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date: 21 January 2019

Neuronal mRNA Translation in Addiction

Abstract and Keywords

Addictive drugs trigger persistent synaptic and structural changes in the neuronal reward circuits that are thought to underlie the development of drug-adaptive behavior. While transcriptional and epigenetic modifications are known to contribute to these circuit changes, accumulating evidence indicates that altered mRNA translation is also a key molecular mechanism. This chapter reviews recent studies demonstrating how addictive drugs alter protein synthesis and/or the translational machinery and how this leads to neuronal circuit remodeling and behavioral changes. Future work will determine precisely which neuronal circuits and cell types participate in these changes. The chapter summarizes current methodologies for identifying cell type-specific mRNAs whose translation is affected by drugs of abuse and gives recent examples of the mechanistic insights into addiction they provide.

Keywords: addiction, mRNA translation, addictive drugs, translational machinery, protein synthesis, drug-adaptive behavior

Introduction

Drug addiction involves persistent neurobiological alterations, leading to dysregulated reward signals and increased cravings, and ultimately to habits compromising life decision making (Koob & Volkow, 2016). A critical step toward identifying neural mechanisms underlying these complex behavioral alterations was the development of rodent models that mimic distinct features of drug-related behavior (Box 1) (Belin-Rauscent et al., 2016). Over the past decades, considerable progress has been made in the identification of the neuronal substrates by which addictive drugs can hijack synaptic plasticity mechanisms in key reward circuits, including the ventral tegmental area, the nucleus accumbens, the extended amygdala, and the prefrontal cortex (Luscher & Malenka, 2011). In addition to transcriptional and epigenetic modifications, accumulating evidence indicates that altered translational control might be a key process triggering long-lasting changes and participating in the emergence of drug-adaptive behaviors.

Translation is a complex process as its initiation, elongation, and termination steps are controlled by coordinated interactions between ribosomes and translational factors. Initiation refers to the recruitment of the ribosome and the tRNA carrying the first amino acid residue at the mRNA start codon. Initiation is the major rate-limiting step and is therefore tightly regulated by several eukaryotic initiation factors (eIFs; Buffington et al., 2014). Elongation is another checkpoint of translation, during which the polypeptide chain is formed by the sequential addition of amino acids. This step requires two eukaryotic elongation factors (eEF1 and eEF2) whose functions are also regulated (Dever & Green, 2012). Finally, in addition to their well-characterized roles in stabilization and mRNA transport, RNA-binding proteins (RBPs) and microRNAs also play an important role in translational control.

In this chapter, we review recent reports that addictive drugs regulate translational control. We focus mainly on mTORC1 signaling and the role of the initiation factor eIF2. We also discuss how these translation control mechanisms can contribute to long-lasting neuronal circuit adaptations and drug-adaptive behavior.

Role of Protein Synthesis in Drug-Altered Behavior and Neuronal Plasticity

The first indications that protein synthesis is involved in drug-related behavior came from Karler and colleagues, who reported that inhibiting protein synthesis prevented sensitized behavioral responses to cocaine and amphetamine (Karler et al., 1993). Since then, several studies have shown that most, if not all, long-lasting behavioral alterations of addictive drugs require protein synthesis. Systemic or intra-cerebro-ventricular administrations of, the translation inhibitors, anisomycin or cycloheximide attenuate locomotor sensitization to cocaine and morphine (Bernardi et al., 2007; Luo et al., 2011; Valjent et al., 2010) and different phases of conditioned place preference induced by morphine, cocaine, nicotine, and methamphetamine (Fan et al., 2010; Kuo et al., 2007; Milekic et al., 2006; Robinson & Franklin, 2007; Taubenfeld et al., 2010; Valjent et al., 2006; Xue et al., 2017; Yu et al., 2013b). Blockade of protein synthesis also impairs the acquisition of cocaine self-administration (Mierzejewski et al., 2006) and alcohol-, cocaine-, and nicotine-seeking induced by exposure to cues previously associated with drug intake (Dunbar &Taylor, 2016; von der Goltz et al., 2009; Xue et al., 2017). Finally, the local infusion of these inhibitors was instrumental to identify those brain areas in which protein synthesis was essential to control specific components of drug-related behavior (Figure 1).

Neuronal mRNA Translation in AddictionClick to view larger

Figure 1. Key brain areas where protein synthesis inhibitors control specific components of drug-adaptive behavior. Shaded areas represent brain structures in which infusion of anisomycin or cycloheximide (*) reduce specific (a) cocaine-, (b) morphine-, and (c) alcohol-altered behavior. (PFc, prefrontal cortex; AcbC, nucleus accumbens core; VTA, ventral tegmental area; CEA, central amygdala; BlA, basolateral amygdala; Hipp, hippocampus; dSub, dorsal subiculum; CPP, conditioned place preference.)

Addiction-related behaviors in rodent models are thought to result in part from persistent synaptic adaptations in reward circuits, known as drug-evoked plasticity (for review see (Luscher, 2016). Thus, enhancement of excitatory synaptic transmission in mesolimbic dopamine neurons occurs in response to addictive drugs. This synaptic modification, which is characterized by a transient increase in AMPAR/NMDAR ratio, is sensitive to protein synthesis inhibitors (Argilli et al., 2008). Similarly, blocking protein synthesis prevents the accumulation of calcium-permeable AMPARs in medium-sized spiny neurons of the nucleus accumbens during protracted withdrawal from cocaine self-administration (Scheyer et al., 2014).

Addictive drugs also trigger persistent morphological changes in the size of cell bodies and in spine morphology in various neuronal types including mesolimbic dopamine cells, nucleus accumbens medium-sized spiny neurons, and prefrontal cortex pyramidal neurons (Russo et al., 2010). These structural remodelings are likely underpinned by de novo protein synthesis. Indeed, protein synthesis inhibitors attenuated the increase in spine density, in the nucleus accumbens and in the lateral amygdala, of animals that underwent conditioned place preference to cocaine and methamphetamine, respectively (Marie et al., 2012; Yu et al., 2016). Despite this evidence, the translation-regulating mechanisms underpinning the long-lasting neural plasticity induced by addictive drugs have only just begun to be elucidated.

Regulation and Role of mTORC1 Pathway in Drug Addiction

The role of the mammalian or mechanistic target of rapamycin complex 1 (mTORC1) pathway in protein-synthesis-dependent synaptic plasticity and memory formation has been the focus of considerable study over the last decade (Santini et al., 2014). The mTORC1 complex is regulated by the convergence of distinct signaling cascades that depend on numerous receptors that respond to tyrosine phosphorylation, ions, and other second messengers (Figure 2). mTORC1 positively controls the initiation of translation by regulating the formation of the eIF4F complex (composed of eIF4G, eIF4A, and eIF4E) that recognizes the 5′-m7G cap-structure of mRNAs. Indeed, activated mTORC1 controls crucial core components of the translation machinery: the p70 ribosomal S6 kinases 1 and 2 (p70S6K1 and p70S6K2) and the eIF4E-binding proteins (4E-BPs; Santini et al., 2014). The 4E-BPs prevent the formation of the eIF4F complex by interacting with the cap-binding protein eIF4E. mTORC1-mediated phosphorylation of 4E-BP releases eIF4E, thereby allowing its assembly with eIF4G and eIF4A, which is crucial to recruit the ribosome during translation initiation. mTORC1 also mediates eIF4G and p70S6K phosphorylation. Activated p70S6K can in turn phosphorylate eIF4B leading to increased eIF4A catalytic activity. Activated p70S6K also regulates the ribosomal protein of the 40S ribosomal subunit, rpS6, whose phosphorylation state has been implicated in the translation of certain mRNAs (Biever et al., 2015b; Puighermanal et al., 2017). The regulation of mTORC1 pathway by addictive drugs and its role in drug-adaptive behaviors are dealt with in two separate sections: (a) regulation of mTORC1 and its downstream effectors and (b) role of mTOR in drug-induced behaviors and neuronal plasticity.

Neuronal mRNA Translation in AddictionClick to view larger

Figure 2. Translation initiation control by the mTORC1 signaling pathway. mTORC1 mediates cap-dependent translation via the phosphorylation of its primary downstream substrates: 4E-BPs and p70S6Ks. 4E-BPs compete with the scaffolding protein eIF4G for a common binding site on eIF4E. mTORC1-mediated phosphorylation of 4E-BPs prevents their binding to eIF4E, which allows eIF4E to assemble with eIF4G and eIF4A to form the eIF4F complex and bind the mRNA cap structure (m7GpppN). mTORC1 also controls translation through the phosphorylation of p70S6Ks, which in turn phosphorylates eIF4B (a cofactor of eIF4A), the ribosomal protein S6, and eEF2K (a kinase of eEF2 involved in translation elongation). Rapamycin binds to FKBP12 and forms a complex that directly binds and inhibits mTORC1.

The regulation of the mTORC1 pathway by addictive drugs has been one of the most studied molecular mechanisms involved in translation control. Indeed, with the notable exception of amphetamine, all addictive drugs studied regulate the phosphorylation state of mTORC1 and/or its direct downstream substrates (p70S6K and 4E-BP) in specific brain areas (Table 1). Interestingly, phosphorylation of these factors is also altered in animals that learn to self-administer drugs, and in animals exposed to context or cues previously associated with drug intake (Table 1). The regulation of rpS6 phosphorylation (Ser235/6 and Ser240/4) in response to addictive drugs or during drug-related behaviors has been widely studied and reviewed recently (Biever et al., 2015b). In contrast, little is known regarding the modulation of eIF4B or eIF4G. To date only one study described an increased phosphorylation of both translation initiation factors, in the hippocampus after THC administration (Puighermanal et al., 2009). Finally, addictive drugs also regulate the translation initiation factor eIF4E. Indeed, acute administration of d-amphetamine or THC increases eIF4E phosphorylation in the striatum and the hippocampus, respectively (Biever et al., 2015a; Puighermanal et al., 2009; Sutton & Caron, 2015). Phosphorylation is also enhanced in the nucleus accumbens after repeated exposure to cocaine or cues induced cocaine-seeking (Sutton & Caron, 2015; Werner et al., 2018). Although eIF4E phosphorylation has been widely associated with cap-dependent translation, recent studies have identified a small subset of phospho-eIF4E-sensitive mRNAs in distinct brain areas (Amorim et al., 2018; Cao et al., 2015; Gkogkas et al., 2014). Future studies are required to elucidate the mRNAs whose translation depends on eIF4E phosphorylation in the context of drug addiction. Overall, addictive drugs, including cocaine, methamphetamine, morphine, alcohol, THC, and nicotine, hijack mTORC1 signaling and/or translational machinery factors in multiple addiction-related brain areas.

Table 1. Regulation of mTORC1 (S2488), p70S6K (T389), and 4E-BP1 (T37/46) by drugs of abuse and drug-related behaviors in vivo

Drugs of Abuse (doses, mg/kg)

Species

p-mTOR

p-p70S6K

p4E-BP1

Brain Areas

References

Cocaine

5

Mouse

ND

=

=

VTA

Huang et al. (2016)

15

= 1

ND

ND

Acb

Sutton and Caron (2015)

10

Rat

ND

ND

Acb

Luo et al. (2016)

15

Mouse

= 2

Acb

Sutton and Caron (2015)

ND

=

ND

Acb

Bailey et al. (2012)

20

ND

ND

Acb

Cahill et al. (2016)

Amphetamine

5

Mouse

=

ND

ND

Striatum

Rapanelli et al. (2014)

10

Mouse

=

= 3

=

Striatum

Biever et al. (2015a)

10

ND

=

=

Striatum

Biever et al. (2017)

Methamphetamine

2

Rat

ND

↑(NA)

ND

Acb

Narita et al. (2005)

Nicotine

0.35

Rat

ND

BlA

Gao et al. (2014)

Morphine

25 (pellet)

Mouse

=

ND

VTA

Mazei-Robison et al. (2011)

75 (pellet)

Rat

=

=

4

VTA/Acb

Alcohol

2.5 (g/kg)

Mouse

ND

Acb

Neasta et al. (2010)

THC

10

Mouse

5

Hipp

Puighermanal et al. (2009)

ND

ND

Striatum/Amy/PFc

Puighermanal et al. (2013)

Drug-Related Behaviors

Retrieval of cocaine-related memories

Mouse

↓ (NA)

↓ (NA)

ND

Acb/Hipp

Shi et al. (2014)

ND

Acb

Wang et al. (2010)

Alcohol Binge 20% (4h/d)

ND

Acb

Neasta et al. (2010)

Single Alcohol Drinking

ND

Acb

Neasta et al. (2010)

Cue-Induced Cocaine-Seeking

Rat

= 6

=

= 7

Acb

Werner et al. (2018)

Cocaine SA

ND

ND

Acb

Cahill et al. (2016)

Withdrawal from Cocaine SA

ND

Acb

James et al. (2014)

Morphine-induced CPP

ND

Hipp

Cui et al. (2010)

Retrieval of Alcohol-Related Memories

ND

CEA/OFc/mPFc

Barak et al. (2013)

Notes: (*) repeated administration. NA, not available; ND, not determined;

(1) p-mTOR S2481 (↑), T2446 (=);

(2) p-mTOR S2481 and T2446 (↑);

(3) p70S6K T421/424 (=);

(4) 4E-BP1 T37/46 (=) in the Acb;

(5) p70S6K T421/424 (↑);

(6) p-mTOR S2481 (=);

(7) p-4E-BP1 S65 (↑).

Several pharmacological and genetic studies support a functional role for mTORC1 in drug-related behaviors. For example, systemic administration of the mTORC1 inhibitor rapamycin prevents both the induction and expression of cocaine or nicotine-induced locomotor sensitization in rats (Gao et al., 2014; Wu et al., 2011). Unlike in rats, only the expression of locomotor sensitization to cocaine is altered in mice (Bailey et al., 2012). mTORC1 inhibition also reduces cocaine-seeking (James et al., 2016) as well as the expression and the reconsolidation of conditioned place preference induced by morphine, cocaine, and alcohol (Bailey et al., 2012; Lin et al., 2014; Neasta et al., 2010). Finally, alcohol-related behaviors are attenuated in animals treated with rapamycin (Barak et al., 2013; Beckley et al., 2016; Lin et al., 2014; Neasta et al., 2010). Supporting the results obtained by using these preclinical models, a small randomized double-blind clinical trial showed that systemic rapamycin administration suppresses cue-induced drug craving in abstinent heroin addicts (Shi et al., 2009).

A causal link between mTORC1 activation in specific brain areas and drug-related behavior has been established by local infusions of mTORC1 inhibitors. Specifically, microinjections of rapamycin into the nucleus accumbens attenuated many cocaine-related behaviors, including hyperlocomotion, drug-seeking, and cue-induced reinstatement (Cahill et al., 2016; James et al., 2014; Wang et al., 2010; Werner et al., 2018), as well as methamphetamine locomotor sensitization (Narita et al., 2005). Likewise, nicotine-induced locomotor sensitization is prevented by mTORC1 inhibition in the basolateral amygdala (Gao et al., 2014). Finally, binge drinking and alcohol consumption are reduced when rapamycin is infused into the nucleus accumbens, whereas alcohol-seeking behavior requires mTORC1 activation in the central amygdala (Barak et al., 2013; Neasta et al., 2010).

The generation of cell type- and brain area-specific conditional knockout mice of the different components of the mTOR signaling pathway has uncovered its role in specific circuits. For example, selective knockdown of mTOR in the ventral tegmental area was sufficient to impair cocaine-induced conditioned place preference, as well as to prevent the increase in AMPAR/NMDAR ratio and reduction of GABAergic inhibition in dopaminergic neurons induced by cocaine (X. Liu et al., 2018). On the other hand, disruption of mTOR or its mTORC1 partner raptor in D1R-expressing neurons attenuated the enhanced locomotion induced by cocaine (Sutton & Caron, 2015). These results suggest a crucial role of mTOR in mediating cocaine-reward properties and synaptic plasticity. In addition to mTORC1, mTOR can bind other partners including rictor to form complex 2 (mTORC2), which has been involved in structural modifications via cytoskeletal rearrangements. Increasing evidence has demonstrated a role of mTORC2 in drug-related behaviors and structural modifications. Indeed, inactivation of rictor in the ventral tegmental area abolishes morphine-induced conditioned place preference (Mazei-Robison et al., 2011). Strikingly, the hyperlocomotor response to amphetamine is enhanced in mice with reduced mTORC2 function in the dorsal striatum (Dadalko et al., 2015). Lastly, mTORC2 is also a key player in drug-induced synaptic remodeling, through its action on cytoskeleton rearrangements. Notably, inactivation of rictor in the ventral tegmental area blocks the decrease in dopaminergic neuron soma size induced by morphine (Mazei-Robison et al., 2011). Additionally, rictor inactivation prevents mushroom spines from increasing in size and density after consuming alcohol (Laguesse et al., 2018). Altogether, compelling data demonstrate a crucial role of mTOR (either in complex 1 or 2) in drug-related behaviors and neuronal plasticity.

Regulation and Role of the Translational Initiation Factor eIF2α in Drug Addiction

Translation initiation begins with the formation of the 43S preinitiation complex, which comprises the 40S ribosome subunit, some eukaryotic initiation factors, and the ternary complex formed by the interaction of eIF2-GTP and the initiator methionine-charged tRNA. Subsequently, the 43S preinitiation complex binds the mRNA and the eIF4F complex to collectively form the 48S complex that then scans along the mRNA for the start codon. Upon AUG recognition, eIF2 hydrolyzes GTP to GDP and dissociates from the mRNA, permitting the binding of the 60S ribosomal subunit and elongation of the polypeptide chain. eIF2 remains bound to GDP until eIF2B exchanges GDP for GTP on eIF2 allowing therefore another round of initiation. This step is tightly controlled by the state of phosphorylation of eIF2α, which is regulated by the activity of four kinases (HRI, PKR, PERK, and GCN2) and two phosphatase complexes (PP1/GADD34 and PP1/CReP). Phosphorylation of eIF2α reduces the activity of the guanine nucleotide exchange factor of eIF2, eIF2B, thereby reducing ternary complex formation. This ultimately decreases the global protein synthesis and causes the enhancement of the translation of a small number of mRNAs with upstream open reading frames in their 5′UTRs (Buffington et al., 2014).

The regulation of eIF2α phosphorylation by addictive drugs has only recently begun to be assessed. Jian and colleagues were the first to report a rapid and transient eIF2α dephosphorylation in the basolateral amygdala after cocaine- and morphine-related memories are retrieved (Jian et al., 2014). Since then, decreased eIF2α phosphorylation was found in the ventral tegmental area after a single administration of alcohol, nicotine, or methamphetamine (Huang et al., 2016). This decreased phosphorylation was also observed in mice that were acutely or repeatedly given cocaine, and in the nucleus accumbens of rats exposed to cues promoting cocaine-seeking (Placzek et al., 2016a, 2016b; Werner et al., 2018). However, depending on the brain areas analyzed, decreased eIF2α phosphorylation is not systematically observed in response to a single injection of addictive drugs. Indeed, eIF2α phosphorylation is unchanged in the mouse striatum of mice receiving a single injection of cocaine or amphetamine (Biever et al., 2017; Huang et al., 2016). The regimen of drug administration also represents an important factor since mice that are repeatedly given amphetamine do have increased eIF2α phosphorylation in the striatum (Biever et al., 2017). Finally, there are differences between species, as, unlike in mice, acute amphetamine increases eIF2α phosphorylation in the rat striatum and prefrontal cortex (Xue et al., 2016).

The role of eIF2α phosphorylation in drug-related behaviors has been considerably elucidated with the help of a selective inhibitor of eIF2α phosphatases, Sal003. Infusion of Sal003 into intra-basolateral amygdala immediately after morphine or cocaine memory retrieval, impaired the reconsolidation of drug-induced conditioned place preference (Jian et al., 2014). Sal003 infusion into the nucleus accumbens also reduces cocaine-seeking (Werner et al., 2018). eIF2α phosphorylation in the ventral tegmental area appears to be necessary and sufficient to regulate the sensitivity to cocaine, as preventing eIF2α dephosphorylation in this brain area abolishes the increased AMPAR/NMDAR ratio and conditioned place preference induced by cocaine in adolescent mice. Conversely, mice given ISRIB, a pharmacological compound that reverses the effects of eIF2α phosphorylation (Sidrauski et al., 2013) or Eif2s1S/A heterozygous knock-in mice display an enhanced conditioned place preference to a low dose of cocaine (Huang et al., 2016; Placzek et al., 2016a, 2016b).

As mentioned earlier, enhanced eIF2α phosphorylation favor by an indirect mechanism the translation of mRNAs containing upstream open reading frames in their 5′ UTR (Buffington et al., 2014). Activating transcription factor 4 (ATF4) and oligophrenin 1 (OPHN1) have been identified as specific targets through which eIF2α regulates drug-adaptive behaviors. ATF4 is rapidly downregulated in the basolateral amygdala after retrieval of cocaine- and morphine-related memories and this transient downregulation is necessary for the reconsolidation of conditioned place preference to morphine (Jian et al., 2014). OPHN1, on the other hand, appears to be the main conduit through which, eIF2α regulates cocaine sensitivity in the ventral tegmental area. Indeed, reduced OPHN1 levels in this brain structure enhance the rewarding properties of cocaine (Huang et al., 2016). However, the modulation of eIF2α phosphorylation is not systematically associated with altered ATF4 and OPHN1 expression. For example, there were no changes in eIF2α phosphorylation in the striatum of mice repeatedly given amphetamine or in the nucleus accumbens of rats exposed to cues inducing cocaine-seeking (Biever et al., 2017; Werner et al., 2018). Instead, recent work suggests that the translational regulation of selective uORF-bearing mRNAs might depend on the brain areas and the cell type where eIF2α phosphorylation takes place (Biever et al., 2017; Buffington et al., 2014). Altogether, these data illustrated how the translational factors, that play a key role in memory and synaptic plasticity such as eIF2α, can be modulated by addictive drugs and lead to persistent synaptic rearrangements and drug-adaptive behaviors (Costa-Mattioli et al., 2005, 2007, 2009).

RNA-binding Proteins and Addictive Drug Action

RNA-binding proteins (RBPs) participate in post-transcriptional control of gene expression. In addition to their major role in regulating splicing, polyadenylation, stabilization, and mRNA transport, RBPs also critically regulate mRNA translation, mostly as repressors (Hentze et al., 2018). Despite the identification of more than 500 RBPs, only a few are known to be regulated by addictive drugs and to play a role in psychostimulant-related behaviors.

The Fragile X mental retardation protein, FMRP, encoded by the fmr1 gene, is involved in mRNA transport and the control of translation (De Rubeis et al., 2012). To date, only one study has documented the ability of drugs of abuse to regulate FMRP levels. In it, acute cocaine administration increases FMRP levels in the brain (Tiruchinapalli et al., 2008). Neither its expression nor its phosphorylation level changed in synaptoneurosomes from the nucleus accumbens after protracted abstinence from cocaine (Werner et al., 2018). Several studies however indicate that FMRP plays a role in behavioral response to addictive psychostimulant drugs. For example, acute amphetamine-induced psychomotor effects, such as locomotion and stereotypies, are attenuated in Fmr1-deficient mice (Fulks et al., 2010; Ventura et al., 2004). Cocaine-induced hyperlocomotion is reduced (Fish et al., 2013), but this effect is accompanied by an enhancement of stereotypies (Smith et al., 2014). Fmr1 knockout mice also have impaired sensitized locomotor responses and conditioned place preference to cocaine. However, cocaine response is normal in mice with a targeted deletion of FMRP in dopaminergic neurons, suggesting that functional FMRP in this cell type is not critical to mediate cocaine-adaptive behaviors (Smith et al., 2014). Interestingly, nucleus accumbens-specific knockdown of fmr1 gene is sufficient to reduce behavioral sensitization but not cocaine reward (Smith et al., 2014).

One of the mechanisms by which FMRP has been proposed to repress translation is through its CYtoplasmic FMRP-Interacting Proteins, 1 and 2 (Napoli et al., 2008). Mutant CYFIP2 mice have reduced acute and sensitized responses to cocaine and methamphetamine. However the mechanistic role of CYFIP proteins in addiction remains to be determined (Kumar et al., 2013). Determining whether drugs of abuse interfere with the ability of FMRP to properly control the transport and translation of some of its target mRNAs in specific brain areas should help to better understand how FMRP participates in the long-lasting modifications induced by addictive drugs.

The embryonic lethal abnormal vision (ELAV)-like proteins/Hu family belongs to a class of RBPs that are enriched in neurons (Darnell, 2013). The four members (ELAVL1-4 also known as HuR, HuB, HuC, and HuD) preferentially bind to AU-rich motifs in 3′UTRs and are involved in mRNA transport, stability, and regulation of translation (Darnell, 2013). In rat brain, cocaine upregulates both HuR and HuD (Tiruchinapalli et al., 2008) and these proteins also bind mRNAs that are upregulated by cocaine, such as homer (Brakeman et al., 1997) and gap43 (Tiruchinapalli et al., 2008). The ELAV/GAP-43 protein:RNA pairing is also increased in hippocampus during prolonged withdrawal from cocaine self-administration (Pascale et al., 2016). Recently, increased expression of HuD and two of its previously identified targets, Bdnf and Camk2a, was observed in the nucleus accumbens after conditioned place preference to cocaine. A causal link between enhanced HuD expression and the rewarding properties of cocaine was further provided by the use of HuD-overexpressing mice, which displayed an enhanced conditioned place preference induced by a low dose of cocaine (Oliver et al., 2018).

Zipcode-binding protein-1 (ZBP1) belongs to a group of RBPs that regulates neuronal transport and dendritic localization of mRNAs, including β-actin (Huttelmaier et al., 2005). Because ZBP1 is barely expressed in adulthood, a transgenic mouse line overexpressing ZBP1 selectively in forebrain neurons was generated to test the role of this RBP in cocaine-related behaviors (Lapidus et al., 2012). Strikingly, cocaine-induced conditioned place preference is abolished in this mouse line, a phenotype most likely due to the abnormal enhanced expression of ZBP1 target mRNAs as a result of ectopic ZBP1 expression (Lapidus et al., 2012).

Toward the Identification of Drug-Induced mRNA Translation in Genetically Identified Cell Populations

Although polysome profiling and puromycin incorporation are powerful methods to assess whether addictive drugs alter global translational rates, pioneering techniques have been used recently to isolate mRNA and identify translated mRNAs in specific cell types within specific brain areas (Box 2). The first approach, Translating Ribosome Affinity Purification was developed in the Heintz lab (Heiman et al., 2008). TRAP uses a bacterial artificial chromosome in transgenic mice to express an EGFP-tagged ribosomal protein in any cell type of interest, for example, D1R- or D2R-expressing neurons. Tagged ribosomes from these two cell types were immunoprecipitated with anti-GFP-coated magnetic beads and their bound mRNAs were extracted for microarrays analysis. The comparison of the translatome profiles between saline- and cocaine-treated mice revealed hundreds of differentially expressed genes between D1R- and D2R-expressing neuronal populations. Interestingly, repeated cocaine exposure selectively upregulated mRNAs associated with GABAA receptors in D1R-expressing cells. This may help to account for the specific electrophysiological properties of this cell population (Heiman et al., 2008). TRAP and RNA-seq were also used to uncover chronic nicotine-induced upregulation of ribosome-associated mRNAs in discrete populations of α5 nicotinic acetylcholine receptor-positive cells of the interpeduncular nucleus. Among the differentially expressed genes, neuronal nitric oxide synthase and somatostatin genes were found to be key players in nicotine reward (Ables et al., 2017).

Another approach of interest is RiboTag, which is also based on the cell type-specific immunoprecipitation of tagged ribosomes (Sanz et al., 2009). In this method a HA-tagged ribosomal protein is expressed in a Cre-dependent manner (Box 2). This technique was key to uncover that cocaine exposure differentially regulates the expression of the early growth response 3 (Egr3) and one of its targets, the peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), in distinct neuronal populations in the nucleus accumbens. While cocaine enhanced Egr3 and PGC-1α ribosome-associated mRNAs in D1R-expressing cells, it reduced them in D2R-positive cells (Chandra et al., 2015, 2017a). Consequently, Egr3 and PGC-1α overexpression in D1R-expressing neurons enhanced conditioned place preference and locomotor sensitization to cocaine, whereas overexpressing them in D2R neurons had the opposite phenotype (Chandra et al., 2015, 2017a). A bidirectional regulation of translation of dynamin-related protein-1 (Drp1) mRNA has also been reported in the striatum after repeated cocaine administration. This GTPase that regulates mitochondrial fission is upregulated in D1R-expressing cells, but downregulated in D2R-containing neurons. This enhanced expression is functionally relevant since selective knockdown of Drp1 in D1R-positive cells blocked cocaine-seeking behavior. Conversely, overexpression of the fission-promoting Drp1(S637A) mutant enhanced cocaine-seeking after prolonged abstinence (Chandra et al., 2017b). Finally, using the same methodology, the ten-eleven translocation family member TET1 mRNA was found to be translationally upregulated in pyramidal neurons of the dorsal hippocampus during memory retrieval, where it plays a crucial role in cocaine-associated memory reconsolidation (C. Liu et al., 2018). It is worth mentioning that many of these studies assessed the levels of mRNAs bound to ribosomes, but that does not necessary imply that they are translationally regulated. Indeed, association with ribosomes is not always associated with mRNAs being translated into proteins since stalled polyribosomes on repressed mRNAs have been reported (Graber et al., 2013). Combination of transcriptional and/or translational effects can however be easily assessed by referring the abundance of each ribosome-bound mRNA to its abundance in the input fraction that contains all the mRNAs of the cell.

Perspectives

There is now compelling evidence that repeated exposure to addictive drugs triggers de novo protein synthesis leading to long-lasting changes in circuit function and behavior. Therefore, identifying novel regulated mRNAs and how and where their translation occurred might help to better understand the action of addictive drugs.

Most past studies assessing translational control by addictive drugs have focused on initiation factors. However, elongation is also an important step of translation and future studies should tackle this issue. For example, the phosphorylation of the eukaryotic elongation factor 2 (eEF2) decreases the rate of peptide chain elongation and promotes the translation of a subset of mRNAs involved in synaptic plasticity (Park et al., 2008; Scheetz et al., 2000; Verpelli et al., 2010). In this regard, repeated amphetamine exposure increases phospho-eEF2, which parallels a decrease in global translation and an upregulation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) in D1R-expressing cells (Biever et al., 2017).

Most research into mTOR signaling in the context of drug addiction has focused on mTORC1-dependent protein synthesis. However, mTOR orchestrates numerous cellular processes and whether other physiological roles of mTORC1 are involved in drug-related plasticity and/or behavior remains to be addressed. For example, mTORC1 inhibition induces the formation of autophagic vacuoles in prejunctional dopaminergic axons, which evokes dopamine release and decreases synaptic vesicle numbers (Hernandez et al., 2012). Given that addictive drugs trigger dopamine release, it will be interesting to examine any possible mTOR-dependent effect in autophagy. The contribution of mTORC2 in the adaptive responses associated with drugs of abuse is also poorly understood and should be investigated more carefully in the future.

Mechanisms of translational control by addictive drugs have been studied in different brain areas such as the ventral tegmental area, striatum, and amygdala, which all contain intermingled heterogeneous cell types. Of note, the signaling pathways responsible for these mechanisms can produce different outcomes depending on the cell population. For example, eIF2α phosphorylation promotes translation of Atf4 in glutamatergic neurons, whereas it inhibits translation of Ifnγ in GABAergic cells (Buffington et al., 2014). Therefore, subsequent studies, assessing the cell type where addictive drugs modulate signaling cascades controlling translation, are required. Glial cells require particular attention as most studies have focused on neurons. On the other hand, the development of approaches such as the bacTRAP or RiboTag has significantly contributed to uncover the specific cell types in which translation of some mRNAs is regulated by addictive drugs (Ables et al., 2017; Chandra et al., 2015; Heiman et al., 2008; C. Liu et al., 2018). However, more thorough studies of the subset of mRNAs that is translated in specific cell populations and of their association with addiction-related processes are necessary to better understand the actions of drugs of abuse. The TRAP and RiboTag analytic techniques will be key to determining the mRNAs that are translated in a specific circuit during an addiction-related behavioral task. These approaches will be particularly powerful when combined with Cre-dependent viral vectors and transgenic mouse lines with promoters of immediate early genes, such as c-fos and Arc (Guenthner et al., 2013).

Neuronal function depends on highly localized molecular signaling and the precise distribution of mRNAs, and their translational regulators, at particular subcellular compartments needs to be addressed in more detail. Local translation has been reported in both dendrites (Holt and Schuman, 2013) and axons (Shigeoka et al., 2016). However, the precise subcellular localization of the mRNAs that are dysregulated by drugs of abuse is still unknown. This knowledge would allow a level of selectivity, both in terms of which mRNAs, but also as to which different neuronal sub-regions should be targeted for therapeutic benefit. Overall, the elucidation of the complex mechanisms of translational control as well as the mRNAs that are translated in response to drugs of abuse at both the cellular and subcellular level should provide novel targets for treatments of addictive processes.

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