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Erasing Drug Memories Through the Disruption of. Memory Reconsolidation: A Review of Glutamatergic. Mechanisms. Torry S. Dennis and Linda I. Perrotti1.
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Erasing Drug Memories Through the Disruption of Memory Reconsolidation: A Review of Glutamatergic Mechanisms

Torry S. Dennis and Linda I. Perrotti1 Department of Psychology University of Texas at Arlington

Over the past decade, a growing body of research has sought to investigate how the pharmacological disruption of memory reconsolidation can degrade or erase memories. Much of this research has focused specifically on disrupting memories that are considered bad or maladaptive for the ultimate purpose of translation to a human population. While most of the research was pioneered in fear memory, recent studies have focused on degrading drug-cued memories in the context of addiction. Essentially, this research seeks to disrupt cues as predictors of reward or drug availability. A core component of this reconsolidation process is glutamate signaling. An overall review of the literature suggests that disruption of glutamate signaling under reconsolidation parameters is sufficient to erase drug-related memories. This review will focus on specific studies that examine the glutamatergic mechanisms of reconsolidation disruption in the context of drug addiction.

Introduction Drug addiction can be characterized as a disorder of maladaptive learning and memory (Everitt, Dickinson, & Robbins, 2001). Addictive drugs have the ability to hijack the natural reward system and influence the strength of memories that predict reward (Everitt et al., 2001; Hyman, 2005; Hyman, Malenka, & Nestler, 2006; Torregrossa, Corlett, & Taylor, 2011). These memories can be linked to external cues in the environment that have previously been accompanied by drug use (Crombag & Shaham, 2002). Cues can take multiple forms, including environments where drugs are regularly consumed (Wing & Shoaib, 2008) or any paraphernalia used to prepare or consume the drug (Robbins, Ehrman, Childress, & O’Brien, 1999; Tolliver et al., 2010). These cues have no innate prediction for drug

1 Correspondence concerning this article should be addressed to Linda I. Perrotti, Department of Psychology, University of Texas at Arlington, Arlington, TX 76019, USA. E-mail: [email protected]

101 Journal of Applied Biobehavioral Research, 2015, 20, 3, pp. 101–129 © 2015 Wiley Periodicals, Inc.

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reward, but acquire a conditioned value through their association with the drug of abuse (Di Ciano & Everitt, 2004). Exposure to these cues in addicted persons can elicit craving, enhance motivation to seek out the drug, and can ultimately facilitate relapse (Di Ciano & Everitt, 2004; Epstein et al., 2009; Fuchs, See, & Middaugh, 2003; Volkow et al., 2006). It is therefore important to pursue research that can effectively degrade these cues as predictors of drug availability and reward. A relatively new direction in the field of addiction has sought to do just that through the manipulation of memory systems (Sorg, 2012). Memories are not permanent and flawless records of our past experience, but rather the manifestation of malleable networks of neurons that undergo augmentation and updating as a course of normal functioning (Lee, 2009). When memories are accessed, they return to a labile state that requires reconsolidation to take place for the memory to be preserved (Kaang, Lee, & Kim, 2009; Misanin, Miller, & Lewis, 1968). If the reconsolidation process is disrupted, the strength of the activated network is decreased and, consequently, the salience of the memory is degraded (Nader, Schafe, & Le Doux, 2000). A growing body of research has focused on selectively disrupting the reconsolidation process for memories that are considered disruptive or maladaptive (Brown, Lee, & Sorg, 2008; Brunet et al., 2008; Nader et al., 2000; Sadler, Herzig, & Schmidt, 2007; Schiller et al., 2009; Wouda et al., 2010). This research has been pioneered by groups focusing on disrupting fear memories to treat posttraumatic stress disorder (PTSD) (Diergaarde, Schoffelmeer, & De Vries, 2008). However, there is a growing body of literature that seeks to disrupt memories for cues that have previously been paired with drugs of abuse (Sorg, 2012). This review will address advancements in the pharmacological treatment of addiction focusing on the disruption of the glutamatergic mechanisms involved in reconsolidation of drug-paired memories. Specifically, this paper will (1) discuss general reconsolidation mechanisms; (2) characterize the glutamatergic mechanisms underlying the destabilization and reconsolidation processes of memory; (3) describe studies that have sought to disrupt drug-cued memories through these mechanisms; and (4) discuss current limitations and the need for further research. General Reconsolidation Mechanisms Consolidation Versus Reconsolidation While this review is focused primarily on the reconsolidation process, it is important to describe the distinction between consolidation and reconsolidation. Consolidation refers to the initial acquisition of a memory whereas reconsolidation refers to the reorganization and resolidification of that original memory following its reactivation (Besnard, Caboche, & Laroche, 2012). Some suggest consolidation and reconsolidation are two distinct events (Alberini, 2005)

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while others suggest they ultimately represent the same underlying processes (Dudai, 2012; McKenzie & Eichenbaum, 2011). For instance, Alberini (2005) argues that these processes are distinct in that consolidation recruits brain areas/ circuits that reconsolidation does not, and that initial consolidation is always accompanied by lability (something not always observed after reactivation of a memory). However, others suggest that even initial consolidation is actually reconsolidation into existing memory networks and that, ultimately, consolidation and reconsolidation are the same process (Dudai, 2012; McKenzie & Eichenbaum, 2011). It has also been suggested that the discrepancies seen between consolidation and reconsolidation in the literature are largely the artifact of the design of the experiments and the limitations of the boundary conditions (discussed next) of the reconsolidation process (for an excellent review, see McKenzie & Eichenbaum, 2011). While the debate continues, this paper will focus on those experiments that are designed specifically to measure reconsolidation. Boundary Conditions There are several conditions that must be considered when studying the reconsolidation process. Factors have been identified that can limit reconsolidation of a memory; these are referred to as “boundary conditions” (Besnard et al., 2012; Tronson & Taylor, 2007). These include factors such as the strength of the memory (Eisenberg, Kobilo, Berman, & Dudai, 2003; Morris et al., 2006), the amount of time that has passed since the memory was originally encoded (Frankland et al., 2006; Milekic & Alberini, 2002), and the length of reexposure to a memory-reactivating stimulus during a reactivation trial (Pedreira & Maldonado, 2003; Suzuki et al., 2004). For example, very old memories and very strong memories that result from repeated training sessions are resistant to reconsolidation, but a labile state can be achieved if reexposure to the cue is sufficiently long (Suzuki et al., 2004). There is also evidence that the memory is more vulnerable to destabilization (and thus reconsolidation) if there is a violation of expectation (Winters, Tucci, & DaCosta-Furtado, 2009). For example, if the outcome of a particular cue presentation is unexpected, the memory linked to that cue is more susceptible to disruption. These factors must be considered while examining the paradigms that seek specifically to measure reconsolidation. Not considering these factors can potentially lead to false negatives and erroneous interpretations of the data. Current Scope of the Reconsolidation Field Once retrieved and destabilized, memory can be updated with new information and must actively undergo reconsolidation to once again become stable (Lee,

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2008; Nader et al., 2000). Although the mechanisms have not been fully elucidated, a number of factors contribute to this active reconsolidation process. Most broadly, protein synthesis is required for the reconsolidation of the memory (Debiec, LeDoux, & Nader, 2002; Lee, 2008; Nader et al., 2000). One of the pioneering papers in the field of reconsolidation established that reconsolidation of fear memory could be disrupted through the “post-reactivation” administration of a protein synthesis inhibitor into the amygdala of a rat (Nader et al., 2000). Since the publication of this paper, research in this field has rapidly expanded. An increased number of animal models (crab, chick, fish, fruit fly, honeybee, mouse, nematode, rat, rabbit, sea slug, snail), memory types (fear, spatial, recognition, motor, odor cued, drug paired, conditioned taste aversion), and injection sites (prefrontal cortex, basolateral amygdala, nucleus accumbens, hippocampus, intracerebroventricular, systemic) have been utilized in exploring these reconsolidation mechanisms (Besnard et al., 2012). Although a number of neurotransmitter systems, signaling molecules, and transcription factors have been implicated in these processes, a core component is glutamatergic signaling (Tronson & Taylor, 2007). By understanding the molecular mechanisms of memory destabilization and reconsolidation, we can better understand the conditions by which these maladaptive memories can be pharmacologically altered. Glutamatergic System Involvement in Memory Reconsolidation Glutamate Receptors and Synaptic Plasticity In order to discuss the importance of the glutamate system in reconsolidation, one must first examine the basic components of this system (most notably, glutamate receptors). Glutamate receptors have an established history of importance in synaptic plasticity of learning and memory. Specifically, NMethyl-D-aspartic acid (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors are crucial for a type of synaptic plasticity called long-term potentiation (LTP) (Cooke & Bliss, 2006). While LTP has been most extensively studied in the hippocampus, brain areas associated with addiction neurocircuitry (ventral tegmental area, nucleus accumbens, amygdala, bed nucleus of stria terminalis) also show evidence of LTP-induced plasticity (Kauer & Malenka, 2007). Under the classic model of LTP, stimulation of AMPA receptors at the membrane by glutamate results in an influx of sodium ions. This influx increases the membrane potential of the postsynaptic cell. At the same time, glutamate also binds to the NMDA receptor, but ions cannot flow through it until the membrane potential reaches a sufficiently high voltage needed to eject a magnesium ion blocking the ion channel of this receptor. Once the membrane potential reaches this threshold, the magnesium ion is removed and

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both sodium and calcium enter the cell through this channel. The influx of calcium activates second messenger systems that enhance the strength of the connection between the presynaptic and postsynaptic neurons (Malenka & Bear, 2004). One way in which these systems work is through the trafficking and insertion of additional AMPA receptors into the postsynaptic membrane, making the postsynaptic cell more sensitive to the incoming glutamate release (Lisman & Zhabotinsky, 2001). These mechanisms of LTP (including the activation of specific second messenger systems) share similarities with the molecular processes involved in reconsolidation (Nader & Hardt, 2009). Most of the work seeking to pharmacologically disrupt memory has focused on manipulating the function of NMDA receptors.

Role of NMDA Receptors in Reconsolidation NMDA receptor activation has been repeatedly shown to be necessary for reconsolidation. Blockade of the NMDA receptor with an antagonist before, during, or after reactivation of a memory consequently blocks the reconsolidation process (Akirav & Maroun, 2006; Kim, Moki, & Kida, 2011; Torras-Garcia, Lelong, Tronel, & Sara, 2005). This has been shown to be true in a number of different types of memory paradigms. In a paper by Kim et al. (2011), NMDA receptor antagonists were used to test reconsolidation of spatial memory. Administration of the NMDA receptor antagonist (2R)-amino-5phosphonovaleric acid (APV) into the dorsal hippocampus following reactivation in a Morris water test (a test known to depend on spatial memory) disrupted reconsolidation (Kim et al., 2011). Another study by Akirav and Maroun (2006) investigated the role of NMDA receptors in the reconsolidation of object recognition memory. Here, administration of APV into the ventromedial prefrontal cortex following reactivation of the memory resulted in the disruption of reconsolidation in an object recognition task (Akirav & Maroun, 2006). A separate study by Torras-Garcia et al. (2005) investigated reconsolidation of odor-cued appetitive memory through an odor discrimination task. Intracerebroventricular administration of the NMDA receptor antagonist APV following reactivation of the memory through reexposure to the reinforced odor cue disrupted the subsequent memory for that cue (Torras-Garcia et al., 2005). In addition to the previously described research with protein synthesis inhibitors, post-reactivation administration of NMDA receptor antagonists into the basolateral amygdala has been shown to disrupt the reconsolidation of fear memories (Lee, Milton, & Everitt, 2006b). A fair number of other paradigms that address drug-related reward using NMDA receptor antagonists have been utilized; however, these will be covered in great detail later in the review.

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Drug Memories and Glutamate Most of the studies investigating the disruption of drug-related memories use variations of two behavioral paradigms: conditioned place preference (CPP) and self-administration. CPP is a Pavlovian paradigm that measures the rewarding properties of drugs by evaluating preference for drug-paired cues (Tzschentke, 2007). In this paradigm, an apparatus that consists of at least two distinct chambers or environments is used. These chambers are separated by retractable doors, and differ in visual (color, pattern) and often tactile (type of floor) cues (Bardo & Bevins, 2000). During the procedure, rodents receive an experimenteradministered injection of a drug of abuse and are confined to one of the two chambers. In a separate session, saline is administered and the rodent is placed in the opposing chamber. After a predetermined number of conditioning sessions, the rodent is allowed to freely explore both the drug-paired and saline-paired chambers. If a drug is rewarding, rodents will spend more time in the chamber that is associated with administration of the drug (for a full review of CPP, see Tzschentke, 2007). This preference reflects the Pavlovian link of the drug with cues in the environment and the ability of these cues to elicit a conditioned response (Bardo & Bevins, 2000). The second paradigm most often used is drug self-administration. The selfadministration paradigm measures the reinforcing properties of drugs by determining the extent to which rodents will respond to receive these drugs (Panlilio & Goldberg, 2007). An operant box is used for this paradigm. Rodents are placed into this box and are trained to self-administer a drug of abuse through responses such as lever presses or nose pokes. Such a response most often results in an intravenous infusion of a drug of abuse, although in some variations the drug is made available to drink (Mello & Negus, 1996; von der Goltz et al., 2009). Drug availability is often cued and multiple ratios of reinforcement can be used to establish responding for the drug and measure motivation to administer the drug. After training for responding has been established, a common way to assess behavior is through the use of cue- and drug-primed reinstatement procedures. This paradigm relies on the procedural link between actions (lever press or nose poke) and outcomes (receipt of drug) that is so important in continued drug taking (Vanderschuren & Everitt, 2004). A generic sequence of steps must be taken in all behavioral paradigms that seek to disrupt reconsolidation (Figure 1). These steps are labeled differently across the literature, but for consistency purposes will be commonly labeled throughout this paper. A list and explanation of these steps are provided below. 1. Baseline measures are typically used as a point of reference for data taken later in the experiment.

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Figure 1. Generic representation of the typical behavioral phases used to investigate disruption of reconsolidation mechanisms.

2. Conditioning or training procedures represent the phase in which the desired memory is established. This is the phase in which the addictive drugs form their link with cues or actions. 3. The acquisition test measures the extent to which the memory was established during the conditioning/training phase. 4. Reactivation sessions use cues to reactivate the memory that was established during the conditioning/training trials; this is the phase in which the drug meant to prevent reconsolidation (the amnesic agent) is administered. Subjects can be exposed to the conditioned stimulus (CS) alone or a combination of the CS and unconditioned stimulus (US). 5. The memory test measures whether the amnesic agent administered during the reactivation session was successful in disrupting memory. Memory tests can occur in either a drug-free or drug-primed state. Now that a fundamental explanation of the behavioral paradigms at work has been established, the remainder of this section will focus on reviewing studies that degrade drug memories through the disruption of the glutamate system.

NMDA Receptor Antagonists in the Reconsolidation of Drug Memories Several studies have investigated the role of NMDA receptors in the attenuation of drug-seeking behaviors. While some have focused on enhancing extinction memory through the use of NMDA receptor agonists such as D-cycloserine (Myers & Carlezon, 2012) and D-serine (Hammond, Seymour, Burger, & Wagner, 2013; Kelamangalath, Seymour, & Wagner, 2009; Kelamangalath &

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Wagner, 2010), the majority have focused specifically on the blockade of reconsolidation through the antagonism of the NMDA receptor. A great number of variables must be considered when reviewing this literature. Various behavioral paradigms (CPP, self-administration), drugs of abuse (cocaine, morphine, amphetamine, alcohol), NMDA receptor antagonists (MK-801, memantine, ketamine, D-APV, 7-CTKA), sites of antagonist administration (systemic, nucleus accumbens, ventral tegmental area, basolateral amygdala), number of reactivation sessions (1, 2, 3, 4, 10), time sequence of antagonist administration (before or after reactivation session), reactivation details (CS and US, CS only), time from reactivation session to memory test (days or weeks after), and type of memory test (drug primed, drug free) were used in the investigation of this phenomenon. A breakdown of some of these variables and the results of their use are displayed in Tables 1 and 2. Even with the wide variety of conditions to consider, the majority of these investigations show that drug memory is disrupted through NMDA receptor antagonism when paired with reactivation. With the exception of one study (Brown et al., 2008), systemic injections of NMDA receptor antagonists (MK-801, memantine, ketamine) under reconsolidation conditions in both CPP and self-administration studies resulted in the disruption of the drug memory (Alaghband & Marshall, 2013; Brown et al., 2008; von der Goltz et al., 2009; Itzhak, 2008; Kelley, Anderson, & Itzhak, 2007; Milton et al., 2011; Popik, Wrobel, & Bisaga, 2006; Sadler et al., 2007; Wouda et al., 2010; Zhai, Chen, Li, Liu, & Lu, 2008). Animals treated with NMDA receptor antagonists either responded as if they had never been exposed to the drug of abuse, or the preference for responding for the drug was severely impaired when compared to saline or home cage reactivation controls. The exception to the successful disruption of drug responding came from a paper that ran experiments for both cocaine CPP and cocaine self-administration. The CPP was abolished with administration of MK-801 but the self-administration was not (Brown et al., 2008); there are a number of explanations for this that may be addressed by the boundary conditions of reconsolidation. It was previously discussed that the strength of the memory is a factor. Under the selfadministration paradigm, the CS (cue) and US (drug) undergo a much greater number of pairings than in a CPP paradigm. Therefore, it is possible that the increased strength of the association between the CS and US in the selfadministration paradigm made that particular memory resistant to disruption with a single amnesic trial. An increase in the number of amnesic trials would have likely resulted in the degradation of the memory. This, however, is likely not the only consideration as other self-administration paradigms with systemic injections of NMDA receptor antagonists have shown a disruption of the drug memory (Milton, Lee, Butler, Gardner, & Everitt, 2008; von der Goltz et al., 2009; Wouda et al., 2010). Another possible explanation for the lack of memory disruption in the Brown 2008 paper comes from the way in which the reactivation

MK-801 (0.05 or 0.20 mg/kg) MK-801 (0.3 mg/kg) MK-801 (0.3 mg/kg) MK-801 (0.1 mg/kg) MK-801 (0.2 mg/kg) Memantine (10 mg/kg) MK-801 (0.05 or 0.20 mg/kg) MK-801 (0.1 mg/kg) Ketamine (60 mg/kg) Memantine (7.5 mg/kg) MK-801 (0.1 mg/kg) MK-801 (0.1 mg/kg) MK-801 (0.1 mg/kg) MK-801 (0.1 mg/kg) MK-801 (0.1 mg/kg)

NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist NMDA-R antagonist

Cocaine (20 mg/kg)

Cocaine (20 mg/kg)

Cocaine (12 mg/kg)

Cocaine (12 mg/kg)

Cocaine (12 mg/kg)

Cocaine (0.75 mg/kg)

Cocaine (0.25 mg/ infusion) Morphine (5 mg/kg)

Morphine (10 mg/kg)

Amphetamine (2 mg/kg) Ethanol (10% v/v in 30 μL amounts) Ethanol (12% v/v in 0.19 mL amounts) Ethanol (10% v/v in 0.1 mL amounts) Ethanol (10% v/v in 0.1 mL amounts)

Systemic

Systemic

Systemic

Systemic

Systemic

Systemic

Systemic

Systemic

Systemic

Systemic

Systemic

Systemic

Systemic

Systemic

Cocaine (12 mg/kg)

Drug of abuse (dose)

Systemic

Administration location

Pavlovian instrumental transfer

Conditioned approach

Self-administration

Conditioned place preference Conditioned place preference Conditioned place preference Self-administration

Self-administration

Conditioned place preference Conditioned place preference Conditioned place preference Conditioned place preference Conditioned place preference Conditioned place preference Self-administration

Behavioral paradigm

CS = conditioned stimulus; NMDA = N-methyl-D-aspartic acid; US = unconditioned stimulus.

Amnesic agent (dose)

Class of amnesic agent

NMDA Receptor Antagonists (Systemic Administration)

Table 1

CS exposure only

CS exposure only

CS with small US as gustatory cue CS exposure only

CS exposure only

CS exposure only

CS exposure only

Simultaneous US and CS exposure CS exposure only

CS exposure only

CS exposure only

CS exposure only

CS exposure only

Simultaneous US and CS exposure CS exposure only

Reactivation details

Drug free

Drug free

Ethanol gustatory cue Drug free

Drug free and drug primed Drug-primed reinstatement Drug free

Drug-primed reinstatement Drug free and drug primed Drug free and drug primed Drug free and drug primed Drug free and drug primed Drug free and drug primed Drug-primed reinstatement Drug free

Test details

Yes

Yes

Marginal

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Reconsolidation disrupted?

Sadler et al. (2007) von der Goltz et al. (2009) Wouda et al. (2010) Milton et al. (2011) Milton et al. (2011)

Popik et al. (2006)

Kelley et al. (2007) Alaghband & Marshall (2013) Alaghband & Marshall (2013) Alaghband & Marshall (2013) Brown et al. (2008) Milton et al. (2008) Zhai et al. (2008)

Brown et al. (2008) Itzhak (2008)

Reference

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session was conducted. A violation of expectation through the presentation of cues (CS) in the absence of available drug (US) likely increases the chances of memory destabilization (and thus reconsolidation). In the Brown et al. (2008) paper, both cues and drug were presented simultaneously during the selfadministration reactivation session. This could, in theory, decrease the opportunity for disruption of the drug memory. As with the previous boundary condition (strength of memory), this is not likely the only consideration as the CPP experiment presented within the same Brown et al. paper used simultaneous cue/drug presentation during the reactivation session, but drug memory was disrupted. It is therefore likely that the lack of disruption in self-administration was a combination of the boundary conditions explained above. Other experiments took a more targeted approach. Rather than antagonizing NMDA receptors throughout the entire brain, rats were cannulated and specific brain regions implicated in addiction were targeted. A detailed outline of these experiments is shown in Table 2. In a paper by Milton et al. (2008), the NMDA receptor antagonist D-APV was infused into the basolateral amygdala in a cocaine self-administration paradigm. The basolateral amygdala receives glutamatergic afferent projections from the prefrontal cortex, and sends glutamatergic projections to the central amygdala, bed nucleus of the stria terminalis, and the nucleus accumbens core and shell (Koob & Volkow, 2009). The basolateral amygdala has been previously implicated in the addiction/ motivation circuitry as being necessary for encoding the cue/reward association (Gabriele & See, 2010). It is also thought that this region is involved in the ability of cues to guide goal-directed behavior, but not strict stimulus-response behavior (which is more likely mediated by the dorsal striatum) (Corbit & Balleine, 2005). In the present paper (Milton et al., 2008), administration of D-APV into the basolateral amygdala before the reactivation session resulted in the disruption of cue-induced instrumental responding. This disruption of memory was persistent and was still observed when tested 4 weeks later (Milton et al., 2008). Recent reconsolidation studies using protein synthesis inhibitors confirm that the basolateral amygdala is necessary for the stabilization of Pavlovian and cueinduced instrumental response memories (Fuchs, Bell, Ramirez, Eaddy, & Su, 2009). It is therefore possible that the failure to respond when presented with the cue reflects a disruption of the connections that link the drug-related cues (CS) with the administration of the drug (US). In a paper by Wu, Li, Gao, and Sui (2012), the nucleus accumbens core was targeted using a morphine CPP paradigm. D-APV administered into the nucleus accumbens core prior to the reactivation session disrupted the memory in subsequent tests. Drug-free memory tests 1 day, 1 week, and 2 weeks after the reactivation session showed a persistent disruption of the memory. Additionally, a morphine-primed memory test following the last drug-free memory test did not reinstate drug seeking (Wu et al., 2012). This disruption tracks along with the

D-APV (5 μg)

D-APV (5 μg)

NMDA-R antagonist

NMDA-R antagonist

Nucleus accumbens

Basolateral amygdala

Ventral tegmental area

Conditioned place preference

Cocaine (10 mg/kg)

CS exposure only

Reactivation details

Morphine (5 mg/kg)

Conditioned place preference

Reconsolidation disrupted?

Drug free

Yes

Drug free and drug Yes primed

Test details

Simultaneous Drug free and drug Yes primed US and CS exposure

Cocaine Self-administration CS exposure (0.25 mg/infusion) only

Behavioral paradigm

Drug of abuse (dose)

CS = conditioned stimulus; NMDA = N-methyl-D-aspartic acid; US = unconditioned stimulus.

7-CTKA (5 μg)

NMDA-R antagonist

Class of Amnesic Administration amnesic agent agent (dose) location

NMDA Receptor Antagonists (Targeted Brain Areas)

Table 2

Wu et al. (2012)

Milton et al. (2008)

Zhou et al. (2011)

Reference

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112 DENNIS AND PERROTTI currently accepted role of the nucleus accumbens in addiction. The nucleus accumbens is anatomically and functionally divided into the core and shell (Zahm & Brog, 1992). The core receives major glutamatergic input from the basolateral amygdala and prefrontal cortex and dopaminergic input from the midbrain (Everitt & Robbins, 2005). Glutamatergic and dopaminergic activities converge in this area to direct cue-elicited reward-seeking behaviors (Di Ciano, Cardinal, Cowell, Little, & Everitt, 2001; Di Ciano & Everitt, 2004; Fuchs, Evans, Parker, & See, 2004; McFarland, Lapish, & Kalivas, 2003). Therefore, the disruption of responding does not necessarily indicate an erasure of the CS-US association, but rather the degrading of the connection linking the cues with an appropriate behavioral response. In theory, this means that specifically disrupting the core of the nucleus accumbens might selectively dissociate cues that have previously been paired with drugs of abuse with the drug-seeking patterns that are specifically activated by these cues. While in this narrow and highly controlled paradigm the memory erasure has been deemed a success, alternative measures are necessary to determine whether or not a future vulnerability to relapse is present. Retraining under the same response contingency with a different set of cues would most likely result in a faster reacquisition of the cued response (because the behavioral action pattern was likely not erased). This particular acquisition-disruption-reacquisition phenomenon in the nucleus accumbens core would be best studied in a self-administration paradigm, as a response in this paradigm directly results in drug administration. Another experiment focused on disruption within the ventral tegmental area. The ventral tegmental area is the source of dopaminergic input in the mesolimbic pathway (Koob & Volkow, 2009). It also receives glutamatergic input from the prefrontal cortex which modulates dopamine release throughout the mesolimbic pathway (Carr & Sesack, 2000). In a paper by Zhou et al. (2011), researchers infused the NMDA receptor antagonist (glycine-site) 7-chlorothiokynurenic acid (7-CTKA) into the ventral tegmental area immediately following the reactivation session in a cocaine CPP paradigm. A drug-free memory test given 24 hours after the reactivation session showed a disruption of the memory. The disruption was confirmed 2 weeks after the reactivation session with a drug-primed memory test (Zhou et al., 2011). Overall, a review of this literature indicates that NMDA receptor antagonism, when linked to reactivation, blocks reconsolidation for the drug memory when given systemically and when targeting addiction-relevant neurocircuitry. More research must be conducted before we can confidently say whether one or another brain area completely abolishes the entire representation of the drug. Addiction is a multifaceted problem that engages multiple brain areas, multiple types of learning and memory, and multiple modalities of behavioral expression. More likely than not, the most effective way to knock out all of these factors is through a systemic reactivation-dependent administration of these NMDA receptor

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antagonists. From a clinical treatment perspective, a systemic approach is also ideal. While microinjection into specific brain areas in humans is not unheard of, it is risky and much less practical. From the standpoint of basic science, however, expanded research that zeroes in on the role of these brain areas and their vulnerability to various types of disruption will provide answers to important questions. The behavioral results from these drug addiction studies are consistent with studies testing other memory types (Akirav & Maroun, 2006; Kim et al., 2011; Lee et al., 2006b; Torras-Garcia et al., 2005). It is important, however, to ask how exactly antagonism of a single receptor can disrupt any kind of memory. Most likely, the cellular plasticity (and by extension, learning) that is observed in response to NMDA receptor activation is mediated by NMDA-linked second messenger systems. A potential framework as well as studies that have sought to disrupt drug memories through the blockade of NMDA-linked second messenger pathways will be discussed next. Role of Second Messenger Systems in Drug Memory Reconsolidation NMDA receptor activation sets into motion the second messenger mitogenactivated protein kinase (MAPK) pathway (Wang, Fibuch, & Mao, 2007). The MAPK pathway acts as a mechanism of neural plasticity and has been shown to be necessary for memory reconsolidation (Duvarci, Nader, & LeDoux, 2005; Kelly, Laroche, & Davis, 2003). Entry of calcium into the cell through an NMDA receptor activates calcium/calmodulin-dependent kinase II (CaMKII), which in turn activates PI3-kinase. Ras (the first step in the MAPK pathway) is then activated by PI3-kinase, and the signal is transmitted through the MAPK pathway, being passed from Ras to Raf-1 to MEK to ERK (seen in Figure 2) (Wang et al., 2004). After ERK is phosphorylated (activated), it is able to act upon transcription factors such as elk-1 and cyclic-AMP response element binding protein (CREB) to regulate gene expression and is additionally important in the induction of plasticity-related immediate early genes such as c-Fos (Sgambato et al., 1998; Xia, Dudek, Miranti, & Greenberg, 1996). Many molecules in this pathway and its downstream targets (ERK, Elk, CREB, Zif268) are also necessary for reconsolidation (Tronson & Taylor, 2007). Antagonizing NMDA receptors with APV decreases levels of these molecules (Cammarota et al., 2000; Milton et al., 2008). The function of these molecules is tied to the level at which they are expressed. Therefore, a decrease in the levels of these molecules induced by NMDA receptor antagonism indicates a functional insufficiency and therefore may reflect the mechanism through which memory fails to solidify after reactivation. Administration of drugs (morphine, cocaine, amphetamine) increases ERK phosphorylation (activation) in the mesolimbic pathway (Berhow, Hiroi, &

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Figure 2. NMDA receptor-dependent activation of the MAPK second messenger pathway and subsequent regulation of Elk-1, CREB, and Zif268.

Nestler, 1996; Choe & Wang, 2002; Shi & McGinty, 2006; Valjent et al., 2000). In addiction, activation of this pathway by NMDA and dopamine receptors results in a systemic sensitization that shapes the way an organism approaches drugs of abuse (Wang et al., 2007). Reversal or degradation of this sensitization through the disruption of ERK activity in this pathway has shown some promising results for decreasing or abolishing responding for drug. The way in which experimenters accomplish this is through the use of a MEK inhibitor under reconsolidation parameters, which prevents the phosphorylation (activation) of ERK. A study by Valjent, Corbillé, Bertran-Gonzalez, Hervé, and Girault (2006) investigated the disruption of this system in both cocaine and morphine CPP. Mice were conditioned with cocaine or morphine for a total of three drug pairings. A systemic injection of the MEK inhibitor SL327 was given 1 hour before the reactivation session. Mice were injected with either cocaine or morphine and placed in the previously drug-paired chamber for the reactivation session. When mice were given a memory test 24 hours later, both the cocaine and the morphine groups that received the MEK inhibitor displayed no preference for the chamber that had previously been paired with drug (Valjent et al., 2006). Another research group focused on disrupting reconsolidation of cocaine CPP through the

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inhibition of MEK in the core of the nucleus accumbens. Rats that had previously undergone cocaine conditioning underwent reactivation by exposure to the entire CPP apparatus in a drug-free state. The MEK inhibitor U0126 was infused into the nucleus accumbens core either 30 minutes before or immediately after this reactivation session. Memory tests 1 and 14 days later showed a disruption of the preference. Subsequent tests were conducted with a different MEK inhibitor (PD98059) and the same disruption in preference was observed. Biochemical tests on the brain tissue of rats that received the MEK inhibitor revealed a blunted expression of ERK, CREB, Elk-1, and Fos in response to drug cues 2 and 15 days after the reactivation session. Rats that did not undergo the memory erasure saw potentiated levels of this pathway in response to these cues (Miller & Marshall, 2005). This provides support for the previous claim that levels of these molecules are linked to their function, and that the nucleus accumbens core is important in cue reactivity and the association between cues and actions. Overall, the results from these two MEK inhibitor studies are consistent with the results reported previously in the NMDA receptor antagonist section. This also confirms that ERK phosphorylation (and by extension the MAPK pathway) is a necessary requirement for reconsolidation. One of the downstream targets of the MAPK pathway is zif268. Zif268 is a transcription factor that has also been implicated in the reconsolidation of memories (Bozon, Davis, & Laroche, 2003). Blockade of zif268 with an antisense oligodeoxynucleotide (ASO) disrupts both fear and drug memories (Lee, Di Ciano, Thomas, & Everitt, 2005). Levels of zif268 are linked to NMDA receptor activation and are contingent upon activation of the MAPK signaling cascade (Waltereit & Weller, 2003). Antagonizing NMDA receptors with D-APV decreases expression of zif268 (Milton et al., 2008) whereas enhancing NMDA activity with the administration of D-cycloserine increases zif268 expression (Lee et al., 2009). Therefore, the amnesic properties that NMDA receptor antagonists exert under reconsolidation conditions are potentially mediated through this transcription factor (Tronson & Taylor, 2007). In regard to addiction, exposure to conditioned stimuli that have previously been paired with drugs of abuse increases the expression of zif268 in the ventral tegmental area, nucleus accumbens core, nucleus accumbens shell, and the basal nucleus of the amygdala (Thomas, Arroyo, & Everitt, 2003), indicating its importance in the addiction neurocircuitry and highlighting its role in drug cue-induced neural activation. A few studies have been conducted under reconsolidation conditions to specifically measure erasure of drug memories through the disruption of zif268 (for a breakdown, see Table 3). These studies focus specifically on the role of the basolateral amygdala and the nucleus accumbens core. A study by Theberge, Milton, Belin, Lee, and Everitt (2010) tested the effect of zif268 on cocaine CPP. Rats were trained under a CPP paradigm and given an injection of zif268 ASO

SL327 (30 mg/kg) U0126 (1 μg)

PD98059 (2 μg)

SL327 (30 mg/kg)

Zif268 ASO (1 μL of 2 nmol)

Zif268 ASO (1 μL of 2 nmol)

Zif268 ASO (1 μL of 2 nmol)

Zif268 ASO (1 μL of 2 nmol) Zif268 ASO (1 μL of 2 nmol) Zif268 ASO (1 μL of 2 nmol)

MEK inhibitor MEK inhibitor MEK inhibitor

MEK inhibitor

Zif268 ASO

Zif268 ASO

Zif268 ASO

Zif268 ASO

Basolateral amygdala

Basolateral amygdala

Basolateral amygdala

Basolateral amygdala

Nucleus accumbens core

Nucleus accumbens core

Systemic

Cocaine (10 mg/kg)

Nucleus accumbens core Nucleus accumbens core

Cocaine (0.25 mg/infusion)

Cocaine (0.25 mg/infusion)

Cocaine (0.25 mg/infusion)

Cocaine (10 mg/kg)

Cocaine (0.25 mg/infusion)

Cocaine (10 mg/kg)

Morphine (5 mg/kg)

Cocaine (10 mg/kg)

Cocaine (20 mg/kg)

Drug of abuse (dose)

Systemic

Administration location

Self-administration (second-order schedule of reinforcement)

CS exposure only

CS exposure only

CS exposure only

Self-administration (acquisition of new responding) Self-administration

CS exposure only

CS exposure only

CS exposure only

Simultaneous CS and US exposure

CS exposure only

Simultaneous CS and US exposure CS exposure only

Reactivation details

Conditioned place preference

Self-administration (acquisition of new responding)

Conditioned place preference

Conditioned place preference

Conditioned place preference Conditioned place preference Conditioned place preference

Behavioral paradigm

ASO = antisense oligodeoxynucleotide; CS = conditioned stimulus; US = unconditioned stimulus.

Zif268 ASO

Zif268 ASO

Amnesic agent (dose)

Class of amnesic agent

Second Messenger System Disruptors

Table 3

Drug available under secondorder schedule of reinforcement

Drug free

Drug free

Drug free

Drug free

Drug free

Drug free and drug primed

Drug free

Drug free and drug primed Drug free

Test details

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Reconsolidation disrupted?

Lee et al. (2006a)

Lee et al. (2006a)

Lee et al. (2005)

Theberge et al. (2010)

Theberge et al. (2010)

Theberge et al. (2010)

Valjent et al. (2006)

Valjent et al. (2006) Miller & Marshall (2005) Miller & Marshall (2005)

Reference

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into either the basolateral amygdala or nucleus accumbens core 90 minutes before the reactivation session. In the reactivation session, rats were allowed to explore all chambers of the CPP apparatus in a drug-free state. A memory test given 24 hours after the reactivation session showed that zif268 ASO injections into both the basolateral amygdala and nucleus accumbens core resulted in an abolishment of preference for the previously drug-paired chamber (Theberge et al., 2010). These findings are consistent with the results from both the paradigms utilizing NMDA receptor antagonists and MEK inhibitors. Another study used a traditional self-administration paradigm and set a delay of either 3 or 27 days between the training phase and reactivation session of the procedure (Lee, Milton, & Everitt, 2006a). This essentially addressed the boundary condition that the age of the memory is a factor in how susceptible the memory is to reconsolidation and disruption (Frankland et al., 2006; Milekic & Alberini, 2002). Ninety minutes before the reactivation session, zif268 ASO was infused into the basolateral amygdala. During the reactivation session, 30 noncontingent presentations of the light that had previously been paired with drug administration were given. Subsequent memory tests revealed that the drug memory had been abolished (regardless of the memory age) (Lee et al., 2006a). A separate experiment in the same publication used a modified version of cocaine self-administration. The goal of this experiment was to measure the ability for conditioned stimuli to potentiate responding in an operant task (Lee et al., 2006a). This is meant to mirror the human condition in which cues in the environment that have previously been associated with drugs of abuse potentiate actions that lead to consumption of the drug. Under this paradigm, rats were trained to self-administer cocaine and subsequently underwent a reactivation session with the injection of zif268 ASO into the basolateral amygdala. Following reactivation, rats received training under a second-order schedule of reinforcement. Under this schedule, responses yielded a presentation of the CS, rather than an infusion of the drug. At the end of each session in this phase, rats received a noncontingent infusion of cocaine paired with a 20-second illumination of the CS. Following the second-order schedule of reinforcement training, rats underwent extinction and reinstatement tests. In rats that had been treated with zif268 ASO before the reactivation session, no enhanced responding was observed. Because the presence of the CS during this phase did not potentiate responding, the memory of the CS linked to previous drug administration was concluded to have been abolished (Lee et al., 2006a). A study by Lee et al. (2005) used yet another modified version of selfadministration. Rats were initially trained to self-administer cocaine by nose poking. Once responding was established, rats received a reactivation session. Ninety minutes before the reactivation session, an injection of the zif268 ASO was administered into the basolateral amygdala. This session consisted of a 15-minute exposure to the operant chamber in which the CS (signal light) was

118 DENNIS AND PERROTTI contingently illuminated for 20 seconds upon each nose poke response by the rat. Subsequent tests 1, 2, 5, and 8 days after the memory reactivation examined whether the cues (CS) that had previously been associated with the drug of abuse could facilitate the acquisition of a new type of responding (lever pressing rather than nose poking). This was meant to test the conditioned value of the cue that had previously been paired with drug. During these memory tests, pressing the “active” lever resulted in a 1-second illumination of the CS. If the memory was disrupted, then presentation of the CS should have no meaning to the animal (and should not enhance lever pressing). The results of these tests revealed that rats that had their basolateral amygdala infused with zif268 ASO in a reactivation-dependent manner did not acquire the new lever pressing response (Lee et al., 2005). These results are consistent with the idea that the basolateral amygdala is responsible for the link between the CS and the US. A later experiment by the same group extended the study to include the infusion of zif268 ASO into the nucleus accumbens core under both contingent and noncontingent reactivation sessions. Under these conditions, infusions of zif268 into the nucleus accumbens core did not impair the new acquisition of responding for the lever during the memory test, regardless of reactivation condition (Theberge et al., 2010). This marks one of the few studies throughout the reviewed articles that actually note a lack of memory disruption. However, this particular outcome is not surprising given the proposed function of the nucleus accumbens core. As previously discussed, the core of the nucleus accumbens is thought to link cues with the appropriate behavioral action. Because the action of lever pressing was not present during reactivation, there is no reason that it should have been disrupted. This explains why the knockdown of zif268 in the core of the nucleus accumbens results in a lack of preference for CPP, but does not disrupt the acquisition of a new operant response. These results also confirm the assertion made earlier that targeting the core of the nucleus accumbens does not abolish the entire representation of the drug. The results obtained from these zif268 inhibitor studies show that, just as with the NMDA receptor antagonists and MEK inhibitors, drug memories can be degraded in a reactivation-dependent manner. This set of studies was particularly interesting in the way that behavior was measured. Many of these studies utilized modified versions of the self-administration paradigm, which allowed researchers to focus specifically on the role of the CS in facilitating future responding. While administration of zif268 ASO was successful in disrupting the ability for presentations of a CS to facilitate responding in the same operant task, it did not disrupt the ability for CS presentation to facilitate the acquisition of a new operant response (in the nucleus accumbens core). It would be very interesting to see if systemic or intracerebroventricular injections of these inhibitors would disrupt all representation of the drug memory (including the ability for a CS to facilitate the acquisition of a new type of responding). All in all, these studies confirm and

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extend the reconsolidation literature and suggest a common pathway (NMDA receptor to MAPK activation to zif268 expression) in the reconsolidation process. Concluding Remarks, Limitations, and Future Directions Taken all together, the results of these studies support the notion that glutamate systems play an important role in establishing, reconsolidating, and sustaining drug memories. These studies also confirm that the model of cellular plasticity that is rooted in glutamatergic function also plays an important part in reconsolidation. Activation of NMDA receptors puts into motion the MAPK pathway, which increases the expression of zif268. Accordingly, blockade of any of the mechanisms in this pathway yields an almost identical disruption in memory (type of responding), even across multiple types of paradigms. It is however important to caution against generalizing the results of these studies too far. A decrease in the preference for a drug-paired environment or a decrease in an operant response for a drug does not necessarily mean that the entire representation of the drug has been abolished. This was most clearly illustrated in the experiments targeting the nucleus accumbens core. Responding for drug was abolished with administration of every amnesic drug when testing was performed under the traditional self-administration and CPP paradigms. It was not until experimenters tested whether a CS could establish a new operant response that the behavioral paradigm was able to detect residual memory. This highlights the need in this type of research to consider the multiple circuits at work in the addiction process and to further identify ways that we can detect residual memory. Even with current limitations, this is an exciting avenue of research that is sure to expand our knowledge of learning, memory, and addiction mechanisms. While this review confirms that degradation of established memories through reconsolidation disruption occurs quite predictably in preclinical models, very little of this research has been translated to treatment in humans (Schiller & Phelps, 2011). There are a number of considerations to make for successful translation to take place. The idea of completely abolishing a memory in one trial (as we most often attempt to do in animal research) is a potentially dangerous one. Although the disruption of the target memory is reactivation dependent, it is certainly within the realm of possibility that memories other than the target will become “reactivated,” and thus be vulnerable to disruption. This creates a situation where memories other than the intended target may become disrupted. Although it remains to be tested, repeated treatment with lower doses in a therapeutic setting will likely be necessary for the greatest cost/benefit in a human population. There may, additionally, be perceived ethical barriers to translation. Some have argued that any manipulation of memories should be strictly “hands

120 DENNIS AND PERROTTI off,” and to change any memory (including those that are harmful) represents a threat to one’s “sense of self” (Wasserman, 2004). These apprehensions are deserved and great caution must certainly be taken in administering this treatment. However, memories that drive addiction are maladaptive and present a real sense of harm to the individual (Milton & Everitt, 2012a). As a consequence, some have suggested that the ultimate outcomes of these types of treatments outweigh the risks of continuing to live with these maladaptive memories (Parens, 2010). While no human studies have specifically focused on disruption of reconsolidation by blocking glutamate signaling, there are studies that hint at the involvement of this system. Ketamine has been previously used as a treatment for PTSD (Cukor, Spitalnick, Difede, Rizzo, & Rothbaum, 2009). Ketamine works as a glutamatergic antagonist by blocking the ion channel of the NMDA receptor. It is interesting to posit that perhaps some of the efficacy of these treatments comes from the disruption of established traumatic memories. It would be useful to see if these results would be generalizable to addiction memories. Ketamine, however, may not be the best drug to use as it and many other glutamate receptor antagonists have an abuse potential. A possible option would be to use an NMDA antagonist that has no established abuse potential. There have also been behavioral interventions that attempt to take advantage of reconsolidation mechanisms by focusing on enhancing extinction procedures during the reconsolidation time window. Researchers accomplished this by exposing heroin addicts to a drug-relevant video to reactivate drug-linked memories. Ten minutes or 6 hours later, participants underwent an extinction protocol in which they were shown drug-themed pictures and drug paraphernalia in the absence of drug administration (Xue et al., 2012). Subsequent testing took place 4, 34, and 184 days after the extinction training. Results showed that participants extinguished 10 minutes after reactivation (within the reconsolidation window) reported significantly less craving than those who received extinction training outside of the reconsolidation window (Xue et al., 2012). By doing this, a new “cue/no drug” association is being made within the reconsolidation window, allowing for a stronger updating of the original memory to predict the absence rather than the availability of the drug (Milton & Everitt, 2012b). This is an interesting and exciting approach, as it holds promise for therapeutic treatment of drug abuse without need for pharmacological intervention. However, more research is necessary to ensure that this type of intervention is generalizable to other drugs and contexts and has sufficient validity. Finally, there are a few issues that need to be addressed in future studies. One of these is the inclusion of female rats and women. While we know that estrogen has a modulatory role on memory formation (Zurkovsky, Brown, Boyd, Fell, & Korol, 2007), its role in basic reconsolidation and disruption of memory paradigms has not been characterized and has certainly not been extended to

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addiction studies under reconsolidation conditions. Much of this is likely due to the fact that researchers are still trying to understand basic mechanisms of action for this phenomenon. Nonetheless, it is an important issue that must be considered before a full explanation can be achieved. It is also interesting to think about these reconsolidation mechanisms in the context of various psychological disorders. Would the presence of depression, trait anxiety, or any number of other disorders have a modulatory effect on reconsolidation? In any case, it is clear that much more research is needed to answer these questions. Another issue that needs to be addressed is the nature of impulsivity that can be enhanced by past drug use (Bechara et al., 2001). If the memory linking cues in the environment with the drug (CS-US) is abolished, does this also decrease the impulsivity that is characteristic of these individuals? If the answer is no, then it would seem that the individual may be prone to recidivism given the lack of inhibitory control over impulses and, possibly, an environment that is rich with opportunity for access to illicit drugs. Even if it did decrease this use-dependent impulsivity, great caution must be taken in considering this a “cure-all” for addiction. For the individual, the psychological and social aspects, in addition to the biological, must be taken into account. In conclusion, the disruption of glutamatergic mechanisms in preclinical models has shown promise in decreasing the salience of cues as predictors of reward and drug availability. Future research must focus on fully elucidating the mechanisms at work and must press forward to develop desperately needed treatments for patients suffering from addiction. References Akirav, I., & Maroun, M. (2006). Ventromedial prefrontal cortex is obligatory for consolidation and reconsolidation of object recognition memory. Cerebral Cortex (New York, N.Y.: 1991), 16, 1759–1765. Alaghband, Y., & Marshall, J. F. (2013). Common influences of non-competitive NMDA receptor antagonists on the consolidation and reconsolidation of cocaine-cue memory. Psychopharmacology, 226(4), 707–719. Alberini, C. M. (2005). Mechanisms of memory stabilization: Are consolidation and reconsolidation similar or distinct processes? Trends in Neurosciences, 28, 51–56. Bardo, M. T., & Bevins, R. A. (2000). Conditioned place preference: What does it add to our preclinical understanding of drug reward? Psychopharmacology, 153, 31–43. Bechara, A., Dolan, S., Denburg, N., Hindes, A., Anderson, S. W., & Nathan, P. E. (2001). Decision-making deficits, linked to a dysfunctional ventromedial prefrontal cortex, revealed in alcohol and stimulant abusers. Neuropsychologia, 39, 376–389.

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