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Open Access Research

Haloperidol treatment induces tissue- and sex-specific changes in DNA methylation: a control study using rats

Morihiro Shimabukuro1, Yoshihiro Jinno1*, Chiaki Fuke2 and Yuji Okazaki3

Author Affiliations

1 Department of Molecular Biology, Ryukyu University School of Medicine, Okinawa, Japan

2 Department of Legal Medicine, School of Medicine, University of the Ryukyus, Okinawa, Japan

3 Department of Psychiatry, Mie University School of Medicine, Mie, Japan

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Behavioral and Brain Functions 2006, 2:37  doi:10.1186/1744-9081-2-37

Published: 29 November 2006



We previously found that there is a subtle difference in the global methylation state of blood leukocyte DNA between male subjects with and without schizophrenia. The aim of the current study was to determine whether this difference was a primary effect of the disease state, or a secondary effect of antipsychotics administered to these patients.


We examined the methyl cytosine (mC) content of DNA from the leukocytes, brain, and liver of rats using high performance liquid chromatography. A total of 40 male and female rats received for 21 days daily injection of haloperidol or vehicle solution alone.


In control rats injected with buffer only, there was a sex-dependent difference in mC content in leukocyte DNA (male > female; P = 0.028, n = 10), similar to our previous observations in human peripheral leukocytes. No difference in mC content between the sexes was observed in the brain or liver in buffer-treated animals. Haloperidol treatment slightly decreased the mC content of leukocytes in male rats, but unexpectedly, increased the mC content of leukocytes in females. We observed a trend toward a higher level of mC in the liver in both sexes following haloperidol treatment, compared to buffer-treated animals. In contrast, haloperidol treatment resulted in a decrease in mC content in the brain in females, and this difference was statistically significant (P = 0.026).


These results indicate that haloperidol can affect DNA methylation states in the brain, as well as in certain other tissues, and raise the possibility that antipsychotic drugs play a role in the observed disparity in mC content in male subjects with and without schizophrenia.