Dopamine Hypothesis and Schizophrenia

These flashcards cover key terms and concepts discussed in the lecture on the dopamine hypothesis and its implications for schizophrenia, including evidence supporting the hypothesis, drug treatments, animal models, and genetic factors.

Dopamine Hypothesis

The theory that schizophrenia symptoms are caused by dysfunctional dopaminergic transmission (excess) in mesolimbic and mesocortical regions of brain

Dopaminergic Agonists

Drugs that enhance dopaminergic transmission, potentially inducing schizophrenic symptoms in non-schizophrenic individuals.

Polygenic Risk Scores (PRS)

Genetic indicators counting the number of risk genes involved in dopamine transmission that affect likelihood of disease

Dopamine receptors

Proteins that bind dopamine and mediate its effects; increased numbers found in patients with schizophrenia.

INCREASED D2 RECEPTORS

A finding in studies where individuals with schizophrenia exhibit heightened levels after treatment, though causation remains unclear.

Neuroleptics

Antipsychotic medications used to treat schizophrenia, categorized into typical and atypical.

Typical Neuroleptics

Older antipsychotic medications, primarily effective for positive symptoms but with significant side effects.

• phenothiazines

• thioxanthenes

• butyrophenes

Atypical Neuroleptics

Newer antipsychotics with fewer side effects and treat both positive and negative symptoms.

haloperidol

• more specific binding affinity for DA receptors

Tardive Dyskinesia

A condition characterized by involuntary movements, often resulting from long-term use of antipsychotic medications.

Animal Models for Schizophrenia

Experimental systems using animals to study the genetic and environmental factors contributing to schizophrenia.

what key gene is involved in dopaminergic transmission, where specific alleles are linked to increased risk of schizophrenia.

COMT gene

Environmental Stressors

Conditions such as isolation or trauma that can increase the risk of developing schizophrenia.

Drug-induced schizophrenia model

An animal model that uses drugs to replicate dopaminergic abnormalities for study.

Negative Symptoms of Schizophrenia

Symptoms that reflect a decrease in emotional range and behaviors, such as social withdrawal or lack of motivation.

Cortisol

A hormone often used as a biomarker for stress response in studies.

Pharmacokinetics

The study of how drugs are absorbed, distributed, metabolized, and excreted by the body.

Blood-brain barrier permeability

The ability of substances to cross from the bloodstream into the brain, crucial for drug development.

polygenic disorder

implication of multiple genes

pathway disorder

implication of multiple genes in a single or multiple signalling pathways leading to disorder

entorhinal cortex

region of brain associated with cognition

cytoarchitectural abnormalities in cortex associated with Scz

• decreased number of small neurons in superficial layers

• increased number of large neurons in deeper layers

why is cortical thickness greater in people with schizophrenia?

inadequate synaptic pruning

how do we know Scz is NOT neurodegenerative?

no gliosis → no neurodegeneration

gliosis = CNS immune response to injury

structural brain differences in Scz

• cortical thickness

• ventricular enlargement

• thinner temporal lobe (hippocampus)

psychosocial symptoms of Scz

• adolescent onset

• stress can precipitate illness

• higher rate of relapse in ‘emotionally charged’ home environment

• blunted cortisol response

why does Scz have blunted cortisol response?

• dysfunction in HPA axis (brain’s stress-response system)

• altered dopamine receptor sensitivity → reduced signal cascade needed for cortisol release

• damaged white matter fibres → altered brain connectivity

• maladaptive coping strategies

paradoxical finding:

• blunted reactive cortisol response to acute stressors

• elevated BASAL cortisol

why is incidence of Scz higher in patients born in late winter/ spring?

exposure of mother to viruses during second trimester is higher → viruses to mother during pregnancy = stunted fetal development

viral infection affect genetics. increases polygenic risk score as neurodevelopment occurs during second trimester

can also affect genes involved in dompamine transmission

site of brain dysfunction in Scz

• limbic structures (in temporal lobe) - invovlved in information processing

• disrupted lateralisation in Scz - not enough communication between two hemispheres of the brain

• hypofunctionality in dorsolateral prefrontal cortex (social inhibition, decision making, behavioural control)

• ventral attention network

• basal ganglia - unable to filter out unimportant stimuli

what brain structure is the site of action for antipsychotics?

basal ganglia

cause of positive symptoms like hallucinations?

dopamine hyperactivity in mesolimbic pathway in temporal lobe

cause of negative symptoms?

hypoactivity in the prefrontal cortex

what is the evidence for dopamine hypothesis

• antipsychotics (reserpine) reduce positive symptoms by blocking D2 receptors → depletes dopamine

• amphetamines (increase dopamine) cause psychosis or worsens symptoms

• L-DOPA (precursor of dopamine used to treat Parkinson’s) can trigger psychosis

chlorpromazine

• DA receptor antagonist - blocks D2 receptors

• increases DA turnover

• means more DA in synapse or CSF

is there increased dopamine transmission in Scz?

• no consistent evidence for increased DA release (however it is difficult to collect CSF sample while patient is actively having psychotic episode, where DA release may be highest)

• increase in D2 receptors (could be due to drug treatment)

• is it increased receptors or just increased sensitivity?

antipsychotics (neuroleptics)

only affective against positive symptoms

causes of drug side effects?

off target effects

when chemical has affinity for other receptor

what are the genes implicated in Scz

• DISC-1

• Neuregulin

• catechol-o-methyl-transferase (COMT)

chromosome 22

higher incidence of deletion in Chromosome 22 in Scz

COMT gene

2 COMT allelles: valine 108 + met 108

met-108 gives rise to higher synaptic DA

val-108 linked with Scz and impaired cognitive function

can alter COMT gene in animal models

people who inherit Met108 of COMT more likley to get Scz → higher synaptic DA

DISC-1

caused by chromosomal translocation (disruption in recombination during meiosis)

neuregulin

• found in locus on chromosome 8

• growth factor that interacts with ErbB receptor

• regulates neuronal differentiation and migration

how can we generate animal models for Scz?

over-express met108 of COMT → more DA in synapse → enhances dopaminergic transmissin

expose animal to environmental stress (electric shocks)

measure cortisol (biomarker of stress, lower reactive cortisol in Scz)

can’t determine equivalent symptoms in animal such as hallucinations → Scz is difficult to model

animal model for positive symptoms

look for increased locomotor activity (pseudo measure of positive symptoms)

animal model for negative symptoms

difficult to model

look for reduced social interaction

animal modelling of Scz

• drug induced increased dopaminergic transmission

• increase PRS (genetics increasing DA transmission)

• create lesion in prefrontal cortex or parts of brain with reduced activity in Scz to model

• post-natal stress (isolation)