Posted on:January 27, 2018
Last Updated: January 12, 2022
Time to read: 6 minutes
The dopamine hypothesis stems from early research carried out in the 1960’s and 1970’s when studies involved the use of amphetamine (increases dopamine levels) which increased psychotic symptoms while reserpine which depletes dopamine levels reduced psychotic symptoms.
The original dopamine hypothesis was put forward by Van Rossum in 1967 that stated that there was hyperactivity of dopamine transmission, which resulted in symptoms of schizophrenia and drugs that blocked dopamine reduced psychotic symptoms. 
Dopamine is synthesised from the amino acid tyrosine. Tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase.
DOPA is converted into dopamine (DA) by the enzyme DOPA decarboxylase (DOPADC).
This dopamine is packed and stored into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored until its release into the synapse.
When dopamine is released during neurotransmission, it acts on 5 types of postsynaptic receptors (D1-D5).
A negative feedback mechanism exists through the presynaptic D2 receptor which regulates the release of dopamine from the presynaptic neuron.
Any excess dopamine is also ‘mopped up’ from the synapse by Dopamine transporter (DAT) and stored in the vesicles via VMAT2.
Dopamine is broken down by monoamine oxidase A (MAO-A), MAO-B and catechol-o-methyltransferase (COMT).
THE 4 DOPAMINE PATHWAYS IN THE BRAIN
1.The Mesolimbic Pathway
2.The Mesocortical Pathway
3.The Nigrostriatal Pathway
4.The Tuberoinfundibular (TI) Pathway
Conceptualisation of Schizophrenia
Based on the above understanding, schizophrenia is best conceptualised as a complex entity which involves multiple pathways.
In clinical practice, there can be a disproportionate focus on positive psychotic symptoms.
It is however, important to recognise that affective (e.g depressive), negative and cognitive symptoms are a core part of schizophrenia and should be taken into account in treatment.
The aim of treatment, thus, is to modulate treatment creating a balance between effectiveness and reduction of side effects.
The balance is achieved by optimal dopamine blockade in the mesolimbic pathway while preserving (or enhancing) dopamine transmission in the other pathways.
DOPAMINE AND SCHIZOPHRENIA
The dopamine hypothesis of schizophrenia has moved from the dopamine receptor hypothesis (increased dopamine transmission at the postsynaptic receptors) to a focus on presynaptic striatal hyperdopaminergia.
According to Howes and Kapur-
Read more on the molecular imaging of dopamine abnormalities in schizophrenia.
Concept of Salience
Usually, dopamine’s role is to mediate motivational salience and thereby gives a person the ability to determine what stimulus grabs their attention and drives the subsequent behaviour.
Schizophrenia is associated with an aberrant attribution of salience due to dysregulated striatal dopamine transmission.
Dysregulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent which provides a basis for psychotic phenomena such as ideas of reference, where everyday occurrences may be layered with a with a heightened sense of bizarre significance. Furthermore, this misattribution of salience can lead to paranoid behaviour and persecutory delusions. 
LIMITATIONS OF THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA
Current research shows that one-third of individuals with schizophrenia do not respond to non-clozapine antipsychotics despite high levels of D2-receptor occupancy.
Furthermore, a study using tetrabenazine (used as augmentation) which depletes presynaptic dopamine was not found to be effective in augmenting a clinical response in schizophrenia. 
Therefore, for a significant number of patients with schizophrenia, the basis of their symptoms is either unrelated to dopaminergic dysfunction or is associated with something more than just dopamine excess.
Alternatively, this could also mean that for some patients with schizophrenia there might be a non-dopaminergic sub-type of schizophrenia.
The current dopamine hypothesis of schizophrenia does not adequately explain the cognitive and negative symptoms. Current treatments which modulate dopamine transmission have only modest effects in improving these symptoms.
It has taken two decades for the dopamine hypothesis to evolve and reach its current state. More recent evidence shows another neurotransmitter, glutamate playing an essential role in schizophrenia.
The future likely holds a lot more secrets about schizophrenia which should unravel with the advances in understanding the brain.
Simplified Guide to Mechanisms of Action of Oral Antipsychotics
8. Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial.
Remington, G., Kapur, S., Foussias, G., Agid, O., Mann, S., Borlido, C., … & Javaid, N. (2012). Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial. Journal of clinical psychopharmacology, 32(1), 95-99.