CREST in the nucleus accumbens core regulates cocaine conditioned place preference, cocaine-seeking behavior, and synaptic plasticity
- Yasaman Alaghband1,2,3,
- Enikö Kramár1,2,
- Janine L. Kwapis1,2,4,
- Earnest S. Kim5,
- Thekla J. Hemstedt1,2,
- Alberto J. López1,2,3,
- André O. White1,2,3,
- Amni Al-Kachak1,2,
- Osasumwen V. Aimiuwu1,2,
- Kasuni K. Bodinayake1,2,
- Nicole C. Oparaugo1,2,
- Joseph Han1,2,
- K. Matthew Lattal5, and
- Marcelo A. Wood1,2,3,4
- 1Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, California, 92697
- 2Center for the Neurobiology of Learning and Memory (CNLM), Irvine, California, 92697
- 3Irvine Center for Addiction Neuroscience (ICAN), University of California, Irvine, Irvine, California 92697
- 4Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California, 92697
- 5Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239
- Corresponding Author: Marcelo A. Wood, Address: Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, 2205 McGaugh Hall, Irvine, CA, 92697, Email: mwood{at}uci.edu, Phone: (949)824-2259
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Author contributions: Y.A., E.A.K., J.L.K., E.S.K., M.L., and M.A.W. designed research; Y.A., E.A.K., J.L.K., E.S.K., T.J.H., A.J.L., A.O.W., A.A.-K., O.V.A., K.K.B., N.C.O., and J.H. performed research; Y.A., E.A.K., E.S.K., and M.L. analyzed data; Y.A., E.A.K., E.S.K., M.L., and M.A.W. wrote the paper.
Abstract
Epigenetic mechanisms result in persistent changes at the cellular level that can lead to long-lasting behavioral adaptations. Nucleosome remodeling is a major epigenetic mechanism that has not been well explored with regards to drug-seeking behaviors. Nucleosome remodeling is carried out by multi-subunit complexes that interact with DNA or chromatin structure and possess an ATP-dependent enzyme to disrupt nucleosome-DNA contacts and ultimately regulate gene expression. Calcium RESponsive Transactivator (CREST) is a transcriptional activator that interacts with enzymes involved in both histone acetylation and nucleosome remodeling. Here, we examined the effects of knocking down CREST in the nucleus accumbens (NAc) core on drug-seeking behavior and synaptic plasticity in male mice as well as drug-seeking in male rats. Knocking down CREST in the NAc core results in impaired cocaine-induced conditioned place preference (CPP) as well as theta-induced long-term potentiation (LTP) in the NAc core. Further, similar to the CPP findings, using a self-administration procedure, we found that CREST knockdown in the NAc core of male rats had no effect on instrumental responding for cocaine itself on a first-order schedule, but did significantly attenuate responding on a second-order chain schedule, in which responding has a weaker association with cocaine. Together, these results suggest that CREST in the NAc core is required for cocaine-induced CPP, synaptic plasticity, as well as cocaine-seeking behavior.
SIGNIFICANCE STATEMENT
This study demonstrates a key role for the role of Calcium RESponsive Transactivator (CREST), a transcriptional activator, in the nucleus accumbens (NAc) core with regards to cocaine-induced conditioned place preference (CPP), self-administration (SA), and synaptic plasticity. CREST is a unique transcriptional regulator that can recruit enzymes from two different major epigenetic mechanisms: histone acetylation and nucleosome remodeling. In this study we also found that the level of potentiation in the NAc core correlated with whether or not animals formed a conditioned place preference. Together the results indicate that CREST is a key downstream regulator of cocaine action in the NAc.
Footnotes
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The authors declare no competing financial interests.
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We thank Evan Jeffries and Kay Linker for critical feedback on the manuscript. This work was supported by the National Institute on Drug Abuse grant (DA025922) to KML and MAW, the National Institute of Mental Health grant (MH101491) to MAW, and National Institute on Drug Abuse and National Institute on Aging grants (F32 DA043998 and T32 AG000096-33) to YA.
- Received October 9, 2017.
- Revision received August 29, 2018.
- Accepted September 6, 2018.
- Copyright © 2018 the authors
