title: High doses of the histone deacetylase inhibitor sodium butyrate trigger a stress-like response.
abstract: The hypothalamic-pituitary-adrenal (HPA) axis is activated by a wide range of stimuli, including drugs. Here we report that in male rats, a dose of sodium butyrate (NaBu) that is typically used to inhibit histone deacetylation (1200 mg/kg) increased the peripheral levels of HPA hormones and glucose. In a further experiment, we compared the effects of two different doses of NaBu (200 and 1200 mg/kg) and equimolar saline solutions on peripheral neuroendocrine markers and brain c-Fos expression to demonstrate a specific stress-like effect of NaBu that is not related to hypertonicity and to localise putatively involved brain areas. Only the high dose of NaBu increased the plasma levels of stress markers. The equimolar (hypertonic) saline solution also activated the HPA axis and the c-Fos expression in the paraventricular nucleus of the hypothalamus (PVN), a key area for the control of the HPA axis, but the effects were of a lower magnitude than those of NaBu. Regarding other brain areas, group differences in c-Fos expression were not observed in the medial prefrontal cortex or the medial amygdala, but they were observed in the central amygdala and the lateral ventral septum. However, only the latter area of the NaBu group showed enhanced c-Fos expression that was significantly higher than that after hypertonic saline. The present data indicate that high doses of NaBu appear to act as a pharmacological stressor, and this fact should be taken into account when using this drug to study the role of epigenetic processes in learning and emotional behaviour.
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Humberto
authors.initials: H
authors.lastname: Gagliano
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: Delgado-Morales
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Ancor
authors.initials: A
authors.lastname: Sanz-Garcia
authors.affiliation: Institut de Neurociències and Unitat de Fisiologia Animal (Facultat de Biociències), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Electronic address: Antonio.Armario@uab.cat.
authors.forename: Antonio
authors.initials: A
authors.lastname: Armario
mesh_terms: D000107:Acetylation; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D020148:Butyric Acid / Q000008:administration & dosage* / Q000009:adverse effects; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D006657:Histones / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008805:Mice, Inbred A; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000097:blood; D013312:Stress, Physiological / Q000187:drug effects* / Q000502:physiology
chemical_list: D001786:Blood Glucose; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D016760:Proto-Oncogene Proteins c-fos; D020148:Butyric Acid; D000324:Adrenocorticotropic Hormone; D012964:Sodium; D003345:Corticosterone
keywords: Hypothalamic–pituitary–adrenal axis; PVN; Sodium butyrate; Stress