Histone deacetylase activity and brain-derived neurotrophic factor (BDNF) levels in a pharmacological model of mania

Abstract

Objective: In the present study, we aimed to examine the effects of repeated D-amphetamine (AMPH) exposure, a well-accepted animal model of acute mania in bipolar disorder (BD), and histone deacetylase (HDAC) inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC) and peripheral blood mononuclear cells (PBMCs) of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF) protein and mRNA levels in these samples. Methods: We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li), 200 mg/kg sodium valproate (VPT), 2 mg/kg sodium butyrate (SB), or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma. Results: AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels. Conclusion: Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity.

Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF, NGF and GDNF levels in brain of Wistar rats

“…In the present study, as well as Li and VPA, SB reversed the ouabaininduced hyperactivity in rats. Indeed, in recent studies from our laboratory research it was reported that SB treatment prevented and reversed the manic-like behaviors induced by ouabain and Damphetamine (Arent et al, 2011;Moretti et al, 2011;Resende et al, 2013;Stertz et al, 2014;Valvassori et al, 2013;Steckert et al, 2013).…”

Epigenetic approaches for bipolar disorder drug discovery

“…Moretti et al [75] showed in a rat model of mania induced by d-amphetamine (d-AMPH) that sodium butyrate reversed the d-AMPH-induced hyperactivity, and also the d-AMPHinduced decrease in activity of mitochondrial respiratory chain complexes. In another study using the d-AMPH-induced rat model of mania [107], it was found that the d-AMPH-induced hyperactivity in rats was associated with increased HDAC activity in the PFC of the rats. Lithium and the HDACis sodium valproate and sodium butyrate reversed the increase in locomoter activity and partially reversed the increase in HDAC activity.…”

“…DNMT: DNA methyltransferase; HDAC: Histone deacetylase; NA: Not available. VPA, TSA HDACi Lymphocyte culture [60] VPA HDACi Cultured rat cortical neurons [74] MS-275 HDACi Mouse [106] Sodium butyrate HDACi Rat [75] Sodium butyrate HDACi Rat [107] Sodium butyrate HDACi Rat [108] Sodium butyrate HDACi Rat [109] Sodium butyrate HDACi Rat [110] Cpd-60 HDACi Mouse can cause mania when given to patients with MDD may give some insight into the pathophysiology of MDD and BD.…”

Understanding the molecular mechanisms underlying mood stabilizer treatments in bipolar disorder: Potential involvement of epigenetics

“…[74]. Adding to the acetylating effects of lithium, Stertz and colleagues [75] also showed that therapeutic concentrations of lithium caused reduction in HDAC activity in the prefrontal cortex of rats. As a result, amphetamine induced mania was significantly ameliorated.…”