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Published in final edited form as: Biol Psychiatry. 2017 Dec 29;84(3):213–222. doi: 10.1016/j.biopsych.2017.12.008

Role of dorsal striatal histone deacetylase 5 in incubation of methamphetamine craving

Xuan Li, Maria B Carreria 2, Kailyn FR Witonsky 1, Tamara Zeric 1, Olivia M Lofaro, Jennifer M Bossert 1, Jianjun Zhang 3, Felicia Surjono 1, Christopher T Richie 1, Brandon K Harvey 1, Hyeon Son 4, Christopher W Cowan 5, Eric J Nestler 6,*, Yavin Shaham 1,*
PMCID: PMC6026084  NIHMSID: NIHMS931052  PMID: 29397902

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 rat dorsal striatum and incubation of Meth craving. Here we used viral constructs to study the causal role of dorsal striatal HDAC5 in this incubation.

Methods

In Exp. 1 (over-expression), we injected adeno-associated virus (AAV) bilaterally into dorsal striatum to express either GFP (control) or a mutant form of HDAC5 (mHDAC5), which strongly localized to the nucleus. After training rats to self-administer Meth (10 days, 9 h/d), we tested the rats for relapse to Meth seeking on withdrawal days 2 and 30. In Exp. 2 (knockdown), we injected AAV bilaterally into dorsal striatum to express either a short hairpin RNA against luciferase (shLUC, control) or against HDAC5 (shHDAC5). 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 dorsal striatum decreased Meth seeking on withdrawal day 30 but not 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 striatal HDAC5 in incubation of Meth craving. These findings also set up future work to identify HDAC5 targets that mediate this incubation.

Keywords: methamphetamine, incubation, HDAC5, dorsal striatum, epigenetics, relapse

Introduction

A key feature of drug addiction is high relapse rates during abstinence (1, 2). In rats, drug seeking progressively increases or incubates after withdrawal from drug self-administration (3–5). This incubation phenomenon was observed in rats across several drug classes (6–10), including methamphetamine (Meth) (11). Incubation of Meth craving was also observed in Meth-dependent patients (12). Recently, we and others have begun to explore mechanisms of incubation of Meth craving (13–17), extending previous studies that primarily focused on incubation of cocaine craving (4, 5, 18). In these studies, we found that reversible inactivation of either central amygdala (16) or dorsal striatum (DS) (15) decreased “incubated” Meth seeking after prolonged withdrawal. The Wolf group demonstrated a critical role of calcium-permeable AMPA receptors in nucleus accumbens (NAc) in this incubation (17). We also used a choice-based procedure to achieve voluntary abstinence and found that either systemic injections of a positive regulator of mGluR2 (AZD8529) (13) or inactivation of relapse-test activated Fos-neurons in dorsomedial striatum (14) decreased incubated Meth seeking after voluntary abstinence.

In the current study, we examined the role of the epigenetic enzyme, histone deacetylase 5 (HDAC5), in DS in incubation of Meth craving. HDAC5 is a member of class IIa HDACs that also includes HDAC4, 7 and 9 (19). Like other HDACs, HDAC5 generally suppresses gene expression by deacetylating histones (20). HDAC5 regulates gene expression and other signaling pathways in an activity-dependent manner by shuttling between the nucleus and cytoplasm, depending on its phosphorylation state (21, 22). Previous studies have shown that systemic injections of non-specific HDAC inhibitors decrease reinstatement of cocaine-induced conditioned place preference (CPP) in mice (23), and reinstatement of cocaine (24) and nicotine (25) seeking in rats, but enhance heroin seeking in rats (26). The Wood group demonstrated in mice that systemic injections of an HDAC3 (a class-I HDAC) inhibitor facilitate cocaine CPP extinction (27) while genetic deletion of HDAC3 in NAc enhances cocaine CPP acquisition (28). Kennedy et al. (29) found in mice that genetic deletion of HDAC1 (another class-I HDAC) in NAc or NAc injections of a class-I HDAC inhibitor decrease cocaine locomotor sensitization.

Here, we focused on HDAC5 in DS based on both earlier studies with cocaine and our recent study with Meth. For cocaine, previous studies showed a role of NAc HDAC5 in cocaine locomotor sensitization and CPP (30, 31); a recent study also showed a role of NAc HDAC5 in cocaine CPP and reinstatement induced by exposure to cocaine cues and cocaine priming injections (32). For Meth, we found that Hdac5 mRNA expression is increased in both DS homogenates and relapse-test activated DS neurons after prolonged withdrawal, when Meth seeking is high (15). Based on the latter evidence, we hypothesized that HDAC5 positively regulates incubation of Meth craving. There are no specific pharmacological compounds to manipulate HDAC5 function (33). Therefore, we used viral approaches to either overexpress or knockdown DS HDAC5 expression and determined whether these manipulations would increase or decrease, respectively, incubation of Meth craving. To overexpress HDAC5, we used an adeno-associated virus (AAV) expressing a mutant form of HDAC5 that increases its nuclear localization (32). To knockdown HDAC5 expression, we used an AAV expressing a short-hairpin against Hdac5 mRNA (34). After HDAC5 knockdown, we also measured mRNA expression of other DS HDACs (to determine whether HDAC5 knockdown leads to compensatory changes of other HDACs) and potential HDAC5 downstream targets identified in the previous study with HDAC5 knockout mice (30). Finally, we determined the effect of HDAC5 knockdown within either dorsomedial or dorsolateral striatum (DMS or DLS) on incubation of Meth craving to determine the role of HDAC5 in the two major DS anatomical sub-regions in this incubation.

Methods and Materials

Subjects, apparatus, intravenous surgery, meth self-administration, withdrawal phase, and relapse tests

See Supplemental Online Material (SOM)

AAV preparation & injections; immunohistochemistry, image acquisition & HDAC5 immunofluorescence quantification, RNA extraction, cDNA synthesis & qPCR, Immunoblotting

See SOM

Exp. 1: Effect of overexpressing nuclear HDAC5 in DS on incubation of Meth craving (Fig. 2A)

Figure 2. Overexpressing nuclear HDAC5 in dorsal striatum (DS) potentiated incubation of Meth craving.

Figure 2

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(A) Timeline of the experiment. (B) Left: representative anatomical locations of AAV injections (red dots) into DS [mm from Bregma (97)]; Right: representative images of GFP immunostaining from AAV-GFP group, HDAC5 immunostaining from AAV-mHDAC5 group, and HDAC5 (red) +DAPI (blue) double staining from AAV-mHDAC5 group (C) Left: representative images of HDAC5 immunostaining from DS of AAV-GFP and AAV-mHDAC5 groups; Right: relative HDAC5 fluorescent intensity in DS. Data are presented as fold change of mean values in the AAV-GFP group. * p<0.001; n=10-13 per group. Error bars indicate SEM. (D) Relapse test on withdrawal days 2 and 30: Data are mean±SEM of responses on the previously active lever and on the inactive lever during the 30-min relapse test on withdrawal day 2 and the first 30 min of the 3-h relapse test on withdrawal day 30. * Different from day 2, p<0.05, n=10-13 per group. (E) Relapse test on withdrawal day 30: Data are mean±SEM of responses on the previously active lever and on the inactive lever during the 3-h relapse test. During testing, lever-presses led to contingent presentations of the tone-light cue previously paired with Meth infusions during training, but not Meth. * Different from AAV-GFP, p<0.01, n=10-13 per group.

We performed intravenous surgery on two groups of rats (total n=23) and injected AAV2-GFP (n=10) or AAV2-mHDAC5 (n=13) bilaterally into the DS (see SOM and Fig. 2B). A week after surgery, we trained both groups of rats for Meth self-administration. On withdrawal day 2, we tested the rats for relapse to Meth seeking in a 30-min session. On withdrawal day 30, we tested the rats for relapse in a 3-h session. Active lever-presses during testing [the operational measure of drug seeking in incubation of craving studies (3, 4)] resulted in contingent presentations of the tone-light cue, previously paired with Meth infusions, but not the drug. After the final relapse test, we perfused the rats and processed their brains for immunohistochemistry (both GFP and HDAC5; see SOM). The duration of the test session on day 1 was 30 min to minimize carryover effect of extinction learning, which may subsequently decrease drug seeking on day 30 testing (35, 36).

We also validated HDAC5 knockdown at the protein levels in drug-naïve rats. We injected AAV-mHDAC5 into one DS hemisphere and AAV-mHDAC5 into the other hemisphere. Three weeks later, when AAV expression is maximal (37), we collected DS tissue for subsequent immunoblotting assays (see SOM and Fig. S1A).

Exp. 2: Effect of knocking down HDAC5 expression DS on incubation of Meth craving (Fig. 3A)

Figure 3. Knocking down HDAC5 expression in DS decreased incubation of Meth craving.

Figure 3

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(A) Timeline of the experiment. (B) Left: representative anatomical location of AAV injections (red dots) DS [mm from Bregma (97)]; Right: a representative schematic of DS tissue collection (red circle). (C) Hdac mRNA expression. Data are presented as fold change of mean values in the AAV-shLUC group. Error bars indicate SEM. * p<0.05; n=9-11 per group (D) Relapse test on withdrawal days 2 and 30: Data are mean±SEM of responses on the previously active lever and on the inactive lever during the 30-min relapse test on withdrawal day 2 and the first 30 min of the 3-h relapse test on withdrawal day 30. * Different from day 2, p<0.05, n=11 per group. (E) Relapse test on withdrawal day 30: Data are mean±SEM of responses on the previously active lever and on the inactive lever during the 3-h relapse test. * Different from AAV-shHDAC5, p<0.01, n=11 per group. (F) Gene expression of potential HDAC5 targets. Data are presented as fold change of mean values in the AAV-shLUC group. Error bars indicate SEM. *p<0.05; n=10-11 per group.

We performed intravenous surgery on two groups of rats (total n=22) and injected AAV-shLUC (n=11) or AAV-shHDAC5 (n=11) bilaterally into the DS (see SOM). A week after surgery, we trained both groups of rats for Meth self-administration. On withdrawal day 2, we tested the rats for relapse in a 30-min session. On withdrawal day 30, we tested the rats for relapse in a 3-h session. After the final relapse tests, we collected DS tissue for subsequent qPCR analysis.

We also independently validated HDAC5 knockdown at both the mRNA (n=4) and protein (n=4) levels in drug-naïve rats. We injected AAV-shLUC into the DS of one hemisphere and AAV-shHDAC5 into the other hemisphere. We collected DS tissue three weeks for subsequent qPCR and immunoblotting assays (Fig. S1B).

Exp. 3: Effect of knocking down HDAC5 expression in DMS or DLS on incubation of Meth craving (Fig. S2 and Fig. S3)

We performed intravenous surgery on four groups of rats (total n=47). We injected AAV-shLUC or AAV-shHDAC5 into DMS (AAV-shLUC, n=11; AAV-shHDAC5, n=13) or DLS (AAV-shLUC, n=10; AAV-shHDAC5, n=13). A week after surgery, we trained the rats for Meth self-administration. On withdrawal day 2, we tested the rats for relapse in a 30-min session. On withdrawal day 30, we tested the rats for relapse in a 3-h session. After the final relapse tests, we collected DMS and DLS tissue for subsequent qPCR analysis.

Statistical analysis

See SOM

Results

Exp. 1: Effect of overexpressing nuclear HDAC5 in DS on incubation of Meth craving

The goal of Exp. 1 was to examine whether DS HDAC5 plays a sufficient role in incubation of Meth craving. For this purpose, we delivered AAV into the DS to overexpress a nuclear-localized HDAC5 (AAV-mHDAC5, Fig. 2B-C) and examined whether this overexpression would increase incubation on Meth craving.

Self-administration training (Fig. 1A)

Figure 1. Meth self-administration training.

Figure 1

Open in a new tab

Data are mean ± SEM number of Meth infusions (0.1 mg/kg/infusion) and active and inactive lever-presses during the ten 9-h daily self-administration sessions for Exp. 1 (total n=23) and Exp. 2 (total n=22). During training, active lever presses were reinforced on an FR1 20-s timeout reinforcement schedule and Meth infusions were paired with a 5-s tone-light cue.

See SOM

HDAC5 protein expression (Fig. 2C)

AAV-mHDAC5 group showed ~2-fold increase of HDAC5 immunofluorescence intensity in DS compared with the AAV-GFP group (t21=4.5, p<0.001). We also validated AAV-mHDAC5 using immunoblotting in drug-naïve rats and obtained similar results (Fig. S1A).

Relapse tests (Fig. 2D-E)

DS HDAC5 overexpression increased Meth seeking on withdrawal day 30, but not day 2. As we tested the rats for relapse in a 30-min session on day 2 and in a 3-h session on day 30, we performed two analyses. The first analysis of the relapse tests on day 2 and 30 included the between-subjects factor of Virus Condition (AAV-GFP, AAV-mHDAC5), the within-subjects factor of Withdrawal Day (2, 30), and inactive lever as a covariate; for this analysis, we used the data from the 30-min relapse test on day 2 and the first 30 min of the relapse test on day 30. The analysis showed significant main effects of Withdrawal Day (F1,19=42.9, p<0.001) and Virus Condition (F1,19=5.6, p=0.029) and an approaching significant interaction between the two factors (F1,19=3.5, p=0.075). The second analysis of day 30 only included the between-subjects factor of Virus Condition, the within-subjects factor of Session Minute (30 min intervals), and inactive lever as a covariate; for this analysis, we used the data from the 3-h relapse test. The analysis showed main effects of Virus Condition (F1,21=5.4, p=0.030) and Session Minutes (F5,105=34.6, p<0.001), but no interaction between the two factors (p>0.1); the lack of interaction suggests that HDAC5 over-expression had no effect on within-session extinction learning.

In summary, the data in Exp. 1 demonstrated that DS HDAC5 overexpression modestly potentiated incubated Meth seeking, and establish that HDAC5 in this region plays a sufficient role in this incubation.

Exp. 2: Effect of knocking down HDAC5 expression in DS on incubation of Meth craving

The goal of Exp. 2 was to examine whether HDAC5 also plays a necessary role in incubation of Meth craving. For this purpose, we delivered AAV into the DS to express a short-hairpin RNA against HDAC5 (AAV-shHDAC5), which decreased Hdac5 expression at both the mRNA and protein levels (Fig. S1). We examined whether this downregulation would decrease incubation of Meth craving. We used AAV expressing a short hairpin RNA against nanoluciferase, not expressed in mammals, as the control AAV (AAV-shLUC).

Self-administration training (Fig. 1B)

See SOM

Gene expression of HDACs (Fig. 3C)

We first validated HDAC5 knockdown in DS of drug-naïve rats (Fig. S1). HDAC5 of the AAV-shHDAC5 injected hemisphere decreased to ~50% of AAV-shLUC injected hemispheres at both the mRNA (t3=6.8, p=0.006) and protein (t3=4.3, p=0.023) levels. HDAC5 knockdown (Fig. 3C; t19=12.7, p<0.001) also led to a compensatory increase in expression of Hdac1 and Hdac4 mRNA levels (Hdac1: t19=2.7, p=0.015; Hdac4: t19=2.6, p=0.016).

Relapse tests (Fig. 3D-E)

HDAC5 knockdown decreased Meth seeking on withdrawal day 30, but not day 2. We performed two analyses identical to those described in Exp. 1. The first analysis of days 2 and 30 included the between-subjects factor of Virus Condition (AAV-shLUC, AAV-shHDAC5), the within-subjects factor of Withdrawal Day, and inactive lever as a covariate; for this analysis, we used the data from the 30-min relapse test on day 2 and the first 30 min of the relapse test on day 30. The analysis showed a significant interaction between Withdrawal Day and Virus Condition (F1,18=12.0, p=0.003). The second analysis of day 30 included the between-subjects factor of Virus Condition, the within-subjects factor of Session Minutes, and inactive lever as a covariate; for this analysis, we used the data from the 3-h relapse test. This analysis showed a significant interaction between Virus Condition and Session Minutes (F5,100=5.1, p<0.001).

Gene expression of potential HDAC5 targets (Fig. 3F)

Based on previous study in HDAC5 knockout mice (30), we measured mRNA expression of ten HDAC5 targets. Consistent with previous findings, Gnb4 and Suv39h1 in the DS of the AAV-shHDAC5 group increased compared with AAV-shLUC controls (Gnb4: t19=3.0, p=0.007; Suv39h1: t19=3.1, p=0.006). In contrast, other genes either did not change (Grin2a, Kcnk4, Kcnq5, Rgs20, Rapgef6, Abca5, Cuedc1, p>0.05) or decreased (Tacr1: t19=2.7, p=0.015).

In summary, the data in Exp. 2 demonstrated that dorsal striatal HDAC5 knockdown decreased incubated Meth seeking, indicating that HDAC5 in this brain region plays an important role in incubation of Meth craving. Additionally, downregulation of HDAC5 led to increased expression of other HDACs and some HDAC5 targets.

Exp. 3: Effect of knocking down HDAC5 expression in DMS or DLS on incubation of Meth craving

The goal of Exp. 3 was to examine whether the role of DS HDAC5 in incubation of Meth craving is sub-region specific. For this purpose, we delivered AAV-shHDAC5 into either DMS or DLS and examined whether downregulation of HDAC5 in either region would decrease incubation of Meth craving.

Self-administration training (Fig. S2)

See SOM.

Gene expression of HDAC5 (Fig. S3C)

We validated HDAC5 knockdown in DMS and DLS. HDAC5 expression in DMS or DLS of the AAV-shHDAC5 group decreased to ~50% of its respective AAV-shLUC group (DMS: t20=7.8, p<0.001; DLS: t20=8.0, p<0.001).

Relapse tests (Fig. S3D-F)

HDAC5 knockdown in DMS or DLS had no significant effect on Meth seeking on either withdrawal day 2 or 30. We analyzed the DMS and DLS HDAC5 knockdown experiments separately. We performed two analyses in each experiment like those described in Exp. 1, except that we did not use inactive lever presses as a covariate (see SOM). The first analysis included the between-subjects factor of Virus Condition and the within-subjects factor of Withdrawal Day; for this analysis, we used the data from the 30-min relapse test on day 2 and the first 30 min of the relapse test on day 30. The analysis showed significant main effects of Withdrawal Day (DMS: F1,22=20.2, p<0.001; DLS: F1,21=62.4, p<0.001), but not Virus Condition (DMS: F1,22=0.6, p=0.811; DLS: F1,21=3.2, p=0.087). For the DMS, the interaction between the two factors was not significant (p>0.05), whereas for the DLS the interaction was approaching statistical significance (F1,21=3.5, p=0.074). The second analysis of day 30 included the between-subjects factor of Virus Condition and the within-subjects factor of Session Minutes; for this analysis, we used the data from the 3-h relapse test. This analysis showed a main effect of Session Minute (DMS: F5,110=18.3, p<0.001; DLS: F5,105=29.5, p<0.001), but again no interaction between Virus Condition and Session Minutes (p values>0.05).

In summary, the data in Exp. 3 demonstrated that HDAC5 knockdown in DMS or DLS alone had no significant effect on incubated Meth seeking.

Discussion

We used AAVs to study the role of HDAC5 in DS in incubation of Meth craving. The main finding of our study is that HDAC5 overexpression or knockdown in DS increased or decreased, respectively, ‘incubated’ Meth seeking during late withdrawal. In contrast, neither HDAC5 overexpression nor knockdown in DS influenced Meth seeking during early withdrawal. Additionally, HDAC5 knockdown in DS changed the transcriptional profiles of some of its putative downstream targets and increased the expression of other Hdacs (Hdac1 and 4). Finally, HDAC5 knockdown in either DMS or DLS alone had no effect on incubation of Meth craving. Together, our results demonstrated that HDAC5 function in the entire DS, but not a specific sub-region, plays an important role in incubation of Meth craving.

Role of epigenetic mechanisms in DS in animal models of addiction

Previous studies on epigenetic mechanisms assessed cocaine-induced psychomotor stimulation and CPP (28–31, 38–44), cocaine self-administration (40, 45–50), extinction of cocaine or morphine CPP (23, 27, 51–53), and cocaine cue- and cocaine priming-induced reinstatement (24, 44, 54). Recent epigenetic studies also examined extinction and reinstatement of nicotine seeking (25), heroin-priming induced reinstatement (26), and alcohol consumption (55–59). However, only one published study has examined the causal role of persistent epigenetic adaptations in drug seeking after prolonged withdrawal from extended access drug self-administration. Massart et al. (60) reported that incubation of cocaine craving is associated with time-dependent changes of DNA methylation in NAc and that DNA methylation positively regulates this incubation. Our current study extends this previous work and provides new evidence that histone modification plays a causal role in persistent drug seeking after prolonged withdrawal.

Our results on the role of epigenetic mechanisms in DS in relapse extend previous studies on the role of epigenetic changes in the NAc (41, 42), mPFC (46, 48, 57), amygdala (56), and VTA (51, 61) in the behavioral effects of addictive drugs. Our results are also in agreement with previous studies on the role of DS (either DMS or DLS, or both) in cue- or context-induced cocaine (62–65), Meth (15, 66), and heroin (67) seeking. Recent evidence also indicates a role of DS in alcohol taking and seeking (68–74).

Regarding epigenetic mechanisms in DS, the only evidence available comes from the Kenny group who demonstrated critical roles of local microRNA-212 (75) and methyl CpG binding protein 2 (MeCP2, a transcriptional repressor) (50) in escalation of cocaine self-administration. Taken together with our data, these findings highlight the role of epigenetic mechanisms in DS in drug reward and relapse.

Role of striatal HDAC5 in the behavioral effects of psychostimulant drugs

Our focus on HDAC5 was initially inspired by two publications on the role of HDAC5 in cocaine’s effects. At the molecular level, Renthal et al. (30) and Taniguchi et al. (31) demonstrated that repeated cocaine exposure induces transient changes in striatal HDAC5 activity. At the behavioral level, Renthal et al. (30) reported that HDAC5 knockout mice show increased cocaine CPP and that viral overexpression of HDAC5 in NAc decreases drug CPP. Taniguchi et al. (31) reported that viral overexpression of a nuclear-localized HDAC5 in NAc decreases cocaine CPP. Very recently, Taniguchi et al (32) extended their previous findings and reported that viral overexpression of the nuclear-localized HDAC5 decreases cue-induced and cocaine priming-induced reinstatement of cocaine seeking. Overall, these data indicate that cocaine alters HDAC5 activity in NAc and that HDAC5 in NAc negatively regulates cocaine reward and relapse.

In contrast, we found a time-dependent increase of Hdac5 mRNA expression in rat DS (but not NAc, unpublished data) when Meth seeking is high (incubated) (15). Together with our current study, these data indicate that HDAC5 in DS positively regulates incubation of Meth craving. What might account for the different roles of striatal HDAC5?

One factor is the duration and amount of drug exposure, which are significantly lower in CPP or short-access self-administration than in extended-access self-administration studies. Indeed, it is well-established that extended drug self-administration causes different physiological and behavioral effects from cocaine CPP or short-access cocaine self-administration (5, 76–78). Another factor is the drug itself: cocaine versus Meth. Recent evidence suggests that the mechanisms of relapse to cocaine and Meth seeking are at least partially dissociable (79). For example, we found that inactivation of ventral mPFC, which inhibits incubation of cocaine craving (80), has no effect on incubation of Meth craving (16). Additionally, Fos expression in NAc only increased after context-induced reinstatement of cocaine but not Meth seeking (66, 81).

As an epigenetic enzyme, HDAC5 can affect many genes (30), which leads to two final questions: 1) What are HDAC5’s targets? and 2) Does HDAC5 exerts its role in incubation of Meth craving through these targets? Comprehensive answers to these questions are beyond the scope of our current paper, but we did an initial exploration. Based on previous microarray data in HDAC5 knockout mouse NAc after cocaine exposure (30), we probed gene expression of ten potential HDAC5 targets after HDAC5 knockdown in DS (Exp. 2). We found four genes that showed a consistent expression pattern with the previous study in mice: increased mRNA expression for Gnb4 and Suv39h1, but no change for Grin2a and Kcnk4, while several other genes either did not change (Kcnq5, Rgs20, Rapgef6, Abca5, Cuedc1) or exhibited decreased mRNA expression (Tacr1). We also probed Npas4, an HDAC5’s target recently identified by Taniguchi et al (32). However, we found that Npas4 mRNA expression decreased after HDAC5 knockdown in DS (data not shown). These inconsistencies can be due to the complexity of epigenetic regulation where multiple epigenetic factors modulate gene expression simultaneously (82).

Another potential factor is the compensatory increase of HDAC1 and HDAC4 after HDAC5 knockdown in DS. Based on previous evidence implicating a role of striatal HDAC1 in cocaine locomotor sensitization (29) and a role of striatal HDAC4 in cocaine CPP (83), it is possible that increased HDAC1 or HDAC4 expression (or both) contributes to the decreased incubated Meth seeking after HDAC5 knockdown in DS.

Finally, it should be noted that probing a transcriptional profile after reducing HDAC5 expression can only indirectly identify HDAC5’s targets. Direct evidence comes from chromatin immunoprecipitation (ChIP) against HDAC5 followed by qPCR or genome-wide sequencing. Indeed, HDAC5’s role in regulating gene expression also depends on its deacetylase activity (84–87) and subcellular localization (21, 22). However, elucidating genomic binding, enzymatic activity, or subcellular localization of HDAC5 is beyond the scope of our current paper and will be explored in the future.

Overall, our data suggest that HDAC5 modulates incubation of Meth craving by altering the transcriptional regulation of its direct or indirect gene targets. For example, upregulation of Suv39h1 [a histone methyltransferase acting as a transcription repressor (88, 89)] may contribute to this incubation by remodeling connectivity of activated neurons (90). Additionally, upregulation of Gnb4 [a G-protein that modulates calcium and potassium ion channels (91)] may contribute to incubation of Meth craving by activating G-protein-gated inwardly rectifying potassium (GIRK) currents (92, 93).

Methodological and interpretation issues

From an anatomical and functional perspective, a main question is whether the role of DS HDAC5 in incubation of Meth craving is sub-region specific. This is a relevant question, because there is evidence showing that DMS and DLS play different roles in cue- and context-induced drug seeking in rat relapse models (79). To answer this question, we performed sub-region specific HDAC5 knockdown in DMS or DLS. Our data showed that knocking down HDAC5 expression in DMS or DLS alone had no significant effect on incubation of Meth craving (Fig. S3), suggesting that HDAC5 function in the entire DS, but not a specific sub-region, must be manipulated to appreciably control incubation of Meth craving.

Another main question is whether the role of DS HDAC5 in incubation of Meth craving is cell-type specific. Endogenous HDAC5 is enriched in neurons (94). For Exp. 1, we used AAV2 serotype (95) to increase the neurotropism of HDAC5 expression. For Exp. 2, we used AAV1, which expresses in both neurons and glial cells (95). Therefore, we cannot exclude the possibility that the behavioral effects in our study are mediated by non-neuronal HDAC5 such as glia cells. We believe that this possibility is unlikely, because we previously found that blockade of toll-like receptor 4, an innate immune receptor expressed in primarily in microglia, contributes to incubation of heroin but not Meth craving (36).

Another unresolved issue is whether HDAC5 in D1-expressing, D2-expressing, or both cell types in DS is critical for incubation of Meth craving. Based on our recent studies showing that incubation of Meth craving is associated with increased activity [assessed by the neuronal activity marker, Fos (96)] in both DS cell types (14, 15), we speculate that HDAC5 activity in both D1- and D2-expressing DS neurons is important for this incubation. In future studies, we hope to develop cell-type specific approaches to test whether perturbing HDAC5 expression in different DS cell types would have a similar effect on incubation of Meth craving.

Finally, our data suggest that HDAC5 plays a selective role in incubated Meth seeking during late withdrawal, but not “non-incubated” Meth seeking during early withdrawal. However, this conclusion should be made with caution for two reasons. First, under our experimental conditions, viral expression has been at its maximal expression for a longer duration during late versus early withdrawal. Second, as drug seeking is substantially lower during the early versus late withdrawal relapse tests, negative findings during the early withdrawal relapse tests after DS HDAC5 overexpression or knockdown can be due to a floor effect of low operant responding during early withdrawal.

Conclusions

We demonstrated that DS HDAC5 plays an important role in incubation of Meth craving. This finding is consistent with our previous study showing time-dependent increases of DS HDAC5 mRNA expression during this incubation (15). In contrast, this novel role of HDAC5 in Meth seeking after extended-access drug self-administration contrasts with previous findings on the enzyme’s role in cocaine’s behavioral effects (assessed by CPP, locomotor sensitization, and short-access self-administration) (30–32), indicating that there are dissociated epigenetic mechanisms across drug classes, striatal regions, and behavioral procedures. Finally, HDAC5 likely exerts its role in incubation of Meth craving through its downstream gene targets, which can be further characterized by combining RNA-seq and ChIP-seq in future studies. Finally, from a clinical perspective, our study suggests that selective HDAC5 inhibitors could be a potential therapeutic target for decreasing Meth craving and relapse after prolonged withdrawal.

Supplementary Material

supplement

Acknowledgments

This research was supported by the National Institute on Drug Abuse, Intramural Research Program (YS) and NIDA extramural funds (P01 DA008227 to EJN, R01 DA032708 to CWC). MBC received support from a NIH predoctoral fellowship (F31 DA035073). JZ received support from China Scholarship Council (No. 201604910135). HS was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST), Republic of Korea (No. 2016R1A2B2006474). AAV particles expressing shRNA (HS provided the plasmid) were constructed and packaged by the NIDA Intramural Genetic Engineering and Viral Vector Core.

Footnotes

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Author contributions: XL, CWC, EJN, and YS conceived the project, provided intellectual input, and wrote the paper. XL, KW, TZ, OML, JMB, JZ and FS carried out experiments. MBC, CTR and BKH developed and validated the AAV constructs. HS provided the plasmids.

Financial Disclosure

All authors report no biomedical financial interests or potential conflicts of interest.

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