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Biol Psychiatry. 2018 Aug 1;84(3):213-222. doi: 10.1016/j.biopsych.2017.12.008. Epub 2017 Dec 29.

Role of Dorsal Striatum Histone Deacetylase 5 in Incubation of Methamphetamine Craving.

Author information

1
Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland. Electronic address: annali@umd.edu.
2
Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas.
3
Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland.
4
CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
5
Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, South Korea.
6
Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina.
7
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York.

Abstract

BACKGROUND:

Methamphetamine (meth) seeking progressively increases after withdrawal (incubation of meth craving). We previously demonstrated an association between histone deacetylase 5 (HDAC5) gene expression in the rat dorsal striatum and incubation of meth craving. Here we used viral constructs to study the causal role of dorsal striatum HDAC5 in this incubation.

METHODS:

In experiment 1 (overexpression), we injected an adeno-associated virus bilaterally into dorsal striatum to express either green fluorescent protein (control) or a mutant form of HDAC5, which strongly localized to the nucleus. After training rats to self-administer meth (10 days, 9 hours/day), we tested the rats for relapse to meth seeking on withdrawal days 2 and 30. In experiment 2 (knockdown), we injected an adeno-associated virus bilaterally into the dorsal striatum to express a short hairpin RNA either against luciferase (control) or against HDAC5. After training rats to self-administer meth, we tested the rats for relapse on withdrawal days 2 and 30. We also measured gene expression of other HDACs and potential HDAC5 downstream targets.

RESULTS:

We found that HDAC5 overexpression in dorsal striatum increased meth seeking on withdrawal day 30 but not day 2. In contrast, HDAC5 knockdown in the dorsal striatum decreased meth seeking on withdrawal day 30 but not on day 2; this manipulation also altered other HDACs (Hdac1 and Hdac4) and potential HDAC5 targets (Gnb4 and Suv39h1).

CONCLUSIONS:

Results demonstrate a novel role of dorsal striatum HDAC5 in incubation of meth craving. These findings also set up future work to identify HDAC5 targets that mediate this incubation.

KEYWORDS:

Dorsal striatum; Epigenetics; HDAC5; Incubation; Methamphetamine; Relapse

PMID:
29397902
PMCID:
PMC6026084
[Available on 2019-08-01]
DOI:
10.1016/j.biopsych.2017.12.008

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