ABSTRACT: Some individuals are more vulnerable than others to chronic psychiatric illnesses, such as drug addiction or depression, but the neural and molecular mechanisms responsible for this are poorly understood. Although addiction and depression are known to have a strong genetic component, recent evidence has suggested that epigenetic mechanisms, such as histone acetylation, may also contribute. However, the mechanisms which integrate drugs of abuse or stress with changes in chromatin structure remain unclear. Here, we identify the activity-dependent class II histone deacetylase, HDAC5, as a central integrator of these stimuli with changes in chromatin structure and gene expression. We found that chronic, but not acute, exposure to cocaine or stress decreases HDAC5 function in the nucleus accumbens (NAc), a major brain reward region, which allows for increased histone acetylation and transcription of HDAC5 target genes. This regulation is behaviorally important, as loss of HDAC5 causes hypersensitive responses to chronic, not acute, cocaine or stress. Coupling gene expression microarrays and several bioinformatic approaches, we have gone on to identify the most likely HDAC5 target genes responsible for the behavioral maladaptations. One HDAC5 target, the Substance P Receptor, is upregulated in HDAC5 knockout mice, has increased histone acetylation on its promoter, and modulates cocaine reward, as measured by conditioned place preference. These findings suggest that proper balance of histone acetylation is a crucial factor in the saliency of a given emotional stimulus, and that disruption of this balance is involved in the transition from normal adaptive responses to chronic psychiatric illness. Keywords: genetic modification and its impact on cocaine responses in the nucleus accumbens
