AO1 - Dopamine Hypothesis Schizophrenia

• Dopamine is a neurotransmitter. It is one of the chemicals in the brain which causes neurons to fire. The original dopamine hypothesis stated that schizophrenia suffered from an excessive amount of dopamine. This causes the neurons that use dopamine to fire too often and transmit too many messages.
• Dopamine works in the brain to stimulate the action of neurons at the synapse. It is believed that too much dopamine causes the onset of schizophrenia.
• Dopamine is synthesised from the amino acid tyrosine. Tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase.
• Dopamine is stored in synaptic vesicles until its release across the synapse during transmission.
• When dopamine is released during synaptic transmission it acts on five types of postsynaptic receptors (DI-D5).
• The original dopamine hypothesis was put forward by Van Rossum (1967) and stated that there was hyperactivity of dopamine transmission, which resulted in symptoms of schizophrenia and drugs that blocked dopamine reduced psychotic symptoms.
• In 1967 Jacques Van Rossum proposed that “overstimulation of dopamine receptors could be part of the aetiology” of schizophrenia (Baumeister & Francis, 2002).
• In schizophrenia a negative feedback mechanism exists through the presynaptic D2 receptor which regulates the release of dopamine from the presynaptic neuron.
• It is suggested that antipsychotic drugs which block dopamine via D2 receptors are effective in reducing the positive symptoms of schizophrenia.
• Most antipsychotic drugs will act on the overfiring D2 receptor on the presynaptic neuron, as well as block the receptor sites on the postsynaptic neuron preventing them from absorbing excess dopamine.
• L-DOPA is a drug which converts to dopamine and is often given to patients with Parkinson's disease but has found to create schizophrenia like symptoms. Dopamine itself does not cross the blood-brain barrier and therefore cannot be used to treat Parkinson’s instead L-DOPA, which does cross the blood-brain barrier is used.
• Hallucinogenic drugs such as LSD create psychotic type symptoms and work on the dopamine circuit.
• High dopamine activity leads to acute episodes of schizophrenia, and positive symptoms which include; delusions, hallucinations, confused thinking.
• Hyperdopaminergia is the term used to describe high levels of dopamine in the brain.
• An excess of dopamine receptors in pathways from the sub cortex to Broca’s area, which is responsible for speech production, may explain symptoms of schizophrenia such as speech poverty or auditory hallucinations.
• Davis et al (1991) proposed the addition of cortical hypodopaminergia, which is abnormally low levels of dopamine in the brain's cortex.
• Low levels of dopamine in the prefrontal cortex, which is responsible for thinking, could explain the cognitive deficits in people with schizophrenia.
• Post-mortem studies like Owen et al (1987) have found that there are generally a large number of dopamine receptors in people with schizophrenia.
• Owen et al (1987) found there was increased dopamine in the caudate nucleus and putamen of patients with schizophrenia.
• Falkai et al (1988) found an increased amount of dopamine in the left side of the amygdala in the limbic system of patients with schizophrenia.
• The dopamine hypothesis of schizophrenia claims that hyperactivity of dopamine D2 receptor neurotransmission in subcortical and limbic brain regions contributes to positive symptoms of schizophrenia (Toda & Abi-Dargham, 2007).
• The dopamine hypothesis of schizophrenia states that there is dysregulation of neurotransmission in brain dopaminergic circuits with excessive dopaminergic signalling in the mesolimbic pathway (causing positive symptoms) and reduced signalling in the mesocortical pathway (resulting in negative symptoms) (Miyamoto et al., 2012).
• Howes & Shatalina (2022) suggest that presynaptic dopamine dysfunction results in increased availability and release of dopamine, which has been associated with symptoms of schizophrenia.
• Dopaminergic transmission in the prefrontal cortex is mediated by D1 receptors, and D1 dysfunction has been linked to cognitive impairment and negative symptoms of schizophrenia.
• The brain's pleasure pathway is known as the mesocorticolimbic pathway. Dopamine is released when we do something that makes us feel good, this flood of dopamine can lead to euphoria. This could possibly link with some of the symptoms of schizophrenia.
• The mesolimbic pathway is the site of the rewards pathway which mediates pleasure and reward. Antipsychotics can block D2 receptors in this pathway reducing pleasure effects.
• Davis et al (1991) suggested an increase in dopamine in the mesolimbic pathway is associated with positive symptoms of schizophrenia.
• Davis et al (1991) suggested an increase in dopamine in the mesocortical pathway is associated with negative symptoms of schizophrenia.
• Hyperactivity of dopamine in the mesolimbic pathway is linked to an increase in positive symptoms of schizophrenia.
• Decreased dopamine in the mesocortical pathway is said to be responsible for the negative and depressive symptoms of schizophrenia.
• It is also reported that upregulation of D2 receptors in the caudate nucleus of patients with schizophrenia directly correlates with poorer performance in cognitive tasks involving corticostriatal pathways (Hirvonen et al., 2004).
• Studies have shown an increased density of the dopamine D2 receptor in post-mortem brain tissue of schizophrenia sufferers (Seeman et al., 2000).
• A dopamine antagonist (anti-dopaminergic) is a type of drug which blocks dopamine receptors by receptor antagonism. This means that they stop the neurons from releasing excessive dopamine into the system which results in the severe positive symptoms of schizophrenia.
• Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis.
• A dopamine agonist is a drug that activates receptors in the brain which produce dopamine, a chemical that helps regulate movement and mood.
• An agonist is a substance that acts like another substance and therefore stimulates an action at the synapse.
• Clinical trials suggests that some dopamine agonists may produce a mild improvement in negative symptoms of schizophrenia like affective flattening, depressed mood, alogia and avolition.
• Lindstroem et al (1999) radioactively labelled a chemical called L-DOPA, which is used by the brain to produce dopamine. They administered the L-DOPA to ten untreated patients with schizophrenia as well as 10 people in a control group. Using a PET scan they were able to trace what happened to the L-DOPA. The L-DOPA was taken up more quickly in the patients with schizophrenia, suggesting that they were producing more dopamine than the control group.
• Javitt (2000) found that glycine, a glutamate receptor agonist, reversed drug induced psychosis in rats and improved the symptoms of people with schizophrenia.