Dopamine & Schizophrenia

Several lines of evidence suggest that the symptoms of schizophrenia may arise from excess dopamine activity in some areas of the brain and deficient activity in others. Before discussing the dopamine hypothesis, it will be helpful to review the dopaminergic pathways in the brain and the role of dopamine receptors.

Neurons that secrete dopamine are primarily located in the mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways. In addition, at least five dopamine receptor subtypes are located in these dopaminergic pathways, denoted by subscripts D1to D5. Although evidence suggests that the striatum, limbic system, and cortex have more dopamine receptors than the rest of the brain, other findings indicate that in people with schizophrenia, the prefrontal cortex has decreased levels of various dopamine receptors.

What is the Dopamine Hypothesis in schizophrenia?

The dopamine hypothesis initially stated that in people with schizophrenia, certain regions of the brain contain excess dopamine, thereby causing symptoms of the disease, particularly positive symptoms. The dopamine hypothesis arose from, and has since been supported by, several observations :

• Most antipsychotic drugs that are effective in treating the positive symptoms of schizophrenia block dopamine D2 receptors.
• Drugs that increase dopamine levels in the brain, including amphetamines and cocaine, mimic the positive symptoms of schizophrenia.

A higher density of D2 receptors has been found postmortem in the frontal cortex of people with schizophrenia. It is not clear, however, whether the increased dopaminergic activity is due to too much dopamine, too many dopamine receptors, excessive dopamine receptor sensitivity, or a combination of all three factors. In recent years, refinements of the dopamine hypothesis have suggested that certain symptoms of schizophrenia and some side effects associated with antipsychotic medications are associated with four specific dopaminergic pathways.

The hypothesis has also been expanded to propose that decreased dopaminergic activity may be a factor. Specifically, hypodopaminergic functioning in certain areas of the brain may be responsible for the cognitive deficits and negative symptoms seen in schizophrenia. Important questions that remain about the dopamine hypothesis include the degree to which specific dopamine receptor subtypes or dopaminergic pathways are involved.

What is the link between Dopamine Receptor Subtypes and Positive and Negative Symptoms?

D2 receptors are associated with positive symptoms of schizophrenia because drugs that block these receptors relieve psychotic symptoms. Because D3 and D4 receptors are related to D2 receptors, drugs that affect these receptors may also have treatment potential. Other evidence suggests that D1 receptors may play a role in negative symptoms. Similarly, D5 receptors, which were discovered recently and are related to D1 receptors, may play a role in negative symptoms. Currently, however, the function of many dopamine receptors is not clear, and they have not been definitively associated with specific symptoms or treatment effects.

Other Dopamine-Related Findings

In recent years, a number of findings have suggested that other dopamine-related factors, in addition to those described by the dopamine hypothesis, are involved in schizophrenia. For example:

• As noted earlier, while positive symptoms may involve excess dopaminergic functioning in the mesolimbic pathway, negative symptoms appear to involve decreased activity in the mesocortical pathway.
• Although antipsychotic drugs can rapidly block dopamine receptors, it may be days before a patient’s symptoms are relieved. This suggests that the initial abnormalities seen in schizophrenia may involve a hypodopaminergic state.
• Drugs that block certain dopamine receptor subtypes are not always effective.
• Some antipsychotic drugs (atypical agents) block dopamine and serotonin receptors.
• Dopamine interacts with many other neurotransmitter systems that may play a contributory role.
• Since dopamine antagonists are effective in treating all forms of psychosis, dopaminergic hyperactivity is not unique to schizophrenia.