I was born curious. How did things work? Could I build it? Mysteries, puzzles and adventures, especially the cryptographic adventure in Edgar Allen Poe's "Gold Bug", preoccupied me as a young boy in Montreal. From building model airplanes and working with home chemistry sets, it was only a small step into science.

But how did I become a medical researcher? My American classmates at McGill medical school recommended a rotating internship at Harper Hospital in Detroit. That internship made me realize that my best efforts at curing the sick were limited. I never seemed to cure anybody—the same patients kept coming back, their high blood pressure still high, or their asthma still severe. A turning point occurred one late night at the Detroit Children's hospital. While re-starting an intravenous infusion of plasma into a hemophiliac ten-year-old boy, I noticed his mother sitting there in the dark. "I have two other hemophiliac children, and I'm expecting a baby," she said. I felt defeated, because this woman was bringing disease into the world faster than I could stamp it out. That's when I decided to go into medical research. Perhaps I could do something I liked, while, hopefully, the research would do some good to patients by solving a medical problem on a long-term basis.

I then turned to a Ph.D. program at Rockefeller University in New York, and my wife, a psychiatrist, invited me to visit the wards at Manhattan State Hospital. The sight of two thousand patients who had schizophrenia or psychosis was unforgettable. She said, "Why don't you do something useful? Why don't you find the cause of schizophrenia?"

As a first step in searching for the cause of schizophrenia, I decided to determine how antipsychotic drugs worked. The next step would be to see whether "the antipsychotic site of action" was overactive in schizophrenia. For the next ten years, therefore, I searched for an "antipsychotic receptor" in the brain. Because it was known that nanomolar concentrations of haloperidol alleviated hallucinations and delusions in psychotic patients, I looked for any site in the brain which was sensitive to this low concentration of one nanomole of haloperidol per liter of plasma water. For this purpose, I examined the brain striatum (which consists of the putamen and caudate nucleus), because it contained dopamine and because it was known that haloperidol and other antipsychotic drugs elicited a Parkinson-like or dopamine-deficient-like syndrome of tremor and rigidity.

I finally discovered this nanomolar binding site in 1974¹, and 1975^2,3, and named it the "neuroleptic/dopamine receptor," later re-christened as the dopamine D2 receptor⁴. All the antipsychotic drugs block this site at concentrations related to their clinical potency^5,6. This work provided the first direct evidence that antipsychotic drugs acted on dopamine receptors, because animal work had difficulty concluding which of the catecholamine receptors were selectively blocked by these drugs^7,8.

It then became possible to measure brain D2 receptors in patients. An excess of D2 receptors was found in schizophrenia when using radio-spiperone but not when using radio-raclopride^9,10, possibly because the former labels monomers of D2, while the latter labels both monomers and dimers of D2¹¹.

The "dopamine overactivity hypothesis of psychosis" has been criticized because clozapine and quetiapine are clinically effective antipsychotics with only 10-45% occupation of D2 receptors, in contrast to 60-80% occupation of the D2 receptors by all other antipsychotics¹². The low occupation of D2 by clozapine and quetiapine is explained by their rapid release from D2, transiently occupying high levels of D2 receptors in patients but only for the first few hours after ingestion^12,13. Moreover, recent work on imaging both D2 and serotonin-2 receptors in patients taking antipsychotics fails to find evidence for a contribution from the occupation of serotonin receptors in either the antipsychotic action or the Parkinson-eliciting action.

While dopamine dysregulation probably leads to the psychotic episode, further research needs to uncover underlying mechanisms that predispose the brain to the dysregulation of the dopamine system. Although the dopamine hypothesis remains the best explanation for the origin and treatment of clinical signs and symptoms of psychosis, the new principles, some of which are mentioned above, are now leading to effective medications essentially free of the old side-effects.