Dopamine Hypothesis History

The dopamine hypothesis evolved from animal studies conducted in the 1960s showing that neuroleptic drugs blocked dopamine receptors in the brain. An article by van Rossum published in 1966 is often cited as the first expression of the dopamine theory of schizophrenia, but in fact, the article concerned only the mode of action of neuroleptic drugs. It stated: “The hypothesis is therefore put forward that dopamine receptor blockade is an important factor in themode of action of neuroleptic drugs.” In a book published the same year, van Rossum4 remarked that this discovery may have “fargoing consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could then be part of the aetiology.”

By 1974, it appears that the dopamine hypothesis was already influential, being described as “shared by many investigators” and as exerting “a substantial influence on the design of experiments.” It was not clearly accepted or even formulated in the scientific literature, however, until the mid-1970s. Indeed, for many researchers, the dopamine hypothesis remained a hypothesis about antipsychotic drug action rather than the etiology of schizophrenia.9
As late as 1973, Steven Matthysse,10 in one of the first reviews of research pertaining to a possible dopamine theory of schizophrenia, argued “this simple hypothesis is by no means the only possible interpretation (of some research data). It is not even the most plausible.” A year later he was more confident, stating that “ideas connecting dopamine and schizophrenia have reached a certain maturity.” By 1976 a comprehensive review concluded that “the evidence for a role of dopamine in the pathophysiology of schizophrenia is compelling but not irrefutable."

Among other things, the rediscovery of clozapine and observations that neuroleptic drugs did little, if anything, for negative manifestations of schizophrenia appeared to contradict the theory. Clozapine is a relatively unselective