These studies in drug abuse, together with findings in models of leaning and memory, depression, and chronic pain, suggest that histone acetylation controls the saliency of a wide variety of environmental stimuli [20, 34, 53, 54, 57, 58, 79, 80]. In fear conditioning, a commonly used behavioral test of learning and memory, HDAC inhibitors significantly improve formation of long-term memory [57, 58]. In social defeat stress, a behavioral model which elicits a depression-like syndrome in mice [81, 82], mice lacking HDAC5 develop a stronger depressive-like syndrome than wild type mice [54]. After spinal nerve injury, which elicits a chronic pain syndrome, HDAC5 knockout mice also become hyperalgesic to mechanical stimuli [79]. While reduced HDAC activity hypersensitizes mice to stress or pain, it also significantly potentiates the efficacy of several antidepressants [79, 83, 84]. Finally, as discussed above, inhibition of HDACs in the NAc potentiates the rewarding effect of psychostimulants while overexpressing HDACs in this brain region attenuates this behavior [53, 54]. Thus, pharmacological and genetic manipulations that result in elevated histone acetylation appear to potentiate the saliency of many types of environmental stimuli.
