Enhancement of laminar FosB expression in frontal cortex of rats receiving long chronic clozapine administration

Exp Neurol. 2001 Apr;168(2):392-401. doi: 10.1006/exnr.2000.7612.


The frontal cortex (FrC) and cingulate cortex (CgC) are critical sites for normal cognitive function, as well as cognitive dysfunction in schizophrenia. Thus, modulation of synaptic transmission within these cortical areas may, in part, account for the therapeutic actions of antipsychotic drugs such as haloperidol and clozapine. FosB and DeltaFosB are immediate-early gene (IEG) products sensitive to changes in response to chronic neuroleptic drug administration. We quantitatively examine whether there are light microscopic regional and/or laminar variations in FosB or DeltaFosB in the FrC or CgC of normal adult rats, or animals receiving 6 months administration of either drinking water clozapine, or depot haloperidol. Only animals receiving chronic haloperidol developed vacuous chewing movements, the equivalent of tardive dyskinesia in humans. In control animals, the deep and superficial layers of the FrC showed a higher area density of FosB, but not DeltaFosB immunoreactive cells than the medial layers of FrC or any of the CgC layers. In animals receiving clozapine, but not haloperidol there was increase in the area density of FosB immunoreactive neurons in all FrC layers, but the major increase occurs in medial layers. These findings suggest that FosB expression identifies those FrC neurons that are most active during normal waking behaviors and are further activated following chronic administration of atypical neuroleptics without motor side effects. The results also indicate that the actions of clozapine are attributed in large part to modulation of the output of frontal cortical pyramidal neurons residing in the medial layers.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Clozapine / pharmacology*
  • Frontal Lobe / drug effects*
  • Frontal Lobe / metabolism
  • Gyrus Cinguli / drug effects*
  • Gyrus Cinguli / metabolism
  • Male
  • Neurons / drug effects*
  • Neurons / metabolism
  • Proto-Oncogene Proteins c-fos / drug effects*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • Antipsychotic Agents
  • Proto-Oncogene Proteins c-fos
  • Clozapine