other addictive drugs, like nicotine and alcohol, increase dopamine levels in the reward system?

Answer 8

Others (e.g. nicotine, alcohol) indirectly increase DA
levels in reward system via effects on other NT systems

drugs only have affect if their interfering with a system that lready exists

Question 9

how do cues associated with pleasure trigger da release in the reward system

Answer 9

Via classical conditioning, stimuli (cues) associated with pleasure/reward trigger DA release in reward system

eg pavlov system

– cues acquire motivational salience, become attention-
grabbing, & elicit subjective feelings of ‘wanting’.

Question 10

classical conditioning/ association and drug use effect on da release

Answer 10

This can also occur with repeated drug use –
– environmental cues (people, places, objects) associated with
drug use trigger DA release, focus attention on the drug-
related cue & elicit drug craving

Question 11

what is da’s broader role

Answer 11

DA is also thought to play a broader role in signalling
‘motivational salience’ (or significance) of stimuli
(therefore, not limited to rewards)
–
– i.e., stimuli that are potential threats, or that are novel,
unexpected, or related to current goals

Question 12

what is schizophrenia

Answer 12

Schizophrenia means ‘split mind’.
* N.B., not ‘multiple personalities’.

-condition that combines two different types of symtomps

Question 13

what are the ‘positive’ and ‘negative’ symptoms of schizophrenia

Answer 13

Positive’ symptoms (psychosis)
= Presence of abnormal experiences & behaviour:
* Hallucinations - perceiving something thats not there (perception of non-present stimuli), usually auditory.
* Delusions (beliefs that don’t correspond to reality).
* Linked to increased DA-ergic activity, especially in nucleus accumbens.

‘Negative’ symptoms
= Absence of normal experiences & behaviour:
* Lack of motivation, inability to feel pleasure (= anhedonia), social withdrawal.
* Linked to reduced DA-ergic activity, especially in PFC.

seems an increase in one pathway and decrease in another pathway

it is not yet clear how the increased DA and reduced DA (in different
systems) relate to each other – e.g., whether one produces the other – or what the initial cause of either is. (Recent evidence suggests that disruption involving glutamate receptors might precede both.

Question 14

drugs that increase DA activity in the brain

Answer 14

• l dopa (levodopa)
• amphetamine and cocaine

Question 15

l dopa

Answer 15

occurs naturally
Precursor molecule, converted into DA in the brain (by enzymes)
– Treatment for Parkinson’s disease since 1960s
( dopamine given will affect all pathways not just one- so
– Can produce schizophrenia-like symptoms (delusions,
hallucinations) in patients

Question 16

amphetamine and cocaine

Answer 16

– Can increase positive symptoms in schizophrenia
– Can cause schizophrenia-like symptoms in non-schizophrenics:
amphetamine psychosis (recognized since 1950s

Question 17

drugs that reduce DA activity in the brain

Answer 17

• Antipsychotics: used to treat positive symptoms of
  schizophrenia
  – Chlorpromazine, the first effective anti-psychotic drug (1950)
  – DA antagonists – i.e., they block DA receptors

-if antipsyc helps schizophrenia, it can indicate too much dopamine activity

– Sometimes described as neuroleptics (= ‘taking hold of nerves’)
because they make movement difficult (at high doses)
-will affect other pathways as well so possible cause Parkinson’s symptoms

Question 18

antipsychotic side effects

Answer 18

Neuroleptic antipsychotics can cause Parkinson’s-like side-
effects:
– problems with movement – tremor, rigidity;
– ‘extrapyramidal symptoms’; linked to reduced activity in nigrostriatal
DA-ergic system.

• They can also lead to unpleasant subjective reactions –
  feelings of restlessness, emptiness, anhedonia & apathy (loss
  of interest); they can worsen the negative symptoms
  = ‘neuroleptic-induced dysphoria’, linked to reduced DA activity in
  mesolimbic DA-ergic system.
• Such side-effects can lead to patients stopping medication, and
  to relapse.

Question 19

what is the dopamine hypothesis of schizophrenia
-what can back this up

Answer 19

Positive symptoms are caused by excessive levels of
dopaminergic activity”

• This fits with the DA-blocking function of neuroleptic drugs, which
  reduce positive symptoms.
• And it fits with the increase in positive symptoms caused by drugs
  that increase DA-ergic activity (incl. amphetamine, cocaine, L-dopa).
• (A more recent “glutamate hypothesis” of schizophrenia suggests that changes in
  DA activity might themselves happen because of changes in glutamate receptors.)
• N.B.: This is a good example of scientists using evidence (drug
  effects) to generate hypotheses (of neurochemical basis of
  condition); then testing and modifying them with new evidence.

Question 20

what is the salience hypothesis of schizophrenia

Answer 20

The salience hypothesis of schizophrenia suggests that individuals with schizophrenia have an altered perception of salience, or importance, in their environment. According to this hypothesis, normal experiences or stimuli that are typically not significant can become overly salient or meaningful to those with schizophrenia

This altered salience can lead to the development of symptoms such as delusions and hallucinations, as the brain misattributes significance to neutral or irrelevant stimuli. For example, everyday events may be interpreted as having special meaning, contributing to the formation of false beliefs or sensory experiences

Question 21

salience hypothesis of schizophrenia
-what kind of explanation is this
-what is attribution of salience
-how is salient stimulus signalled
example of psychosis

Answer 21

Neurocognitive explanation for role of DA in psychosis.

• Attribution of salience = cognitive process whereby stimuli
  become attention-grabbing & motivationally significant.
• Usually, salient stimulus or event is signalled by dopamine release
  in nucleus accumbens (mesolimbic pathway).
• In psychosis, process is disrupted so increased dopamine coincides
  with stimuli & events with no real significance.
• Hence, psychosis involves the ‘misattribution of salience

Question 22

how aberrant salience might produce psychosis

Answer 22

prodomal period - somethings not right but it doesnt get get you diagnosed

Prodromal period: occurs before specific positive symptoms are
evident, can last from days to years.
* Characterized by ‘aberrant salience signalling’ – recurring feelings that something odd, but important or threatening, is happening which the individual cannot explain or understand.

• These experiences lead to delusional beliefs, as ‘top-down’ cognitive processes are employed to try to make sense of them; therefore, meaningful to the individual & within cultural context.
  (trying to make sense or make a story so that the fear or threat they feel makes sense)
• Hallucinations are internally generated stimuli (thoughts, mental
  images, ‘inner voice’) allocated inappropriate salience & processing
  resources.
• Therefore, psychotic symptoms could be considered a normal
  reaction to an abnormal situation (aberrant DA signalling).

Question 23

the effect of antipsychotics , what can they do overtime

Answer 23

• Antipsychotics don’t directly eliminate hallucinations or delusional beliefs.
• Instead, they make them less salient & less distressing; also, less likely to form.
• Over time, beliefs can change in absence of aberrant salience (e.g., Kapur, 2004), esp. if aided by psychotherapy (e.g. CBT).
• Psychotherapy may be more likely to succeed if combined with antipsychotic drug to weaken ‘attachment’ to delusional beliefs

Question 24

, improvement in positive symptoms in
patients taking antipsychotics ________over time

Answer 24

progresses