Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatr. Jul 19, 2021; 11(7): 355-364
Published online Jul 19, 2021. doi: 10.5498/wjp.v11.i7.355
History of the dopamine hypothesis of antipsychotic action
Mary V Seeman
Mary V Seeman, Department of Psychiatry, University of Toronto, Toronto M5P 3L6, Ontario, Canada
Author contributions: Seeman MV is the sole author and has approved the final version.
Conflict-of-interest statement: I am the widow of one of the investigators mentioned in the text.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Mary V Seeman, OC, MDCM, DSc, Professor Emerita, Department of Psychiatry, University of Toronto, 260 Heath Street West, Suite #605, Toronto M5P 3L6, Ontario, Canada.
Received: February 25, 2021
Peer-review started: February 25, 2021
First decision: April 20, 2021
Revised: April 22, 2021
Accepted: June 22, 2021
Article in press: June 22, 2021
Published online: July 19, 2021

The dopamine hypothesis of how antipsychotic drugs exert their beneficial effect in psychotic illness has an interesting history that dates back to 1950. This hypothesis is not to be confused with the dopamine hypothesis of schizophrenia; the aim of the latter is to explain the etiology of schizophrenia. The present review does not deal with schizophrenia but, rather, with the historical development of our current understanding of the dopamine-associated actions of the drugs that reduce the symptoms of psychosis. This historical review begins with the serendipitous discovery of chlorpromazine, a drug synthesized around a chemical core that initially served to produce man-made dyes. This molecular core subsequently contributed to the chemistry of antihistamines. It was with the aim of producing a superior antihistamine that chlorpromazine was synthesized; instead, it revolutionized the treatment of psychosis. The first hypothesis of how this drug worked was that it induced hypothermia, a cooling of the body that led to a tranquilization of the mind. The new, at the time, discoveries of the presence of chemical transmitters in the brain soon steered investigations away from a temperature-related hypothesis toward questioning how this drug, and other drugs with similar properties and effects, modulated endogenous neurotransmission. As a result, over the years, researchers from around the world have begun to progressively learn what antipsychotic drugs do in the brain.

Keywords: Chlorpromazine, Haloperidol, G-Protein coupled receptors, Binding assays, Receptor imaging, High affinity states

Core Tip: This history starts with the synthesis of chlorpromazine in 1950 and traces the steps taken to discover how this drug, and related drugs, work to reduce, sometimes to reverse, the delusions and hallucinations associated with psychosis. The task to understand how these drugs work in the brain continues, as many unknowns remain.