Subcortical dopaminergic deficits in a DISC1 mutant model: a study in direct reference to human molecular brain imaging

Hum Mol Genet. 2013 Apr 15;22(8):1574-80. doi: 10.1093/hmg/ddt007. Epub 2013 Jan 11.


Imaging of the human brain has been an invaluable aid in understanding neuropsychopharmacology and, in particular, the role of dopamine in the striatum in mental illness. Here, we report a study in a genetic mouse model for major mental illness guided by results from human brain imaging: a systematic study using small animal positron emission tomography (PET), autoradiography, microdialysis and molecular biology in a putative dominant-negative mutant DISC1 transgenic model. This mouse model showed augmented binding of radioligands to the dopamine D2 receptor (D2R) in the striatum as well as neurochemical and behavioral changes to methamphetamine administration. Previously we reported that this model displayed deficits in the forced swim test, a representative indicator of antidepressant efficacy. By combining the results of our two studies, we propose a working hypothesis for future studies that this model might represent a mixed condition of depression and psychosis. We hope that this study will also help bridge a major gap in translational psychiatry between basic characterization of animal models and clinico-pharmacological assessment of patients mainly through PET imaging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Brain Mapping
  • Corpus Striatum / metabolism
  • Corpus Striatum / ultrastructure
  • Dopamine / genetics
  • Dopamine / metabolism*
  • Humans
  • Methamphetamine / administration & dosage
  • Mice
  • Mice, Transgenic
  • Molecular Imaging*
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Positron-Emission Tomography / methods*
  • Protein Binding
  • Radiography
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / isolation & purification
  • Receptors, Dopamine D2 / metabolism*


  • DISC1 protein, human
  • Nerve Tissue Proteins
  • Receptors, Dopamine D2
  • Methamphetamine
  • Dopamine