FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors

•Rats were treated with histone deacetylase (HDAC) inhibitors for seven days.•The two inhibitors used were selective for a subset of class I HDAC enzymes.•Treatment resulted in brain glucose uptake changes as measured by PET imaging.•The study is the first to image chronic HDAC inhibitor effects using FDG-PET. The purpose of this work – the first of its kind – was to evaluate the impact of chronic selective histone deacetylase (HDAC) inhibitor treatment on brain activity using uptake of the radioligand 18F-fluorodeoxyglucose and positron emission tomography (18FDG-PET). HDAC dysfunction and other epigenetic mechanisms are implicated in diverse CNS disorders and animal research suggests HDAC inhibition may provide a lead toward developing improved treatment. To begin to better understand the role of the class I HDAC subtypes HDAC 1, 2 and 3 in modulating brain activity, we utilized two benzamide inhibitors from the literature, compound 60 (Cpd-60) and CI-994 which selectively inhibit HDAC 1 and 2 or HDACs 1, 2 and 3, respectively. One day after the seventh treatment with Cpd-60 (22.5mg/kg) or CI-994 (5mg/kg), 18FDG-PET experiments (n=11–12 rats per treatment group) revealed significant, local changes in brain glucose utilization. These 2–17% changes were represented by increases and decreases in glucose uptake. The pattern of changes was similar but distinct between Cpd-60 and CI-994, supporting that 18FDG-PET is a useful tool to examine the relationship between HDAC subtype activity and brain activity. Further work using additional selective HDAC inhibitors will be needed to clarify these effects as well as to understand how brain activity changes influence behavioral response.