Repeated exposure to cocaine leads to changes in behavior that contribute to drug addiction. Such behavioral changes are thought to result from epigenetic modifications in response to chronic exposure to the drug. Members of the class IIa family of histone deacetylase (HDAC) proteins, such as HDAC5, which deacetylate chromatin and inhibit gene expression, are implicated in modulating behavioral responses to cocaine (see commentary by West). Taniguchi et al. found that increases in cyclic adenosine monophosphate (cAMP) signaling in rat striatal neurons stimulated the nuclear accumulation of a fluorescently tagged form of HDAC5. Sequence analysis revealed that the nuclear localization sequence of HDAC5 contained a conserved serine residue, Ser279. Increased cAMP signaling resulted in a decrease in the abundance of HDAC5 phosphorylated at Ser279 (HDAC5 S279), which was caused by protein phosphatase 2A (PP2A), whose activity was increased by cAMP. Dephosphorylation of Ser279 was required for the nuclear translocation of HDAC5 in response to cAMP. Injection of mice with cocaine led to a decrease in the abundance of HDAC5 S279 and an increase in the nuclear localization of HDAC5. The authors performed cocaine-conditioned place preference assays on mice that retrovirally expressed wild-type or mutant forms of HDAC5 in the nucleus accumbens and found that mice expressing a mutant HDAC5 mimicking the dephosphorylated state exhibited reduced cocaine place preference. Dephosphorylation of HDAC5 had no effect on the behavior of mice in a sucrose preference assay. Together, these data suggest that cocaine, through a cAMP-dependent mechanism, increases the nuclear accumulation of HDAC5, which leads to inhibition of cocaine reward after long exposure to the drug.
M. Taniguchi, M. B. Carreira, L. N. Smith, B. C. Zirlin, R. L. Neve, C. W. Cowan, Histone deacetylase 5 limits cocaine reward through cAMP-induced nuclear import. Neuron 73, 108–120 (2012). [Online Journal]
A. E. West, Regulated shuttling of the histone deacetylase HDAC5 to the nucleus may put a brake on cocaine addiction. Neuron 73, 1–3 (2012). [Online Journal]