History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia

J Hist Neurosci. 2013;22(1):62-78. doi: 10.1080/0964704X.2012.678199.


The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.

Publication types

  • Historical Article

MeSH terms

  • Antipsychotic Agents / history*
  • Antipsychotic Agents / therapeutic use
  • Drug Discovery / history*
  • Haloperidol / history*
  • Haloperidol / therapeutic use
  • History, 20th Century
  • Humans
  • Neurobiology / history*
  • Receptors, Dopamine D2*
  • Schizophrenia / drug therapy
  • Schizophrenia / history*


  • Antipsychotic Agents
  • Receptors, Dopamine D2
  • Haloperidol