lecture 3- dopamine, salience and schizophrenia

Question 1

what are the three dopaminergic (DA-erguc) systems?

Answer 1

• nigrostriatal
• mesocortical
• mesolimbic

Question 3

what are the 3 dopaminergic (DA-ergic) systems?

Answer 3

• nigrostriatal
• mesocortical
• mesolimbic

Question 4

nigrostriatal system

Answer 4

• substantia nigra => (dorsal) striatum
• motor control
• executive function (indirectly, via fronto-striatal circuitry)

Question 5

mesocortical system

Answer 5

• ventral tegmental area => prefrontal cortex
• executive function

Question 6

mesolimbic DA system

Answer 6

• ventral tegmental area=> nucleus accumbens (“ventral striatum”) in basal forebrain
• reward
• motivational “drive”
• salience

Question 7

dopamine, reward and addiction

Answer 7

• Drugs with high potential for abuse/addiction have been shown to increase DA-ergic activity in ventral striatum
• this has led to idea that addictive drugs ‘hijack’ the brains reward system:

=> some drugs (eg amphetamine, cocaine) rapidly and directly increase DA levels within the synapse
=> others (eg nicotine, alcohol) indirectly increase dopamine levels in reward system via effects on other NT systems

Question 8

dopamine, conditioning and attention

Answer 8

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

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

• 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 9

beyond reward - dopamine stimulus salience

Answer 9

• 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 10

schizophrenia means..

Answer 10

split mind

nb NOT ‘multiple personalities’

Question 11

‘positive’ symptoms (psychosis)

Answer 11

= presence of abnormal experience and behaviour:

• hallucinations (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

Question 12

‘negative’ symptoms

Answer 12

= absence of normal experiences and behaviour

• lack of motivation, inability to feel pleasure (=anhedonia), social withdrawal.
• linked to reduced DA-ergic activity, especially in PFC (prefrontal cortex)

N.B.: 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 13

what are the two drugs that increase dopamine in the brain?

Answer 13

• L-dopa (levodopa)
• amphetamine & cocaine

Question 14

L-dopa (levodopa)

Answer 14

– Precursor molecule, converted into DA in the brain

– Treatment for Parkinson’s disease since 1960s

– Can produce schizophrenia-like symptoms (delusions, hallucinations) in patients

Question 15

Amphetamine & cocaine

Answer 15

– Increase levels of DA in synapse

– Can increase positive symptoms in schizophrenia

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

Question 16

drugs that reduce DA activity in the brain

Answer 16

• Antipsychotics: used to treat positive symptoms of schizophrenia

– Chlorpromazine, the first effective anti-psychotic drug (1950)

– DA antagonists – i.e., they block DA receptors

– Sometimes described as neuroleptics (= ‘taking hold of nerves’) because they make movement difficult (at high doses)

Question 17

what are the antipsychotic side-effects?

Answer 17

• 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 18

The dopamine hypothesis of schizophrenia:

Answer 18

“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 19

The salience hypothesis of schizophrenia

Answer 19

• 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 20

How aberrant salience might produce psychosis

Answer 20

• 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.
• 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 21

The effect of antipsychotics

Answer 21

• 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 22

corresponding, improvement in positive symptoms in patients taking antipsychotics progresses over time