Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psycho- pathological conditions, including psychosis and behavioral disturbances associated with cognitive impairment. However, the current treatment strategy for elderly individuals is often ineffective, with an increased incidence of sid effects. The factors contributing to reduced antipsychotic efficacy in the elderly population are not yet full understood. Induction of immediate-early genes such as c-fos has been shown to affect antipsychotic drug activity in the CNS. Both typical and atypical antipsychotics induce c Fos expression in specific brain regions, including the striatum and prefrontal cortex. Our preliminary data shows lower levels of antipsychotic induced c-Fos expression in the nucleus accumbens of aged mice, as well decreased acetylation of histone H3 lysine residue 27 (H3K27) on the c-fos promoter. Co-treatment with valproic acid (VPA), a histone deacetylase HDAC inhibitor, was shown to restore antipsychotic induced c-Fos induction and improve behavioral performance in aged mice. Our preliminary data suggests that an epigenetic mechanism may play a key role in the reduced drug efficacy seen in elderly individuals. In this study, we hypothesize that age-associated decreases in antipsychotic efficacy are the result of epigenetic changes in the brain that can be ameliorated by co-treatment with antipsychotics and HDAC inhibitors. To test our hypotheses, young (3-month old) and aged (24-month old) mice will be treated with haloperidol (HAL, a typical) or clozapine (CLZ, an atypical) alone or in combination with the HDAC1-specific inhibitor entinostat (MS-275) or pan-HDAC inhibitor VPA for 14 days. First, we will investigate the relationship between the acetylation of histone H3 lysine residue 27 (H3K27) on the c-fos promoter and antipsychotic induced c-Fos induction in the brains of aged mice using chromatin immunoprecipitation (ChIP) assays and real-time PCR. We will then examine whether increased c-Fos expression following HDAC inhibitor/antipsychotic co-treatment is specific to dopaminergic or serotoninergic neurons using immunofluorescence double labeling. Using behavioral tests relevant to memory and motor function, we will then investigate whether MS-275 treatment results in cognitive improvements similar to those seen with VPA treatment. This study will shed light on the interactions between aging, antipsychotic drug efficacy, and epigenetic regulation. By advancing our understanding of the epigenetic mechanisms of drug efficacy, it will be possible to develop new psychotropic treatment strategies that maximize benefits while minimizing side effects.

Public Health Relevance

The use of psychotropic medications in the elderly population generates a number of obstacles, including decreased drug efficacy and increased side effects. It is not yet known whether the epigenetic changes that occur with aging play a role in antipsychotic efficacy. In this study, we will investigate whether histone deacetylase inhibitors can improve drug efficacy and decrease extra-pyramidal side effects by regulating epigenetic alterations. This information is essential for developing an alternative treatment strategy for aged patients with psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH100919-01A1
Application #
8445889
Study Section
Special Emphasis Panel (ZRG1-DDNS-C (01))
Program Officer
Evans, Jovier D
Project Start
2012-12-26
Project End
2014-11-30
Budget Start
2012-12-26
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$231,750
Indirect Cost
$81,750
Name
Northwestern University at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Dong, Hongxin; Wang, Shirlene; Zeng, Ziling et al. (2014) Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-? and behavior in Tg2576 mice. Psychopharmacology (Berl) 231:4711-22
Montalvo-Ortiz, Janitza L; Keegan, Jack; Gallardo, Christopher et al. (2014) HDAC inhibitors restore the capacity of aged mice to respond to haloperidol through modulation of histone acetylation. Neuropsychopharmacology 39:1469-78