Individuals suffering from substance-use disorders develop strong associations between the drug's rewarding effects and environmental cues, creating powerful, enduring triggers for relapse. We found that dephosphorylated, nuclear histone deacetylase 5 (HDAC5) in the nucleus accumbens (NAc) reduced cocaine reward-context associations and relapse-like behaviors in a cocaine self-administration model. We also discovered that HDAC5 associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression. Exposure to cocaine and the test chamber induced rapid and transient NPAS4 expression in a small subpopulation of FOS-positive neurons in the NAc. Conditional deletion of Npas4 in the NAc significantly reduced cocaine conditioned place preference and delayed learning of the drug-reinforced action during cocaine self-administration, without affecting cue-induced reinstatement of drug seeking. These data suggest that HDAC5 and NPAS4 in the NAc are critically involved in reward-relevant learning and memory processes and that nuclear HDAC5 limits reinstatement of drug seeking independent of NPAS4. Taniguchi and colleagues find that the epigenetic enzyme, histone deacetylase 5 (HDAC5), reduces relapse-like behaviors in a model of cocaine addiction and that HDAC5 and its target gene, Npas4, are important in the nucleus accumbens for reward-related learning processes.
Bibliographical noteFunding Information:
The authors thank Yuhong Guo, Ben Zirlin, Kelly Girskis, Guohong Xia, and Carly F. Hale for technical assistance and members of the Cowan lab and colleagues at MUSC, McLean Hospital, and UTSW for helpful discussions. We thank Dr. Michael Greenberg for sharing NPAS4 reagents. M.T. was supported by a grant-in-aid of The Fugaku Trust for Medicinal Research and a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation (grant #22765 ). L.N.S. was supported by funds from the Eleanor and Miles Shore HMS Fellowship and the Phyllis and Jerome Lyle Rappaport Foundations . M.B.C. was supported by a NIH predoctoral fellowship ( F31 DA035073 ) and a Rossano Family Fellowship . A.-C.B. received a postdoctoral fellowship from the French Fyssen Foundation . B.W.H. was supported by a NIH predoctoral fellowship ( T32 DA007288 ). R.D.P. was supported by a NIH postdoctoral fellowship ( F32 DA036319 ). This work was supported by grants from the NIH ( DA027664 and DA032708 to C.W.C., DA10460 to D.W.S., MH091220 to Y.L., and DA003906 to P.W.K.). J.S.T. is an Investigator in the Howard Hughes Medical Institute.
© 2017 Elsevier Inc.
- chromatin immunoprecipitation
- cocaine addiction
- conditioned place preference
- drug self-administration
- histone deacetylase
- nucleus accumbens