Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method

A. Breier, T.P. Su, R. Saunders, R. E. Carson, B. S. Kolachana, A. De BartolomeisD. R. Weinberger, N.WeisenfeldA. K. MalhotraW. C. Eclelman and D. Pickar

Proc. Natl Acad. Sci. USA
  94:2569–2574, March 1997.

This study investigated the effects of amphetamine on dopamine concentrations using a different imaging technique, PET.  This technique measures the concentrations of positron-emitting radioisotopes in tissues, including the brain.  These radioisotopes are able to be visualized and the effects of amphetamine on the location and concentration of the radioisotope can again be inferred to be a result of changes in dopamine binding. 

 
The first part of this study involved four adult rhesus monkeys.   A probe was implanted into their brain (at the head of the caudate nucleus, an area with large amounts of dopamine receptors).  This probe measured concentrations of dopamine and measurements could be taken at varying times in the experiment, showing changes in dopamine levels in response to drug administration.  Additionally, PET technology was used to visualize the changes.  The radioisotope used was [¹¹C] raclopride.  The study was performed with amphetamine doses of 0.2 mg/kg and 0.4 mg/kg.  Results from this study showed large increases in dopamine levels in response to the varying amphetamine doses (459% for 0.2 mg/kg and 1365% for 0.4 mg/kg).  The doubled amphetamine dose resulted in doubled dopamine release, which also translated into doubled striatum binding reduction.  These data show that, in monkeys, amphetamine increased dopamine release as well as binding at their receptors. 

For ethical reasons, the clincal aspect of this study used only PET technology. Assuming similarity in functioning of the monkey and human brain in response to amphetamines, analogous PET results should imply similar dopamine release as well.  Amphetamine produced large decreases in [¹¹C] raclopride binding in patients with schizophrenia (22.3%) and controls (15.5%).  Amphetamine is known to lead to increased dopamine release, but the patients with schizophrenia had a larger release compared to controls.  Also, a common psychiatric symptom scoring system showed a correlation between these symptoms increasing and increased dopamine binding.  This evidence further supports a disregulation of the dopamine circuitry in schizophrenia. 

However, not all of the patients had similar reductions in [¹¹C] raclopride binding.  These results are consistent with the previous article reviewed (4 of 11 compared to 6 of 15).  These point to a possibility of a subgroup within patients with schizophrenia who exhibit this enhanced dopamine activity.  In each of the articles, about one-third of the patients exhibited increased dopamine binding and behavioral differences, but the remainder showed less behavioral changes and less dopamine binding.  The consistent results correlating amphetamine-induced dopamine release and binding with psychotic behaviors gives strength to the dopamine hypothesis, but it likely is not the whole picture.