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

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.

SUBMITTER: Li X

PROVIDER: S-EPMC6026084 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Li Xuan X Carreria Maria B MB Witonsky Kailyn R KR Zeric Tamara T Lofaro Olivia M OM Bossert Jennifer M JM Zhang Jianjun J Surjono Felicia F Richie Christopher T CT Harvey Brandon K BK Son Hyeon H Cowan Christopher W CW Nestler Eric J EJ Shaham Yavin Y

Biological psychiatry 20171229 3

<h4>Background</h4>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.<h4>Methods</h4>In experiment 1 (overexpression), we injected an adeno-associated virus bilaterally into dorsal striatum to e ...[more]

PMID: 29397902

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Project description:We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence (using a discrete choice procedure between methamphetamine and food; 20 trials/d) for 19 d. We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization colabeling results, we tested the causal role of DMS D1 and D2 family receptors, and DMS neuronal ensembles in "incubated" methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively. Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of methamphetamine craving). The incubated response was associated with increased Fos expression in DMS but not in DLS; Fos was colabeled with both Drd1 and Drd2 DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMS on abstinence day 18 decreased incubated methamphetamine seeking on day 21. Results demonstrate a role of DMS dopamine D1 and D2 receptors in the incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation. SIGNIFICANCE STATEMENT:In human addicts, abstinence is often self-imposed and relapse can be triggered by exposure to drug-associated cues that induce drug craving. We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we used classical pharmacology, in situ hybridization, immunohistochemistry, and the Daun02 inactivation procedure to demonstrate a critical role of dorsomedial striatum neuronal ensembles in this new form of incubation of drug craving.

Project description:BackgroundThe incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (CP-AMPARs). Through metabotropic glutamate receptor 1 (mGluR1)-mediated synaptic depression, mGluR1 positive allosteric modulators remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving.MethodsRats self-administered saline or methamphetamine under extended-access conditions. Cue-induced seeking tests demonstrated incubation of methamphetamine craving. After withdrawal periods ranging from 1 to >40 days, rats underwent one of the following procedures: 1) whole-cell patch clamp recordings to characterize AMPAR transmission, 2) intra-NAc core injection of the CP-AMPAR antagonist 1-naphthyl acetyl spermine followed by a seeking test, or 3) systemic administration of a mGluR1 positive allosteric modulator followed by a seeking test.ResultsIncubation of methamphetamine craving was associated with CP-AMPAR accumulation in NAc core, and both effects were maximal after ~1 week of withdrawal. Expression of incubated craving was decreased by intra-NAc core 1-naphthyl acetyl spermine injection or systemic mGluR1 positive allosteric modulator administration.ConclusionsThese results are the first to demonstrate a role for the NAc in the incubation of methamphetamine craving and describe adaptations in synaptic transmission associated with this model. They establish that incubation of craving and associated CP-AMPAR plasticity occur much more rapidly during withdrawal from methamphetamine compared with cocaine. However, a common mGluR1-based therapeutic strategy may be helpful for recovering cocaine and methamphetamine addicts.

Project description:Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose-response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.

Dataset Information

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

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

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