ΔFosB induction in prefrontal cortex by antipsychotic drugs is associated with negative behavioral outcomes.
ΔFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased ΔFosB expression following antipsychotic treatment have not been explored. Here, we assessed whether ΔFosB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased ΔFosB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of ΔFosB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that ΔFosB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions.
1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Department of Pharmacology and Toxicology and Institute on Addictions, University at Buffalo, Buffalo, NY, USA.
David M
DM
Dietz
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Pamela J
PJ
Kennedy
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Haosheng
H
Sun
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA.
Ian
I
Maze
Department of Pharmacology and Toxicology and Institute on Addictions, University at Buffalo, Buffalo, NY, USA.
Amy M
AM
Gancarz
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Vincent
V
Vialou
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ja Wook
JW
Koo
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ezekiell
E
Mouzon
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Subroto
S
Ghose
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Carol A
CA
Tamminga
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Eric J
EJ
Nestler
D000328:Adult; D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology
D014150:Antipsychotic Agents; D016760:Proto-Oncogene Proteins c-fos; D006220:Haloperidol