Lecture 3 - Dopamine , salience and schizophrenia Flashcards
what are the main dopaminergic pathways
Dopaminergic (DA ergic) systems
- Nigrostriatal
- Mesocortical
- Mesolimbic
explain the nigrostriatal system
-what can it affect
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
mesocortical system
-what can it affect
ventral tegmental area.- they send axons to → PFC (prefrontal cortex) directly
- so can impact executive function
Mesolimbic system
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
What effect do drugs with high potential for abuse/addiction have on dopaminergic activity in the ventral striatum?
Drugs with high potential for abuse/addiction have been shown to increase DA-ergic activity in ventral striatum
what concept describes how addictive drugs affect the brain
Addictive drugs are thought to “hijack” the brain’s reward system
which drugs increase dopamine levels within the synapse
Some drugs (e.g. amphetamine, cocaine) rapidly and directly increase DA levels within the synapse
How do other addictive drugs, like nicotine and alcohol, increase dopamine levels in the reward system?
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
how do cues associated with pleasure trigger da release in the reward system
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’.
classical conditioning/ association and drug use effect on da release
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
what is da’s broader role
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
what is schizophrenia
Schizophrenia means ‘split mind’.
* N.B., not ‘multiple personalities’.
-condition that combines two different types of symtomps
what are the ‘positive’ and ‘negative’ symptoms of schizophrenia
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.
drugs that increase DA activity in the brain
- l dopa (levodopa)
- amphetamine and cocaine
l dopa
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
amphetamine and cocaine
– Can increase positive symptoms in schizophrenia
– Can cause schizophrenia-like symptoms in non-schizophrenics:
amphetamine psychosis (recognized since 1950s
drugs that reduce DA activity in the brain
- 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
antipsychotic side effects
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.
what is the dopamine hypothesis of schizophrenia
-what can back this up
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.
what is the salience hypothesis of schizophrenia
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
salience hypothesis of schizophrenia
-what kind of explanation is this
-what is attribution of salience
-how is salient stimulus signalled
example of psychosis
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
how aberrant salience might produce psychosis
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).
the effect of antipsychotics , what can they do overtime
- 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
, improvement in positive symptoms in
patients taking antipsychotics ________over time
progresses
