Open access peer-reviewed chapter

Molecular Mechanisms of Drug-Induced Plasticity

Written By

Robert J Oliver and Nora I Perrone-Bizzozero

Submitted: May 27th, 2016 Reviewed: December 16th, 2016 Published: June 21st, 2017

DOI: 10.5772/67289

Chapter metrics overview

1,503 Chapter Downloads

View Full Metrics


Substance-use disorders (SUDs) are a significant societal burden. Like many other conditions, SUDs are characterized by chronic relapse after periods without symptoms. Alterations in synaptic plasticity have been documented after acute and addiction-related behavioral exposures to drugs of abuse. These synaptic alterations are persistent and similar to the chronic relapse state of patients with SUDs, suggesting that reversing these synaptic alterations may prevent relapse. Additionally, many of these synaptic features of addiction mirror those found in other forms of learning and memory. These features suggest that the etiology of this disorder stems from persistent modifications in corticolimbic synaptic plasticity mediated by drug-induced alterations in addiction-related gene (ARG) expression. Understanding the regulation of addiction-related genes and their impact on synaptic plasticity and behavior may inform new pharmacological treatments that reverse these aberrant drug-evoked forms of plasticity in favor of remission.


  • addiction
  • substance-use disorders
  • Fos
  • CREB
  • ADAR
  • BDNF
  • Mef2
  • miR-212
  • miR-9
  • FMRP
  • HuD

1. Introduction

Substance-use disorders (SUDs), or more colloquially known as drug addiction, are a significant societal burden both financially, incurring an estimated $193 billion in costs (, 2011), and emotionally devastating to patients and their families. In opposition to more controlled, casual drug use, SUDs are characterized by uncontrollable bouts of drug consumption in spite of negative life consequences. Patients with this disorder appear to lose interest in normal prosocial activities, instead directing their energy toward the pursuit of these substances. Since addiction is a chronic, relapsing condition, this disorder has been notoriously difficult to manage. A complete review of pharmacological mechanisms of drugs of abuse understanding of the molecular, physiological, and behavioral mechanisms involved in the disorder is necessary for the discovery and implementation of more effective treatments.

The mesolimbic dopamine system is the most well-studied and implicated circuit associated with the disorder. Naturally, this neurocircuit may have evolved as an information-processing center to direct behavior toward environmentally important stimuli predicting the presence of vital resources, for example, food and water. Synaptic plasticity within these regions is implicated in associative learning of these stimuli to guide behavior necessary to receive these rewarding resources. Depending on the frequency and accuracy that a particular stimulus may predict a natural reward, goal-directed behavior toward this stimulus with the intention of obtaining the reward may become habitual. Thus, if an exogenous substance were to recruit this same neurocircuitry, this may elicit similar goal-directed behavior toward obtaining these compounds.

Structurally, drugs of abuse are highly varied and have many specific protein targets within the body (for a review of pharmacological mechanisms of drugs of abuse, see [1]). However, all pharmacological mechanisms of drugs of abuse cause excessive dopamine release originating from the ventral tegmental area within the nucleus accumbens (VTA, NAc; [2, 3]). Not only are these regions involved in this disorder, they also appear to be crucial mediators of appropriate goal-directed behavior toward natural rewards. Dopaminergic projections from VTA neurons are important in regulating motivation to perform integral, evolutionarily conserved behaviors such as feeding and reproduction [4, 5]. Drug-elicited synaptic plasticity also occurs within this region, possibly through similar mechanisms as natural rewards. Mirroring a classical symptom of addiction, the synaptic alterations induced by drugs of abuse inhibit the ability of other non-drug-related experiences to elicit synaptic plasticity [6, 7]. As such, it has been hypothesized that drugs of abuse cause a heightened form of plasticity-dependent associative memory leading to habit formation and addiction-like behaviors [8].

Although drug use is required for the development of addiction, it is most certainly not sufficient to cause this disorder. For example, around 176.6 million Americans from the age of 12 and up drink alcohol but only 17 million are classified as having an alcohol-use disorder (SAMSHA, 2013). Drugs are metabolized and eventually cleared from the body, thus, the drug’s pharmacological effect is not sufficient. In addition, SUDs are classically characterized by chronic relapse after periods without symptoms [9]. This may occur many years after a patient’s last reported use of a drug, suggesting that some stable functional alteration has occurred within the brain. Repeated drug exposure is required for an accumulation of molecular events that alter plasticity within specific regions affecting the functioning of the entire circuit. These synaptic alterations are persistent and similar to the chronic relapse state of patients with SUDs, suggesting that reversing these synaptic alterations may prevent relapse [9, 10]. Additionally, they appear to be protein-synthesis-dependent forms of plasticity [1113]. Thus, the molecular mechanisms regulating gene expression ending with the translation into functional protein may play a role in the etiology of this disorder and thus may stem from persistent modifications in region-specific synaptic plasticity mediated by drug-induced alterations in addiction-related gene (ARG) expression.

Regulation of these molecules can occur at many different steps. The DNA in the genome is organized into small compact three-dimensional units assembled by histones into nucleosomes, which form the structure of chromatin. As such, basal transcription is necessarily stagnant in the absence of the regulation of gene accessibility. Modifications to the accessibility of genes, by regulation of these structures, are termed epigenetic regulation and have also been found to be an integral component in the development of addiction. Given that the epigenetic control of drug addiction has been elegantly reviewed in previous work [1417], this chapter focuses on other aspects of gene expression control starting at the level of transcription.


2. Transcriptional regulation of addiction-related genes

Transcriptional regulation occurs through transcription factors, which are proteins that respond to intracellular changes leading to association with specific elements in target genes. Since the promoter region where the transcription factor binds to is outside of the coding region of that gene, these sequences are also termed cis-regulatory elements.

2.1. The Fos family transcription factors are differentially altered by drugs of abuse and contribute to addiction-related plasticity and behavior

Although altered transcription of various genes had been suggested by earlier work [18], it was not until the discovery that morphine caused increased striatal expression of a transcription factor, c-Fos, that it was shown that transcription factors may regulate this drug-induced gene expression [19]. Although first found to be regulated by acute morphine treatment, it was found that other drugs of abuse cause specific, dopamine-dependent, alterations in the expression of this transcription factor within addiction-related regions [2022]. Important for the study of relapse, it was found that c-Fos was upregulated in mesolimbic structures following withdrawal, suggesting that it may play a role in the intense drug craving present in this disorder [23]. c-Fos is part of the Fos family of transcription factors, including FosB and ∆FosB, which all heterodimerize with Jun to form the AP-1 transcription factor complex [24]. This complex then associates its specific cyclic AMP response element (CRE), the AP-1 binding site, leading to increased transcription of genes downstream of these sequences.

Fos genes are considered immediate early genes (IEGs), or factors that are basally expressed at low levels but elevated rapidly by specific stimuli (first reviewed in the context of neuronal cells [25]). Since it was upregulated by other plasticity and memory-inducing events, it was hypothesized that c-Fos, and possibly other IEGs, may alter gene expression involved in memory formation [26]. As expected, the upregulation of c-Fos, FosB, ∆FosB, and Jun leads to increased AP-1-mediated transcription within addiction-related regions such as the NAc rapidly after acute drug administration [27]. Due to its regional specificity, it was hypothesized that alterations in these genes may provide a mechanism for reorganization of functional interactions between these brain regions in addiction [28]. Although c-Fos is rapidly upregulated and returns to basal levels quickly, AP-1 binding continues in the absence of elevated c-Fos mRNA or protein expression suggesting that other Fos proteins may replace c-Fos and accumulate during chronic use of drugs. This may provide a molecular trace of chronic drug use in the absence of drug itself. This tolerance to initial c-Fos upregulation appears to be drug agnostic, as acute alcohol exposure blocked the previously observed acute cocaine upregulation of c-Fos, also suggesting that this molecular trace persists for the use of all different drugs [29].

To more specifically test the role of specific transcription factors in addiction, transgenic mice with specific mutations were engineered. The first experiment to utilize this approach used a transgenic mouse with a mutant fosB gene that prevented the production of ∆FosB. It is important to consider that this mutant fosB gene was not targeted to any specific cell type or even to the brain, but throughout the body. These mutant mice showed attenuated chronic induction of AP-1-binding activity, suggesting that the previously observed AP-1 binding without c-Fos upregulation was probably due to ∆FosB [30]. Additionally, this study was the first to link transcriptional regulation with altered addiction-like behavior. These researchers used a model of drug-seeking behavior termed conditioned place preference (CPP), where animals are trained to associate one environment with an experimenter-administered drug and a separate environment with saline [31]. Over time, animals will seek out the drug-paired cues associated with the environment where they received the drug. These fosB-mutant mice showed increased CPP compared to wild-type controls, suggesting that normal ∆FosB AP-1 binding might be involved in a compensatory or adaptive response to drugs. Fos family members have also been found to be upregulated after exposure to drug-paired cues in the absence of the drug itself, suggesting that this CPP effect may be due to the interaction between drug and cues soliciting the availability of the drug, an importance facet in addiction research [32].

Although certain molecular factors may cause increased addiction-like behavior or plasticity within one set of cells, it may cause an opposite effect on these measures in another. Cellular specificity is an important point that has been discussed in neuroscience for some time. In an experiment complimentary to this performed by Schroeder and colleagues, researchers developed an inducible system to specifically overexpress ∆FosB within D1 neurons in the striatum [33]. Neurons within the striatum are primarily GABAergic medium-spiny neurons that mostly express D1 or D2 dopamine receptors. Since D1 receptors are Gs GPCRs, they activate the neuron leading to increased GABA release, while D2 receptors are Gi and are inhibited by dopamine binding. Since drugs of abuse cause hyperdopaminergic conditions within the striatum, both D1 and D2 containing neurons play important but dissociable roles in the development of addiction. Targeted ∆FosB overexpression in D1 neurons showed a similar effect on increased CPP behavior at low doses (5 and 15 mg/kg), but normal CPP behavior at higher doses (20 mg/kg). This suggests that cocaine-induced ∆FosB expression within these cells is necessary and sufficient to promote addiction-like behaviors. Furthermore, GABAergic inhibition from these cells may play a role in CPP behavior. Finally, this is physiologically relevant, as drugs of abuse and to a lesser extent natural rewards cause upregulation of ∆FosB in this specific neuronal subtype [28, 34]. In a similar experiment, nonspecific deletion of ∆FosB throughout the body caused the same behavioral alteration, increased CPP behavior to lower doses of cocaine [30]. Although this finding may seem contradictory, when taken together with previous data, this points to the existence of other regions or possibly neuronal subtypes that act in opposition to D1 neurons. Following up on this, overexpression of ∆FosB within D2 expressing neurons in the striatum produced no effects, illustrating the cellular specificity of these drug-induced alterations [35]. Thus, ∆FosB within these regions or cells may not play a role, or possibly inhibit, the plasticity required for the development of these behaviors.

Another behavioral model frequently used to study addiction is self-administration of drugs [36]. In this model, an intravenous catheter will infuse cocaine into the animal once it has completed a specific behavioral response, usually pressing an active lever in opposition to an inactive lever that produces no effect. This can be used to study motivation to consume drugs, as the requirement for lever pressing can be made harder by increasing the number of presses required to receive an infusion of drug. Animals with a similar inducible ∆FosB genotype as used by Kelz and colleagues showed increased motivation to self-administer cocaine [37]. This was also the first experiment to show that this alteration specifically affected motivation toward drugs and not naturally rewards such as a food pellet.

Transcription factors elicit changes in the expression of genes; thus this work suggests that there must be some downstream targets of Fos proteins that are mediating these effects on addiction-related behavior. Kelz and colleagues first described a downstream target that may alter plasticity involved in these behavioral alterations [33]. Striatal neurons are normally quiescent, even with dopamine input, and thus require glutamate which is an important neurotransmitter in addiction-like behaviors to alter their firing (reviewed in [38]). Kelz and colleagues found that ∆FosB overexpression caused an increase in a specific AMPAR subunit, GluR2 which could lead to altered plasticity [39]. Additionally, they could recapitulate their effects on behavior by viral-mediated overexpression of this subunit in the striatum. Overall, many ∆FosB targets are genes that appear to be previously linked to addiction-like behaviors such as CDK5 and NFkB.

2.2. CREB, a transcription factor well established in learning and memory associated plasticity, plays a role in addiction

Drugs of abuse can cause acute regulation of molecular-signaling cascades that can modify transcription factor activity. For example, many drugs of abuse can cause acute upregulation of the second messenger cAMP within many addiction-associated brain regions [4046]. cAMP response element-binding protein (CREB) is phosphorylated in response to cAMP upregulation by a kinase sensitive to cAMP, protein kinase A (PKA; [47, 48]), calcium-calmodulin dependent kinases (CaMK) and other kinases [49]. The role of CREB in other forms of plasticity-associated memory has been well elucidated [48]. Once phosphorylated, CREB can enter the nucleus and bind to its response element, the cyclic AMP response element (CRE). CREB was first implicated in drug-induced alterations in response to acute and chronic morphine treatment within the locus coeruleus, another brain region associated with addiction [50]. Later, it was found that chronic, but not acute, morphine caused a decrease in CREB within the NAc [51]. Cocaine self-administration was found to be sensitive to PKA inhibition, an upstream regulator of CREB, by increasing lever pressing [52]. Following this experiment, it was later found that NAc overexpression of CREB caused a decrease in cocaine-CPP behavior [41]. Conversely, overexpression of a mutant CREB containing a single-point mutation, alanine for serine at residue 133, that prevents its phosphorylation and blocks its ability to regulate transcription acting as a dominant negative form of CREB, caused an increase in cocaine-CPP behavior. Further correlating the role of this transcription factor in the association of drug cues, researchers found that re-exposure to the original drug-paired environment in CPP without drug caused increased phosphorylation of CREB [53]. Highlighting the differences of behavioral tasks, it was found that NAc overexpression of CREB caused an increase in self-administration behavior [54]. This gene has also been studied in human patients. Researchers found that opioid-dependent patients were more likely to have a polymorphism in a protein that associates with CREB, CREB-binding protein, within a region associated with its activation by phosphorylation [55]. Altogether, it appears that CREB expression is involved in many aspects of addiction-related behavior.

CREB is a nuclear transcription factor that binds to CRE upstream of target genes. CREB regulation has been found to cause upregulation of ARG mRNA such as c-fos, Fosb, brain-derived neurotropic factor (BDNF), and TrkB (e.g., in methamphetamine self-administration [56]). BDNF and its receptor TrkB have a very long history in the study of addiction-related behaviors as well as general plasticity occurring within the brain [57]. Further implicating CREB as a regulator of plasticity, it has been found to be involved in late-phase forms of long-term potentiation (LTP [58]). As mentioned before, NAc neurons are normally quiescent and require glutamate activation with or without dopamine stimulation to fire. CREB has been associated with the regulation of this feature of NAc neuronal membrane excitability [59]. It was found that increased CREB activity leads to enhanced NMDAR-mediated currents, an important receptor for causing action potentials as well as for learning and memory. This regulation increases NAc neuronal-firing probability through enhancement of the membrane excitability. This may partially explain the effect of NAc CREB on behaviors such as self-administration. Thus, CREB regulates the expression of many genes associated with plasticity and addiction-related behaviors.

CREB and ∆FosB are very well-documented addiction-related transcription factors but, undoubtedly, there are many more transcriptional factors that alter addiction-related plasticity and ultimately behavior. Myocyte-enhancing factor 2 (MEF2) was found to be involved in cocaine-induced structural plasticity [60]. Interestingly, it was necessary and sufficient to increase the number of dendritic spines. Structural plasticity or the alteration of the physical synaptic shape has been associated with electrophysiological measurements of plasticity [6163] specifically in addiction [63]. Additionally, it was found that MEF2 regulates a wide network of plasticity-associated genes opening up further exploration into its role in addiction-related plasticity and behavior [64]. Overall, transcriptional regulation of ARG expression can lead to modifications in drug-evoked synaptic plasticity and behavior [65, 66].


3. Posttranscriptional regulation of plasticity and addiction-related transcripts can promote addiction-like behaviors

Posttranscriptional regulation occurs after transcription until the mRNA is translated into a functional protein. Posttranscriptional regulation takes many forms such as mRNA processing, splicing, editing, stability, and translation. mRNA stability and translation have been the most well-characterized posttranscriptional mechanism in plasticity, especially in addiction. Additionally, it appears that mRNA stability may be especially important in the brain, as nearly 20% of brain-expressed genes have been predicted to be controlled through this mechanism [67].

3.1. miRNAs destabilize specific mRNAs which could lead to diminished expression of genes involved in addiction

Stability can be influenced by direct binding of factors to discrete recognition sites. One group of factors involved in this type of mRNA stability are small noncoding RNAs, termed microRNAs (miRNAs). miRNAs are ~20–22 oligonucleotide molecules that are encoded within the genome and make up nearly 2–3% of transcribed genes but are not translated into protein. miRNAs target specific mRNAs through binding of complementary sequences within the miRNA, termed seed regions, to the 3’ untranslated region (UTR) of the mRNA. Association of miRNAs with the 5’UTR of mRNA has also been discovered [68] leading to different cellular effects, but most studies within the brain have focused on the 3’UTR. Accordingly, the rest of this section focuses on this mechanism.

Although the miRNA may associate directly with the mRNA target, the aftereffects of this binding are mediated through a large, supporting protein complex, the RNA-induced-silencing complex or RISC. Through associating with the RISC, an miRNA can target specific mRNAs for degradation or translational repression [69]. This complex contains a multitude of auxiliary proteins, with the most important being Argonaute (Ago; [70]). Ago is the component most directly involved in regulating the mRNA. There are many Ago isoforms, but generally they are separated into those containing nuclease “slicer” activity and those without. Thus, Ago is important for the well-characterized miRNA-induced destruction of mRNA.

Although one miRNA has one specific seed region to bind to mRNAs, mRNAs may have numerous sites complementary for multiple miRNAs. This suggests that a single miRNA targets many mRNAs, affecting a myriad of cellular processes and pathways. This is reminiscent of transcriptional regulation, as one transcription factor may regulate a specific sequence that is upstream of various types of genes. This opens the possibility for an miRNA that may regulate a network of plasticity-associated genes. For example, miR-9-3p was found to diminish Dmd and Sap97 mRNA [71]. These genes are negatively associated with LTP expression, thus miRNA-induced silencing of these mRNAs would reverse this effect. A hippocampal LTP-dependent behavior, the Morris water maze, was also found to be regulated by the expression of this miRNA.

Similar to a group of plasticity- and addiction-associated transcription factors, miRNA expression patterns appear to be similar to IEGs in their temporal- and activity-dependent regulation [7274]. As demonstrated before, many of these IEGs play integral roles in general plasticity and addiction-related plasticity. Similar to IEGs, miRNAs have been associated with neural development, synaptic plasticity, and even behavior [7379].

The role of miRNA-induced posttranscriptional regulation in addiction was first studied in the regulation of the large-conductance-calcium-and-voltage-activated potassium channel (BK). This channel is integral to plasticity by affecting excitability, firing, and transmitter release from neurons [80]. It is also one of the many protein targets of alcohol within the brain, for the most part potentiating its conductance [81]. This channel has been well studied in its role in tolerance to alcohol in the striatum, requiring larger amounts to exert similar effects [82]. This seems to be mediated by decreased BK channel expression in the membrane. A single gene can produce multiple mRNAs with the same coding region but with different 3’UTRs through the inclusion or exclusion of different exons [83]. Research has shown that the alpha subunit of this BK channel is alternatively spliced both in the coding region and in the 3’ UTR in response to neuronal activity [82, 84]. These researchers also found that alcohol caused a decrease in one specific BK mRNA that has an miR-9-binding site in its 3’ UTR. Given that this isoform of the BK channel mRNA is the most abundant in the striatum and miR-9 expression is increased by alcohol exposure, alcohol tolerance seems to be mediated at least in part by this miRNA [82]. As mentioned before, miRNAs target many mRNAs that contain a complementary sequence in the 3’UTR. Thus, these authors also proposed that miR-9 targets many other mRNAs such as the beta subunit of the GABA receptor, GABRB2, and the D2 receptor. Overall, this suggests that alcohol-mediated upregulation of miR-9 leads to the development of an alcohol-specific regulation of mRNAs associated with plasticity and addiction.

When animals are given extended access to drugs of abuse in a self-administration model, they undergo a specific behavioral response termed escalation of drug use. Uncontrollable use of large amount of drugs is an important facet in the human condition. With this, researchers sought out an miRNA that may be increased by this behavior and found that miR-212, an activity-dependent miRNA regulated by CREB, was upregulated in the dorsal striatum of these animals after extended access [85]. One of the targets of miR-212 is Sprout-related, EVH1 domain containing 1 (SPRED1), a corepressor of serine-threonine protein kinase Raf1, which increases the activity of adenylate cyclase by promoting its phosphorylation. Thus, upregulation of miR-212 during escalated drug use diminishes SPRED1 levels, potentiating cAMP production and CREB activity leading to increased miR-212 expression. When miR-212 was overexpressed within the dorsal striatum, rats in extended access showed decreased levels of cocaine infusions. Oppositely, blocking of miR-212 by a locked nucleic acid (LNA) caused an increase in cocaine infusions. Thus, extended access to cocaine may recruit miR-212 leading to a positive feedback loop that effectively diminishes stereotypical escalation of drug intake. Overall, this suggests miR-212 acts on a pathway involving CREB to enhance its signaling, possibly in a compensatory, protective manner.

3.2. RNA-binding proteins bind to mRNAs and can bidirectionally regulate addiction-associated mRNA translation into protein

RNA-binding proteins (RBPs) are another group of regulators of mRNA stability and translation. Some RBPs recognize discrete sequences in the 3’UTR, such as the AU-rich instability conferring elements (AREs [86]). As with miRNAs, there is potential for a single RBP to affect multiple downstream processes leading to miRNAs and RBPs to be termed “master switches” of gene regulation [87, 88]. This is especially important in the brain, as around 15–20% of brain-specific transcripts contain AREs suggesting these genes are regulated by this type of posttranscriptional regulation [67]. Fragile x-mental retardation protein (FMRP) is an RBP that regulates the translation of nearly 850 brain mRNAs, many associated with synaptic function [89]. One of its regulatory targets are the group I metabotropic glutamate receptors mGluR1 and mGluR5 [9092]. These receptors have been associated with cocaine-evoked behaviors [93, 94]. Thus, Smith and colleagues tested the role of FMRP in addiction-related behaviors [95]. They found that Fmr1 KO mice were deficient in cocaine locomotor sensitization and conditioned place preference. The effect on conditioned place preference was reversed by genetic reduction in mGluR5, suggesting that FMRPs effect on drug-evoked behaviors was due to mGluR5 activity. Finally, they found that FMRP caused a reduction in cocaine-induced structural plasticity suggesting that these behavioral deficits may be caused by this aberrant plasticity.

Although FMRP is the only RBP specifically studied in addiction-like behaviors, many more have been associated with these behaviors [96]. One such family of RBPs is the Hu, or embryonic lethal abnormal vision-like (ELAV-L) proteins. Hu proteins are brain and neuronal specific and are homologous to the Drosophila protein ELAV protein [97, 98]. HuD expression and function is activity dependent, suggesting it may regulate IEGs and other activity-dependent genes associated with plasticity [99101]. In confirmation of this idea, our laboratory has shown that HuD is critical for stabilizing U-rich containing mRNAs during neuronal development and synaptic plasticity [101]; work from our laboratory reviewed in [102, 103]. HuD is a critical regulator of multiple plasticity-associated genes, thus suggesting that it may be involved in addiction-related altered gene expression, plasticity, and ultimately behavior. Overall, posttranscriptional regulation may emerge as an important player tying drug-evoked molecular alterations with behavior.

3.3. mRNA editing can alter the sequence or expression of an addiction-related mRNA leading to alterations in addiction-related plasticity and behavior

mRNA editing is another posttranscriptional regulatory mechanism. The most common mechanism for RNA editing is through covalent modifications of a specific nucleotide, without the alteration of the original DNA-encoded gene. This would generate multiple alternative forms of a protein which may be important in different cellular contexts.

The most common mRNA modification leading to editing is the removal of an amino group and its replacement with an oxygen, termed deamination. This occurs on the N6 position of adenosine nucleotides, converting this nucleotide into an inosine. This position directly contributes to conventional Watson-Crick base pairing, thus allowing inosine to pair with cytosine similar to guanosine. Translationally, this leads to the original adenosine to be read as a guanine, effectively causing an A→G site-directed mutagenesis. This modification is catalyzed by adenosine deaminase that acts on RNA (ADAR) enzymes [104108].

Specific mRNA editing in a neurophysiological context was first described in the GluRA2 subunit of AMPAR [109]. As mentioned before, editing of mRNA is a rapid mechanism to generate multiple alternative forms of a protein depending on environmental circumstances. These receptors are integral to excitatory synaptic signaling, especially in plasticity. Thus, AMPAR editing generates channels that are impermeable to calcium and displays faster recovery rates from desensitization. In terms of drug-induced plasticity, a recent study demonstrated that GluA2 editing by ADAR2 in the NAc of rats regulates cocaine seeking [110]. These researchers studied reinstatement, a specific stage of drug self-administration [36]. Animals first need to learn the required instrumental behavior to receive a reward in self-administration. When the animal reaches an experimenter-determined criterion, then the animal is said to have “acquired” self-administration behavior. If the animal is then presented with the same context and levers, but rewards are withdrawn, the animal will eventually override the previously learned reward-driven behavior. Eventually, the animal will no longer perform the task required for the reward, which is termed extinction. Finally, when an animal is exposed to cues associated with the reward or the reward itself, the animal will reinstate its behavior to receive the reward. Reinstatement is thought to be analogous to relapse in human-addiction patients. In this study, they found that abstinence from cocaine was associated with a decrease in NAc-edited calcium-impermeable AMPAR as well as ADAR2. Next, Schmidt and colleagues overexpressed ADAR2 within the NAc. They found that this diminished cocaine-primed reinstatement of self-administration behavior, suggesting that ADAR2 within the NAc is important for the regulation of relapse-like behavior. Overall, there are many avenues for mRNA editing in drug-induced plasticity and addiction-like behaviors [111].

Another posttranscriptional mRNA modification is the covalent modification of adenosine to N6-methyladenosine (m6A). This modification is carried out by a methyltransferase complex, containing WTAP, METTL14, and KIAA1429. Hence, this complex is usually thought of as the “writers” of m6A modifications. In opposition to the activity of this complex, enzymes have been discovered that promote the demethylation of mRNA, or the “erasers” of these modifications. These modifications have been studied for many years as a stable, unalterable modification. However, with the discovery of m6A demethylases this shifted opinion to suggest that this modification is dynamic and thus could be regulated by physiological conditions (reviewed in [112]). For example, it was reported that regulation of m6A was important to the normal functioning of the circadian rhythm in mammals [113]. Thus, m6A is physiologically relevant in behavior.

The first m6A demethylase to be discovered was the fat mass and obesity-associated protein (FTO). As the name suggests, it was identified as the strongest genetic variation to predispose patients to obesity [114117]. At the opening of this chapter, evidence was presented to show that addiction-related neurocircuitry originally evolved to elicit goal-directed behavior toward food, suggesting this gene may also be involved in other forms of goal-directed behavior. The first study to link these findings was performed in alcoholic patients, finding that the genotype associated with obesity (rs9939609) was inversely correlated with general alcohol consumption, measures of alcohol dependence, as well as cigarette use [118].

Later work found that this gene is expressed in dopaminergic neurons within the midbrain and is increased by acute cocaine administration (20 mg/kg [119]). Cocaine, and to a lesser extent amphetamines, inhibits the dopamine transporter (DAT), leading to increased synaptic dopamine. This in turn leads to hyperactivation of dopamine receptors on both sides of the synapse. The presynaptic terminal contains D2 and D3 receptors, which are inhibitory GPCRs. Thus, the presynaptic dopaminergic neuron will show increased suppression of firing in response to cocaine. In the next set of experiments, these researchers found that Fto-deficient dopaminergic neurons showed diminished cocaine-induced suppression of firing rate, suggesting that signaling through D2/D3 receptors is regulated by Fto. As expected, it was found that protein expression of these downstream targets (DRD3, GIRK2, and NMDAR1) was reduced by Fto deficiency. Functionally, Fto deficiency led to a reduction in GIRK currents, possibly detailing a mechanism for the diminished cocaine-induced suppression of firing rate in dopaminergic neurons. Finally, Fto-deficient mice showed attenuated acute cocaine-induced locomotor activity, suggesting that these genetic and electrophysiological measures translate into this behavioral modification.


4. Conclusion

As shown here, there are many avenues for regulation of ARGs at the transcriptional or the posttranscriptional level. These regulatory mechanisms all have been implicated in the development of this disorder and thus may be involved in the vulnerability of some individuals to substance-use disorders. Understanding the regulation of addiction-related genes and their impact on synaptic plasticity and behavior may inform new pharmacological treatments that reverse these aberrant drug-evoked forms of plasticity in favor of remission.


  1. 1. Lüscher C, Ungless MA. The mechanistic classification of addictive drugs. PLoS Med. 2006;3:2005–10.
  2. 2. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A. 1988;85(July):5274–8.
  3. 3. Nestler EJ. Is there a common molecular pathway for addiction? Nat Neurosci. 2005;8(11):1445–9. Available from:
  4. 4. Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci. 2002;22(9):3306–11.
  5. 5. Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68:815–34.
  6. 6. Kolb B, Gorny G, Li Y, Samaha A-N, Robinson TE. Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens. Proc Natl Acad Sci U S A. 2003;100(18):10523–8.
  7. 7. Hamilton D a, Kolb B. Differential effects of nicotine and complex housing on subsequent experience-dependent structural plasticity in the nucleus accumbens. Behav Neurosci. 2005;119(2):355–65.
  8. 8. Stuber GD, Klanker M, de Ridder B, Bowers MS, Joosten RN, Feenstra MG, et al. Reward-predictive cues enhance excitatory synaptic strength onto midbrain dopamine neurons.Science. 2008 (5896):1690–2. Available from:
  9. 9. McLellana T, Lewis DC, O’Brien CP, Kleber HD. Drug dependence, a chronic medical illness. JAMA J Am Med Assoc. 2000;284(13):1689.
  10. 10. Shen H, Toda S, Moussawi K, Bouknight A, Zahm DS, Kalivas PW. Altered dendritic spine plasticity in cocaine-withdrawn rats. J Neurosci. 2009;29(9):2876–84.
  11. 11. Montiel T, Almeida D, Arango I, Calixto E, Casasola C, Brailowsky S. Long-lasting effects of GABA infusion into the cerebral cortex of the rat. Neural Plast. 2000;7(1–2):1–8. Available from:
  12. 12. Hernandez PJ, Sadeghian K, Kelley AE. Early consolidation of instrumental learning requires protein synthesis in the nucleus accumbens. Nat Neurosci. 2002;5(12):1327–31.
  13. 13. Scheyer AF, Wolf ME, Tseng KY. A protein synthesis-dependent mechanism sustains calcium-permeable AMPA receptor transmission in nucleus accumbens synapses during withdrawal from cocaine self-administration. J Neurosci. 2014;34(8):3095–100. Available from:
  14. 14. Bastle RM, Neisewander JL. Epigenetics and drug. In: Bastle RM, Neisewander JL, William Meil, editors. Recent Advances in Drug Addiction Research and Clinical Applications. InTech, Rijeka, Croatia; 2016. Available from:
  15. 15. Cadet JL, McCoy MT, Jayanthi S. Epigenetics and addiction. Clin Pharmacol Ther. 2016;99(5):502–11. Available from: 1002/cpt.345
  16. 16. Tuesta LM, Zhang Y. Mechanisms of epigenetic memory and addiction. EMBO J. 2014 Apr 28;33(10):1091 LP-1103. Available from:
  17. 17. Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci. 2011;12(11):623–37. Available from: 1038/nrn3111
  18. 18. Fleming EW, Woodson ME, Tewari S. Ethanol and cycloheximide alter protein and RNA synthesis of Cox astrocytoma cells in culture. J Neurosci Res. 1981;6(4):511–24. Available from: 1002/jnr.490060408
  19. 19. Chang SL, Squinto SP, Harlan RE. Morphine activation of c-fos expression in rat brain. Biochem Biophys Res Commun. 1988;157(2):698–704. Available from:
  20. 20. Graybiela M, Moratalla R, Robertson HA. Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum. Proc Natl Acad Sci U S A. 1990;87(17):6912–6.
  21. 21. Young ST, Porrino LJ, Iadarola MJ. Cocaine induces striatal c-fos-immunoreactive proteins via dopaminergic D1 receptors. Proc Natl Acad Sci U S A. 1991;88(4):1291–5.
  22. 22. Persico AM, Schindler CW, O’Hara BF, Brannock MT, Uhl GR. Brain transcription factor expression: effects of acute and chronic amphetamine and injection stress. Mol Brain Res. 1993;20(1–2):91–100.
  23. 23. Hayward MD, Duman RS, Nestler EJ. Induction of the c-fos proto-oncogene during opiate withdrawal in the locus coeruleus and other regions of rat brain. Brain Res. 1990;525(2):256–66.
  24. 24. Milde-Langosch K. The Fos family of transcription factors and their role in tumourigenesis. Eur J Cancer. 2005;41(16):2449–61. Available from:
  25. 25. Sheng M, Greenberg ME. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron. 1990;4(4):477–85.
  26. 26. Curran T, Morgan JI, Butler S. Memories of fos. BioEssays. 1987;7(6):255–8.
  27. 27. Hope BT, Kosofsky B, Hyman SE, Nestler EJ. Regulation of immediate early gene expression and AP-1 binding in the rat nucleus accumbens by chronic cocaine. Proc Natl Acad Sci U S A. 1992;89(13):5764–8. Available from:
  28. 28. Moratalla R, Vallejo M, Elibol B, Graybiel AM. D1-class dopamine receptors influence cocaine-induced persistent expression of Fos-related proteins in striatum. Neuroreport. 1996;8(1):1–5. Available from:
  29. 29. Torres G. Acute administration of alcohol blocks cocaine-induced striatal c-fos immunoreactivity protein in the rat. Synapse. 1994;18(2):161–7.
  30. 30. Hiroi N, Brown JR, Haile CN, Ye H, Greenberg ME, Nestler EJ. FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine’s psychomotor and rewarding effects. Proc Natl Acad Sci U S A. 1997;94(19):10397–402. Available from:\n
  31. 31. Tzschentke TM. Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol. 2007;12(3–4):227–462.
  32. 32. Schroeder BE, Holahan MR, Landry CF, Kelley AE. Morphine-associated environmental cues elicit conditioned gene expression. Synapse. 2000;37(2):146–58.
  33. 33. Kelz MB, Chen J, Carlezon WA, Whisler K, Gilden L, Beckmann AM, et al. Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine. Nature. 1999;401(6750):272–6. Available from: html\npapers3://publication/uuid/F51CD165-BEAE-4D11-BDAB-02B1F29A79C5
  34. 34. Nye HE, Hope BT, Kelz MB, Iadarola M, Nestler EJ. Pharmacological studies of the regulation of chronic FOS-related antigen induction by cocaine in the striatum and nucleus accumbens. J Pharmacol Exp Ther. 1995;275(3):1671–80. Available from:
  35. 35. Zachariou V, Bolanos CA, Selley DE, Theobald D, Cassidy MP, Kelz MB, et al. An essential role for DeltaFosB in the nucleus accumbens in morphine action. Nat Neurosci. 2006;9(2):205–11. Available from:
  36. 36. Roberts DCS, Morgan D, Liu Y. How to make a rat addicted to cocaine. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31(8):1614–24.
  37. 37. Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW. Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine. J Neurosci. 2003;23(6):2488–93. Available from: abstract\n
  38. 38. van Huijstee AN, Mansvelder HD. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction. Front Cell Neurosci. 2015;8(January):1–13. Available from: 3389/fncel.2014. 00466/abstract
  39. 39. Kauer J a, Malenka RC. Synaptic plasticity and addiction. Nat Rev Neurosci. 2007;8(11):844–58.
  40. 40. Cole RL, Konradi C, Douglass J, Hyman SE. Neuronal adaptation to amphetamine and dopamine: Molecular mechanisms of prodynorphin gene regulation in rat striatum. Neuron. 1995;14(4):813–23.
  41. 41. Carlezon Jr. WA, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, et al. Regulation of cocaine reward by CREB. Science. 1998;282(5397):2272–5. Available from:
  42. 42. Berke JD, Hyman SE. Addiction, dopamine, and the molecular mechanisms of memory. Neuron. 2000;25(3):515–32.
  43. 43. Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci. 2001;2(2):119–28.
  44. 44. Shaw-Lutchman TZ, Barrot M, Wallace T, Gilden L, Zachariou V, Impey S, et al. Regional and cellular mapping of cAMP response element-mediated transcription during naltrexone-precipitated morphine withdrawal. J Neurosci. 2002;22(9):3663–72. Available from:\n full.pdf
  45. 45. Shaw-Lutchman TZ, Impey S, Storm D, Nestler EJ. Regulation of CRE-mediated transcription in mouse brain by amphetamine. Synapse. 2003;48(1):10–7.
  46. 46. Walters CL, Kuo YC, Blendy JA. Differential distribution of CREB in the mesolimbic dopamine reward pathway. J Neurochem. 2003;87(5):1237–44.
  47. 47. Shaywitz AJ, Greenberg ME. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 1999;68:821–61.
  48. 48. Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol. 2001;2(8):599–609. Available from:
  49. 49. Sheng M, Thompson MA, Greenberg ME. CREB: a Ca2+-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science. 1991;252:1427–30.
  50. 50. Guitart X, Thompson M a, Mirante CK, Greenberg ME, Nestler EJ. Regulation of cyclic AMP response element-binding protein (CREB) phosphorylation by acute and chronic morphine in the rat locus coeruleus. J Neurochem. 1992;58:1168–71.
  51. 51. Widnell KL, Self DW, Lane SB, Russell DS, Vaidya VA, Miserendino MJ, et al. Regulation of CREB expression: in vivo evidence for a functional role in morphine action in the nucleus accumbens. J Pharmacol Exp Ther. 1996;276(1):306–15. Available from:
  52. 52. Self DW, Genova LM, Hope BT, Barnhart WJ, Spencer JJ, Nestler EJ. Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self administration and relapse of cocaine-seeking behavior. J Neurosci. 1998;18:1848–59. Available from:
  53. 53. Tropea TF, Kosofsky BE, Rajadhyaksha AM. Enhanced CREB and DARPP-32 phosphorylation in the nucleus accumbens and CREB, ERK, and GluR1 phosphorylation in the dorsal hippocampus is associated with cocaine-conditioned place preference behavior. J Neurochem. 2008;106(4):1780–90.
  54. 54. Larson EB, Graham DL, Arzaga RR, Buzin N, Webb J, Green T a., et al. Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats. J Neurosci. 2011;31(45):16447–57.
  55. 55. Kumar D, Deb I, Chakraborty J, Mukhopadhyay S, Das S. A polymorphism of the CREB binding protein (CREBBP) gene is a risk factor for addiction. Brain Res. 2011;1406:59–64.
  56. 56. Krasnova IN, Chiflikyan M, Justinova Z, McCoy MT, Ladenheim B, Jayanthi S, et al. CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat. Neurobiol Dis. 2013;58:132–43.
  57. 57. Li X, Wolf ME. Multiple faces of BDNF in cocaine addiction. Behav Brain Res. 2015;279:240–54. Available from: 1016/j.bbr.2014. 11. 018
  58. 58. Barco A, Alarcon JM, Kandel ER. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell. 2002;108(5):689–703.
  59. 59. Huang YH, Lin Y, Brown TE, Han MH, Saal DB, Neve RL, et al. CREB modulates the functional output of nucleus accumbens neurons: a critical role of N-methyl-D-aspartate glutamate receptor (NMDAR) receptors. J Biol Chem. 2008;283(5):2751–60.
  60. 60. Pulipparacharuvil S, Renthal W, Hale CF, Taniguchi M, Xiao G, Kumar A, et al. Cocaine regulates MEF2 to control synaptic and behavioral plasticity. Neuron. 2008;59(4):621–33.
  61. 61. Yagishita S, Hayashi-Takagia., Ellis-Davies GCR, Urakubo H, Ishii S, Kasai H. A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science. 2014;345(6204):1616–20.
  62. 62. Alvarez V a, Sabatini BL. Anatomical and physiological plasticity of dendritic spines. Annu Rev Neurosci. 2007;30:79–97.
  63. 63. Russo SJ, Dietz DM, Dumitriu D, Morrison JH, Malenka RC, Nestler EJ. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 2010;33(6):267–76. Available from: 1016/j.tins.2010. 02. 002
  64. 64. Flavell SW, Kim TK, Gray JM, Harmin DA, Hemberg M, Hong EJ, et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron. 2008;60(6):1022–38.
  65. 65. Persico AM, Uhl GR. Transcription factors: potential roles in drug-induced neuroplasticity. Rev Neurosci. 1996;7(4):233–75.
  66. 66. Nestler EJ. Transcriptional mechanisms of drug addiction. Clin Psychopharmacol Neurosci. 2012;10(3):136–43. Available from:
  67. 67. Bolognani F, Contente-Cuomo T, Perrone-Bizzozero NI. Novel recognition motifs and biological functions of the RNA-binding protein HuD revealed by genome-wide identification of its targets. Nucleic Acids Res. 2009;38(1):117–30.
  68. 68. Panda AC, Sahu I, Kulkarni SD, Martindale JL, Abdelmohsen K, Vindu A, et al. MiR-196b-mediated translation regulation of mouse insulin2 via the 5ʹUTR. PLoS One. 2014;9(7):1–11.
  69. 69. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.
  70. 70. Sontheimer EJ. Assembly and function of RNA silencing complexes. Nat Rev Mol Cell Biol. 2005;6(2):127–38.
  71. 71. Sim S-E, Lim C-S, Kim J-I, Daekwan Seo X, Chun H, Nam-Kyung Yu X, et al. Cellular/molecular the brain-enriched MicroRNA miR-9-3p regulates synaptic plasticity and memory. 2016;36(33):8641–52.
  72. 72. Nudelman AS, Dirocco DP, Lambert TJ, Garelick MG, Le J, Nathanson NM, et al. Neuronal activity rapidly induces transcription of the CREB-regulated microRNA-132, in vivo. Hippocampus. 2010;20(4):492–8.
  73. 73. Krol J, Busskamp V, Markiewicz I, Stadler MB, Ribi S, Richter J, et al. Characterizing light-regulated retinal microRNAs reveals rapid turnover as a common property of neuronal microRNAs. Cell. 2010;141(4):618–31.
  74. 74. Joilin G, Guévremont D, Ryan B, Claudianos C, Cristino AS. Rapid regulation of microRNA following induction of long-term potentiation in vivo. Front Mol Neurosci. 2014;7:98.
  75. 75. Vo N, Klein ME, Varlamova O, Keller DM, Yamamoto T, Goodman RH, et al. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci U S A. 2005;102(45):16426–31.
  76. 76. Kosik KS. The neuronal microRNA system. Nat Rev Neurosci. 2006;7(12):911–20.
  77. 77. Schratt GM, Tuebing F, Nigh E a, Kane CG, Sabatini ME, Kiebler M, et al. A brain-specific microRNA regulates dendritic spine development. Nature. 2006;439(7074):283–9.
  78. 78. Kim J, Inoue K, Ishii J, Vanti WB, Voronov S V, Murchison E, et al. A MicroRNA feedback circuit in midbrain dopamine neurons. Science. 2007;317(5842):1220–4. Available from: abstract
  79. 79. Fiore R, Siegel G, Schratt G. MicroRNA function in neuronal development, plasticity and disease. Biochim Biophys Acta Gene Regul Mech. 2008;1779(8):471–8.
  80. 80. Storm JF. Potassium currents in hippocampal pyramidal cells. Prog Brain Res. 1990;83:161–87.
  81. 81. Butler A, Tsunoda S, McCobb DP, Wei A, Salkoff L. mSlo, a complex mouse gene encoding “maxi” calcium-activated potassium channels. Sci (New York, NY). 1993;261(5118):221–4. Available from:\npapers3://publication/uuid/DAB5A528-4A25-49DE-8BE9-051FDF21F823
  82. 82. Pietrzykowski AZ, Martin GE, Puig SI, Knott TK, Lemos JR, Treistman SN. Alcohol tolerance in large-conductance, calcium-activated potassium channels of CNS terminals is intrinsic and includes two components: decreased ethanol potentiation and decreased channel density. J Neurosci. 2004;24(38):8322–32. Available from:
  83. 83. Legendre M, Ritchie W, Lopez F, Gautheret D. Differential repression of alternative transcripts: a screen for miRNA targets. PLoS Comput Biol. 2006;2(5):333–42.
  84. 84. Xie J, McCobb DP. Control of alternative splicing of potassium channels by stress hormones. Science. 1998;280(5362):443–6.
  85. 85. Im H-I, Hollander J a, Bali P, Kenny PJ. MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nat Neurosci. 2010;13(9):1120–7. Available from: 1038/nn.2615
  86. 86. Bakheet T, Williams BRG, Khabar KSA. ARED 3. 0: the large and diverse AU-rich transcriptome. Nucleic Acids Res. 2006;34 (suppl 1):D111–4.
  87. 87. Deschênes-Furry J, Perrone-Bizzozero N, Jasmin BJ. The RNA-binding protein HuD: a regulator of neuronal differentiation, maintenance and plasticity. BioEssays. 2006;28(8):822–33.
  88. 88. Keene JD. RNA regulons: coordination of post-transcriptional events. Nat Rev Genet. 2007;8(7):533–43.
  89. 89. Darnell JC, Van Driesche SJ, Zhang C, Hung KYS, Mele A, Fraser CE, et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell. 2011;146(2):247–61.
  90. 90. Ceman S, O’Donnell WT, Reed M, Patton S, Pohl J, Warren ST. Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet. 2003;12(24):3295–305.
  91. 91. Nalavadi VC, Muddashetty RS, Gross C, Bassell GJ. Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: a role in immediate early mGluR-stimulated translation. J Neurosci. 2012;32(8):2582–7.
  92. 92. Narayanan U, Nalavadi V, Nakamoto M, Pallas DC, Ceman S, Bassell GJ, et al. FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A. J Neurosci. 2007;27(52):14349–57.
  93. 93. Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, et al. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci. 2001;4(9):873–4. Available from:
  94. 94. Olsen CM, Childs DS, Stanwood GD, Winder DG. Operant sensation seeking requires metabotropic glutamate receptor 5 (mGluR5). PLoS One. 2010;5(11).
  95. 95. Smith LN, Jedynak JP, Fontenot MR, Hale CF, Dietz KC, Taniguchi M, et al. Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration. Neuron. 2014;82(3):645–58. Available from:
  96. 96. Bryant CD, Yazdani N. RNA binding proteins, neural development and the addictions. Genes Brain Behav. 2015;15(1):169–86. Available from:
  97. 97. Szabo A, Dalmau J, Manley G, Rosenfeld M, Wong E, Henson J, et al. HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal. Cell. 1991;67(2):325–33.
  98. 98. Yao KM, Samson ML, Reeves R, White K. Gene elav of Drosophila melanogaster: a prototype for neuronal-specific RNA binding protein gene family that is conserved in flies and humans. J Neurobiol. 1993;24:723–39.
  99. 99. Bolognani F, Tanner DC, Nixon S, Okano HJ, Okano H, Perrone-Bizzozero NI. Coordinated expression of HuD and GAP-43 in hippocampal dentate granule cells during developmental and adult plasticity. Neurochem Res. 2007;32(12):2142–51.
  100. 100. Tiruchinapalli DM, Ehlers MD, Keene JD. Activity-dependent expression of RNA binding protein HuD and its association with mRNAs in neurons. RNA Biol. 2008;5(3):157–68.
  101. 101. Vanevski F, Xu B. HuD Interacts with Bdnf mRNA and is essential for activity-induced BDNF synthesis in dendrites. PLoS One. 2015;10(2):e0117264. Available from: 1371/journal.pone.0117264
  102. 102. Perrone-Bizzozero N, Bolognani F. Role of HuD and other RNA-binding proteins in neural development and plasticity. J Neurosci Res. 2002;68(2):121–6.
  103. 103. Bolognani F, Perrone-Bizzozero NI. RNA-protein interactions and control of mRNA stability in neurons. J Neurosci Res. 2008;68:481–9.
  104. 104. Bass BL, Weintraub H. An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell. 1988;55(6):1089–98.
  105. 105. Kim U, Wang Y, Sanford T, Zeng Y, Nishikura K. Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. Proc Natl Acad Sci U S A. 1994;91(24):11457–61. Available from:
  106. 106. Kim U, Garner TL, Sanford T, Speicher D, Murray JM, Nishikura K. Purification and characterization of double-stranded-RNA adenosine deaminase from bovine nuclear extracts. J Biol Chem. 1994;269:13480–9.
  107. 107. Melcher T, Maas S, Herba, Sprengel R, Seeburg PH, Higuchi M. A mammalian RNA editing enzyme. Nature. 1996;379:460–4.
  108. 108. Wagnert RW, Smitht JE, Coopermant BS, Nishikurat K. A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells. Proc Natl Acad Sci. 1989;86:2647–51.
  109. 109. Lomeli H, Mosbacher J, Melcher T, Höger T, Geiger JR, Kuner T, et al. Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science. 1994;266(5191):1709–13.
  110. 110. Schmidt HD, McFarland KN, Darnell SB, Huizenga MN, Sangrey GR, Cha J-HJ, et al. ADAR2-dependent GluA2 editing regulates cocaine seeking. Mol Psychiatry. 2014;(February):1–7. Available from: 1038/mp.2014. 134
  111. 111. Rosenthal JJC. The emerging role of RNA editing in plasticity. J Exp Biol. 2015;218:1812–21.
  112. 112. Cao G, Li H-B, Yin Z, Flavell RA. Recent advances in dynamic m6A RNA modification. Open Biol. 2016;6(4):160003. Available from:
  113. 113. Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S, Yoshida M, et al. RNA-methylation dependent RNA processing controls the speed of the circadian clock. Cell. 2013:155(4):793–806.
  114. 114. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889–94. Available from:
  115. 115. Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007;39(6):724–6. Available from: 1038/ng2048
  116. 116. Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CNA, Ph D, et al. An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med. 2008;359(24):2558–66. Available from:
  117. 117. Wardle J, Carnell S, Haworth CMA, Farooqi IS, O’Rahilly S, Plomin R. Obesity associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab. 2008;93(9):3640–3.
  118. 118. Sobczyk-Kopciol A, Broda G, Wojnar M, Kurjata P, Jakubczyk A, Klimkiewicz A, et al. Inverse association of the obesity predisposing FTO rs9939609 genotype with alcohol consumption and risk for alcohol dependence. Addiction. 2011;106(4):739–48. Available from:
  119. 119. Hess ME, Hess S, Meyer KD, Verhagen L a W, Koch L, Brönneke HS, et al. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci. 2013;16(8):1042–8. Available from:

Written By

Robert J Oliver and Nora I Perrone-Bizzozero

Submitted: May 27th, 2016 Reviewed: December 16th, 2016 Published: June 21st, 2017