title: HDAC inhibitors restore the capacity of aged mice to respond to haloperidol through modulation of histone acetylation.
abstract: Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL+VPA and HAL+MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Janitza L
authors.initials: JL
authors.lastname: Montalvo-Ortiz
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Keegan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gallardo
authors.affiliation: Astellas Research Institute of America, Skokie, IL, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gerst
authors.affiliation: Astellas Research Institute of America, Skokie, IL, USA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tetsuka
authors.affiliation: Astellas Research Institute of America, Skokie, IL, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Tucker
authors.affiliation: Astellas Research Institute of America, Skokie, IL, USA.
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Csernansky
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Hongxin
authors.initials: H
authors.lastname: Dong
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D018492:Dopamine Antagonists / Q000097:blood / Q000494:pharmacology*; D016762:Genes, fos / Q000502:physiology; D006220:Haloperidol / Q000097:blood / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D001549:Benzamides; D018492:Dopamine Antagonists; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011725:Pyridines; C118739:entinostat; D014635:Valproic Acid; D006220:Haloperidol