Reduced cortical volume and elevated astrocyte density in rats chronically treated with antipsychotic drugs-linking magnetic resonance imaging findings to cellular pathology

Biol Psychiatry. 2014 Jun 15;75(12):982-90. doi: 10.1016/j.biopsych.2013.09.012. Epub 2013 Oct 19.


Background: Increasing evidence suggests that antipsychotic drugs (APD) might affect brain structure directly, particularly the cerebral cortex. However, the precise anatomical loci of these effects and their underlying cellular basis remain unclear.

Methods: With ex vivo magnetic resonance imaging in rats treated chronically with APDs, we used automated analysis techniques to map the regions that show maximal impact of chronic (8 weeks) treatment with either haloperidol or olanzapine on the rat cortex. Guided by these imaging findings, we undertook a focused postmortem investigation with stereology.

Results: We identified decreases in the volume and thickness of the anterior cingulate cortex (ACC) after chronic APD treatment, regardless of the APD administered. Postmortem analysis confirmed these volumetric findings and demonstrated that chronic APD treatment had no effect on the total number of neurons or S100β+ astrocytes in the ACC. In contrast, an increase in the density of these cells was observed.

Conclusions: This study demonstrates region-specific structural effects of chronic APD treatment on the rat cortex, primarily but not exclusively localized to the ACC. At least in the rat, these changes are not due to a loss of either neurons or astrocytes and are likely to reflect a loss of neuropil. Although caution needs to be exerted when extrapolating results from animals to patients, this study highlights the power of this approach to link magnetic resonance imaging findings to their histopathological origins.

Keywords: Anterior cingulate; antipsychotic; cortex; haloperidol; magnetic resonance imaging; tensor-based morphometry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / adverse effects*
  • Astrocytes / drug effects*
  • Astrocytes / pathology
  • Atrophy / chemically induced*
  • Atrophy / pathology
  • Benzodiazepines / adverse effects
  • Cell Count
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / pathology*
  • Haloperidol / adverse effects
  • Magnetic Resonance Imaging
  • Male
  • Neuroimaging
  • Neurons / drug effects
  • Olanzapine
  • Rats


  • Antipsychotic Agents
  • Benzodiazepines
  • Haloperidol
  • Olanzapine