As a result of drug tolerance, some users of amphetamine would take large doses to experience a "high". From this, these users would develop symptoms of paranoia (auditory hallucinations, bizarre motor behavior, etc), which closely resembled schizophrenic symptoms.

Not only that, but amphetamine worsens symptoms of schizophrenia. Amphetamine is found to promote the release of dopamine and prolong the action of the released transmitter by blocking reuptake.

Drug Abuse as Support of the Dopamine Hypothesis of Antipsychotic Drugs

All of the early antipsychotics were found to block postsynaptic dopamine receptors, particularly D2 receptors. From this, researchers proposed the dopamine hypothesis.


University of Rochester

The dopamine hypothesis posits that schizophrenia is linked to irregularities in the dopamine system. The original theory suggested that the disorder was caused by a general excess of dopamine or an overabundance of dopamine receptors. However, this view has been refined. More recent research indicates that dopamine abnormalities are specific to different brain regions. An oversupply of dopamine in the limbic system is thought to be responsible for positive symptoms like hallucinations and delusions, while a deficit of dopamine in the prefrontal cortex is associated with negative symptoms such as avolition and alogia.

The Dopamine Hypothesis of Schizophrenia

Breedlove, S. & Watson, N. (2017). Behavioral neuroscience, eighth edition. Oxford University Press.

Behavioral Neuroscience 8th Edition

Origins of the Dopamine Hypothesis of Antipsychotics

A major class of antischizophrenic drugs that share an antagonist activity at dopamine D2 receptors

Typical Antipsychotics

The effective dose of these antipsychotic drugs can be predicted given its affinity of D2 receptors, which supports the dopamine hypothesis.

Antipsychotic Drug Affinity for D2 Receptors as Support of the Dopamine Hypothesis of Antipsychotics

One problem of the dopamine hypothesis is that there is no relation between how long it takes for the symptoms to diminish and how long it takes the drugs themselves to block dopamine receptors, which shows that the relation between dopamine and schizophrenia is more complex.

Another problem of the hypothesis is seen in a study by Alpert and Friedhoff in 1980, where some people with schizophrenia do not respond to dopamine antagonsits at all.

Problems with the Dopamine Hypothesis of Antipsychotics

Brisch, R., Saniotis, A., Wolf, R., Bielau, H., Bernstein, H. G., Steiner, J., Bogerts, B., Braun, K., Jankowski, Z., Kumaratilake, J., Henneberg, M., & Gos, T. (2014). The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Frontiers in psychiatry, 5, 47. https://doi.org/10.3389/fpsyt.2014.00047

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