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Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference

Emmanuel Valjent, Anne-Gaëlle Corbillé, Jesus Bertran-Gonzalez, Denis Hervé and Jean-Antoine Girault
PNAS February 21, 2006. 103 (8) 2932-2937; https://doi.org/10.1073/pnas.0511030103
Emmanuel Valjent
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Anne-Gaëlle Corbillé
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Jesus Bertran-Gonzalez
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Denis Hervé
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Jean-Antoine Girault
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  1. Communicated by Paul Greengard, The Rockefeller University, New York, NY, December 22, 2005 (received for review December 4, 2005)

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Abstract

Repeated association of drugs of abuse with context leads to long-lasting behavioral responses that reflect reward-controlled learning and participate in the establishment of addiction. Reactivation of consolidated memories is known to produce a reconsolidation process during which memories undergo a labile state. We investigated whether reexposure to drugs had similar effects. Cocaine administration activates extracellular signal-regulated kinase (ERK) in the striatum, and ERK activation is required for the acquisition of cocaine-induced conditioned place preference (CPP). When mice previously conditioned for cocaine-place preference were reexposed to cocaine in the drug-paired compartment after systemic administration of SL327, an inhibitor of ERK activation, CPP response was abolished 24 h later. This procedure also abolished the phosphorylation of ERK and glutamate receptor-1 observed in the ventral and dorsal striatum, 24 h later, during CPP test. Erasure of CPP by SL327 required the combination of cocaine administration and drug-paired context and did not result from enhanced extinction. Similarly, reexposure to morphine in the presence of SL327 long-lastingly abolished response of previously learned morphine-CPP. The effects of SL327 on cocaine- or morphine-CPP were reproduced by protein synthesis inhibition. In contrast, protein synthesis inhibition did not alter previously acquired locomotor sensitization to cocaine. Our findings show that an established CPP can be disrupted when reactivation associates both the conditioned context and drug administration. This process involves ERK, and systemic treatment preventing ERK activation during reexposure erases the previously learned behavioral response. These results suggest potential therapeutic strategies to explore in the context of addiction.

  • cocaine
  • locomotor sensitization
  • morphine
  • protein kinase inhibitor
  • reconsolidation

Addiction to licit or illicit drugs is a major public health issue worldwide. This behavioral disease results from a combination of environmental and genetic factors that are the focus of intense research. One important property of drugs of abuse is their common ability to increase extracellular dopamine (DA) in the nucleus accumbens (NAcc) (1). They are thought to mimic and divert thereby a physiological learning mechanism that results from the ability of DA neurons to code for errors in reward prediction (2). In support of this model, electrophysiological studies indicate that DA controls the flow of information through the striatum as well as the plasticity of corticostriatal synapses and plays a critical role in the acquisition and expression of drug-related behaviors (3, 4).

Some molecular mechanisms underlying long-lasting behavioral alterations produced by drugs of abuse have been identified (see refs. 5 and 6 for reviews). Recently, the role of extracellular signal-regulated kinase (ERK) 1 and 2, and more specifically ERK2, an intracellular pathway activated by most drugs of abuse, has attracted much attention (7–10). In response to cocaine and various drugs ERK2 is markedly activated in NAcc medium size spiny neurons (9, 11, 12). ERK activation in these neurons requires the coincident stimulation of DA D1 receptors and glutamate NMDA receptors, a cross-talk mediated by protein phosphatase-1 inhibition by DA- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) (12). Activation of ERK results in the direct or indirect phosphorylation of various transcription factors and leads to the induction of immediate-early genes (IEGs) that are essential for long-lasting behavioral alterations (for review, see ref. 13). Importantly, inhibition of mitogen-activated protein kinase/ERK kinase (MEK), the kinase upstream from ERK, by various drugs prevents the induction of long-lasting responses to drugs of abuse including conditioned place preference (CPP) (9, 14, 15) and locomotor sensitization (8, 12). Recent reports show that, following conditioning, ERK phosphorylation and IEG expression are stimulated by drug-associated cues in the absence of drugs and play a role in drug seeking (16, 17). Moreover, results from several laboratories support the role of ERK or its putative downstream effectors in other types of learning and memory, including conditioned taste aversion (18), fear-conditioning (19), spatial memory (20), and object recognition (21).

Reactivation of previously learned memories results in a process, termed reconsolidation, that can lead to their strengthening (22, 23). However, during this process, memory traces become labile and can be altered by various pharmacological manipulations (23–25). The ERK pathway and some of its effectors seem important for reconsolidation (21,26–29). The involvement of ERK in the long-lasting effects of drugs of abuse and its role in memory reconsolidation suggest that drug-induced conditioning could undergo ERK-dependent reconsolidation. Here, we have investigated whether systemic manipulation of the ERK pathway during reactivation by reexposure to drugs of abuse could modify behavioral responses that have already been learned. We show that blockade of the ERK pathway or inhibition of protein synthesis concomitant with reexposure to cocaine or morphine in a previously drug-paired environment specifically and durably erases CPP.

Results and Discussion

Blockade of ERK During Reexposure to Cocaine in a Drug-Paired Environment Erases CPP and Associated Protein Phosphorylation Responses.

Previous work showed that single or repeated cocaine injections activate ERK in many brain regions, including NAcc (9, 11). Blockade of ERK before each conditioning to cocaine prevents the induction of CPP (9). We examined whether blockade of the ERK pathway was able to modify the behavioral response once it had been learned. Mice were conditioned to cocaine in a 6-day unbiased CPP protocol (Fig. 1 A, group II) and were compared with mice that received only saline injections (group I). Conditioning resulted in a robust preference for the drug-paired compartment (Fig. 1 B, group II, test 1) that was still apparent when the same mice were tested 2 days later (test 2) (see also Fig. 6, which is published as supporting information on the PNAS web site). Two other groups of mice were subjected to the same cocaine conditioning protocol and, the day after test 1, were administered either vehicle (group III) or SL327 (group IV), and, 1 h later, were injected with cocaine and placed in the drug-paired compartment. When these animals were tested for CPP the next day (test 2), place preference was abolished in the SL327-pretreated group (IV), but not in the vehicle-pretreated group (III) (Fig. 1 B). The specific disappearance of CPP in SL327-treated mice was still observed 2 weeks later (data not shown). These results show that reexposure to cocaine in the drug-paired environment in the presence of SL327 erases previously acquired CPP.

Fig. 1.
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Fig. 1.

Reexposure to cocaine in drug-paired compartment in the presence of a MEK inhibitor erases CPP and its biochemical correlates. (A) Experimental design: S, saline; C, cocaine, 20 mg/kg; Veh, vehicle; SL327, 30 mg/kg. Each group included 8 mice. (B) After conditioning, mice developed a significant preference for the cocaine-paired side (test 1, F (3,28) = 16.77, P < 0.01). Inhibition of ERK activation by systemic administration of SL327 1 h before cocaine reexposure suppressed the place preference when animals were tested 24 h later (test 2, F(3,28) = 20.79, P < 0.01). Data are means ± SEM. Post hoc comparison (Bonferroni test), group I vs. group II to IV: ∗∗, P < 0.01; group III vs. group IV: ○○, P < 0.01. (C–E) To assess protein phosphorylation during the CPP test, P-ERK and total ERK immunoreactivity were analyzed at the end of test 2, by immunoblotting in NAcc (C), DStr, and prefrontal cortex (Pf Cx), and results were quantified (D). Phospho-Ser-845-GluR1 and total GluR1 were similarly analyzed (E and F). Results were expressed as a ratio of phosphoprotein/total protein and normalized as percentage of controls. Data are means ± SEM (seven to eight mice per group. One way ANOVA for P-ERK2 was as follows: NAcc, F(3,24) = 11.34, P < 0.01; DStr, F(3,27) = 9.41, P < 0.01; Pf Cx, F(3,26) = 4.98, P < 0.01. One way ANOVA for P-GluR1 was as follows: NAcc, F(3,25) = 10.46, P < 0.01; DStr, F(3,25) = 7.24, P < 0.01; Pf Cx, F(3,25) = 0.62, NS. Bonferroni test was as follows: group I vs. group II to IV, ∗, P < 0.05; ∗∗, P < 0.01; group III vs. group IV, ○○, P < 0.01).

To examine the biochemical correlates of the behavioral response, we measured by immunoblotting the activatory phosphorylation of ERK (P-ERK) in the NAcc, dorsal striatum (DStr), and prefrontal cortex of mice in the four groups described above, at the end of the place preference test (test 2, 18 min). P-ERK was increased in the NAcc, DStr, and prefrontal cortex of group II mice that had been conditioned to cocaine place preference, but not in unconditioned group I (Fig. 1 C and D). The P-ERK increase during the test was prevented 24 h after reexposure to cocaine in the presence of SL327 (group IV), but not of vehicle (group III) (Fig. 1 C and D). These results confirm and extend a recent report of ERK phosphorylation in the NAcc core of conditioned rats after CPP test (29). In the same samples, we also examined the phosphorylation of glutamate receptor-1 (P-GluR1), an AMPA glutamate receptor subunit that is phosphorylated on Ser-845 in response to cocaine through cAMP-dependent protein kinase (PKA) activation (30). This phosphorylation is functionally important because it increases the current of GluR1-containing AMPA receptors (31). P-GluR1 immunoreactivity was increased at the end of the CPP test in the NAcc and DStr of cocaine-conditioned mice, but not in the prefrontal cortex (group II, Fig. 1 E and F). This response was prevented in mice reexposed to cocaine, 24 h before, in the drug-paired environment in the presence of SL327 (group IV), but not of vehicle (group III, Fig. 1 E and F). These results show that the place preference test in cocaine-conditioned mice activates similar signaling pathways as exposure of naive mice to cocaine.

Thus, administration of SL327 during reexposure to cocaine in the drug-paired environment had profound consequences 24 h later during the CPP test: it prevented activation of ERK and cAMP-dependent protein kinase (PKA), as indicated by lack of GluR1 phosphorylation, as well as the behavioral response of place preference. This finding shows that biochemical and behavioral aspects of the conditioned reaction acquired during previous training were apparently erased by blockade of the ERK pathway during simultaneous reexposure to conditioned (environment) and unconditioned (cocaine) stimuli. The ERK-dependent molecular mechanisms of the reactivation are not known but could be related to synaptic plasticity necessary to associate environmental cues with an increase in DA release and/or activity.

MEK Inhibitor Does Not Increase Extinction of Cocaine-Induced Conditioning.

When mice are repeatedly injected with saline in the previously drug-paired compartment, an extinction of the conditioned response is observed (32). The effect of SL327 could be accounted for by a powerful extinction of the learned CPP. To test this hypothesis, cocaine-conditioned mice received an injection of saline in the previously drug-paired compartment in the presence of vehicle (group V) or SL327 (group VI) and were compared with four groups treated as in Fig. 1 (Fig. 2 A). When these mice were tested 24 h later (test 2), they still displayed a significant CPP (groups V and VI, Fig. 2 B). This result shows the absence of significant extinction in these mice and rules out a persistent effect of SL327 during the CPP test. On the other hand, a disappearance of the conditioned response was observed in group IV (Fig. 2 B), as was found in the first experiment.

Fig. 2.
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Fig. 2.

Erasure of CPP does not result from extinction and requires administration of SL327 when animals are reexposed to cocaine in the drug-paired environment. (A) Combined experimental design of the two independent experiments reported in B (groups I-VI) and C (different groups I-IV and groups VII-IX). Each group included eight to nine mice. (B) In addition to groups I-IV, treated as in Fig. 1, groups V and VI received vehicle or SL327 injection, respectively, and 1 h later a saline injection just before being placed in drug-paired compartment. All cocaine-conditioned groups had a significant CPP at test 1 (test 1, F(5,44) = 10.02, P < 0.01). At test 2, CPP was erased in SL327/cocaine-treated group IV and slightly diminished in vehicle/saline-treated group V (partial extinction) (test 2, F(5,44) = 15.43, P < 0.01). For test 3, all mice received a cocaine-priming injection immediately before the test. All cocaine-conditioned mice had a strong CPP, except group IV (test 3, F(5,44) = 13.54, P < 0.01). Data are means ± SEM. Post hoc comparison by Bonferroni test was as follows: group I vs. group II to VI, ∗, P < 0.01; group III vs. group IV, ○, P < 0.01; group II vs. group V, #, P < 0.01. (C) Groups I-IV were treated as above. Groups VII and VIII received a cocaine injection on day 9 in their home cage (HC) preceded by vehicle (group VII) or SL327 (group VIII). Group IX did not receive a cocaine reexposure but was treated with SL327 60 min before test 1. Although group IX displayed a dramatic CPP reduction immediately after SL327 injection, the place preference was blocked only in group IV when animals were tested 2 days later (test 1, F(6,49) = 13.99, P < 0.01; test 2, F(6,49) = 13.78, P < 0.01). Post hoc comparison by Bonferroni test was as follows: group I vs. group II to IV and VII to IX, ∗, P < 0.01; group II vs. group IX, #, P < 0.01; group III vs. group IV, ○, P < 0.01.

A characteristic of extinguished conditioned responses is that they can be reinstated by a priming injection of cocaine before testing CPP (33, 34). We tested the effects of a priming injection of cocaine just before the place preference test (test 3, Fig. 2 A and B). Priming did not restore the erased CPP in mice reexposed to cocaine in the drug-paired environment in the presence of SL327 (group IV, test 3, Fig. 2 B). These results further indicate that SL327 does not exert its effects by an increased extinction mechanism. It should also be noted that cocaine treatment in the presence of SL327 does not have aversive properties (9).

The Ability of SL327 to Erase CPP Requires Reexposure to Cocaine in the Drug-Paired Environment.

We then tested whether SL327-induced suppression of previously acquired CPP required reexposure to cocaine in the drug-paired environment, or whether the same effect could be obtained after cocaine injection in a neutral environment. To examine this point, we repeated a protocol similar to that described in Fig. 1, except that additional groups of mice received an injection of cocaine in their home cage in the presence of vehicle (group VII) or SL327 (group VIII) (Fig. 2 A and C). CPP was abolished only in animals that had been reexposed to cocaine in the presence of SL327 in the drug-paired compartment (Group IV, test 2, Fig. 2 C). In contrast, mice that received cocaine in the presence or absence of SL327 in their home cage displayed a normal CPP (groups VII and VIII, test 2, Fig. 2 C).

In mice that received SL327 and were placed in the drug-paired compartment in the absence of cocaine (saline injection), CPP was not suppressed (group VI, Fig. 2 A and B). This finding shows that exposure to drug-associated environment was not sufficient for SL327 to erase CPP. However, in these conditions, mice are placed passively in the drug-paired environment. We therefore examined the effects of SL327 when mice were actively seeking the drug-paired compartment, i.e., during the CPP test (group IX, Fig. 2 A). Injection of SL327 significantly decreased the expression of CPP (group IX, test 1, Fig. 2 C). However, when these animals were tested 2 days later, CPP was restored (group IX, test 2, Fig. 2 C). These results differ from those reported in rats, after bilateral injection of U0126, a MEK inhibitor, in NAcc core, which prevented both immediate and delayed expression of CPP (29). This discrepancy may be due to the different route of administration of the inhibitor. Intracerebral injections do not allow a precise control of the concentration of inhibitors in the injected structure, which may be far above those at which they are selective for their target kinase (35) and, thus, inhibit other pathways. Alternatively, the discrepancy between the two studies could be accounted for by minor differences in the CPP protocol, such as sensory modalities underlying the cues and strength of reactivation.

Blockade of ERK During Reexposure Erases CPP to Morphine.

Despite different mechanisms of action, drugs of abuse share the ability to raise extracellular DA concentration in the NAcc (1) and to increase ERK phosphorylation in this nucleus (11). It was important to determine whether inhibition of ERK activation erased only cocaine-CPP or whether this effect also applied to another drug acting through a different mechanism. We tested morphine in the same experimental paradigm as described in Fig. 1 for cocaine (Fig. 3 A). Mice that were conditioned with morphine developed a strong place preference (group II, Fig. 3 B). When these mice were reexposed to morphine in the presence of SL327 in the drug-paired compartment, no CPP was observed the following day (group IV, Fig. 3 B), as reported above for cocaine.

Fig. 3.
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Fig. 3.

Long-lasting erasure of morphine-CPP by SL327. (A) Experimental design: M, morphine, 5 mg/kg; Veh, vehicle; SL327, 30 mg/kg. Each group included nine mice. (B) After conditioning, mice developed a significant place preference for the morphine-paired side (group II, III, and IV) compared with control group (I) (test 1, F(3,32) = 27.31, P < 0.01). Inhibition of ERK by SL327 during reexposure to morphine (group IV) suppressed place preference when the animals were tested 24 h (test 2, F(3,32) = 25.26, P < 0.01) and 2 weeks later (test 3, F(3,32) = 24.54, P < 0.01). CPP was not restored after a priming injection of morphine at day 25 (test 4, F(3,32) = 13.12, P < 0.01). Data are means ± SEM. Post hoc comparison by Bonferroni test was as follows: group I vs. group II to IV, ∗, P < 0.05; ∗∗, P < 0.01; group III vs. group IV, ○○, P < 0.01; group II vs. group III, ##, P < 0.01.

We examined the duration of morphine-CPP suppression by SL327. When the same groups of mice were tested for CPP 2 weeks later, those that had been conditioned with morphine without reexposure to morphine still displayed a significant CPP, although the response was less pronounced than when tested early (group II, test 3, Fig. 3). The mice that had been reexposed to morphine after a vehicle treatment displayed a robust CPP, indicating that additional training increased the strength of the conditioned behavior (group III, test 3, Fig. 3 B). In contrast, CPP was persistently abolished in mice reexposed to morphine in the drug-paired compartment after injection of SL327 (group IV, test 3, Fig. 3 B). Finally, we examined whether priming by morphine could reactivate CPP in the group of mice in which it had been erased by SL327. On day 25, all mice were tested again for CPP immediately after a priming injection of morphine (test 4, Fig. 3 B). This priming injection restored the CPP of group III to its initial level but did not change the response of SL327-treated group IV (Fig. 3 B). These results show that the ability of SL327 to erase previously learned CPP can be generalized to morphine and lasts for at least 2 weeks.

The Effects of ERK Blockade on Cocaine- or Morphine-Induced CPP Are Mimicked by a Protein Synthesis Inhibitor.

A major role of ERK activation is to control gene expression at both transcriptional (13) and translational (36) levels, and it is likely that its long-lasting consequences require protein synthesis. In addition, reactivation of memories during the reconsolidation phase makes them sensitive to protein synthesis inhibitors (25). We examined whether systemic administration of anisomycin, a protein synthesis inhibitor, after reexposure to morphine or cocaine was capable of erasing previously acquired CPP, using an experimental design similar to that described in Fig. 1 for SL327 (Fig. 4 A). All mice conditioned to cocaine (groups b, d, and f) or morphine (groups c and e) displayed a similar CPP (test 1, Fig. 4 B). Some of these mice were reexposed to the drug for which they had been conditioned, in the drug-paired environment, and then treated with vehicle (groups b and c, test 2, Fig. 4 A and B) or anisomycin (groups d and e, Fig. 4 A and B). CPP was absent the following day in mice in which reexposure was followed by anisomycin (groups d and e, test 2, Fig. 4 B). In vehicle-treated mice CPP was not diminished (groups b and c, test 2, Fig. 4 B). Importantly, injection of saline in the drug-paired compartment followed by anisomycin did not erase the CPP (group f, test 2, Fig. 4 B), showing that a reexposure to the drug, and not a simple injection in the drug-paired compartment, was required to reactivate an anisomycin-sensitive form of memory. These results strongly support the hypothesis that ERK exerts its critical effect through regulation of protein synthesis, presumably by controlling transcription. They also show that simultaneous reexposure to drug and drug-associated context produces effects similar to the reconsolidation described for other types of memory (37).

Fig. 4.
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Fig. 4.

Protein synthesis inhibition after reexposure to morphine or cocaine in the drug-paired compartment erases CPP. (A) Experimental design: C, cocaine 20 mg/kg; M, morphine, 5 mg/kg; Veh, vehicle; Ani, anisomycin, 100 mg/kg. Each group included seven to nine mice. (B) After conditioning, mice developed a significant CPP for the cocaine-paired (groups b, d, and f) or morphine-paired (groups c and e) compartment compared with saline-treated mice (group a) (test 1, F(5,42) = 17.49, P < 0.01). Blockade of protein synthesis after reexposure to cocaine (group d) or morphine (group e) by injection of anisomycin suppressed the place preference when the animals were tested 24 h later (test 2, F(5,42) = 17.47, P < 0.01). Data are expressed as mean ± SEM. Post hoc comparison (Bonferroni test), group a vs. group b–f, was as follows: ∗, P < 0.01; group b or c vs. group d or e, ○, P < 0.01.

Locomotor Sensitization Does Not Undergo Protein-Synthesis Inhibitor-Sensitive Reconsolidation.

In addition to inducing CPP, single or repeated exposures enhance the locomotor effects of many drugs of abuse in rodents, a long-lasting behavioral alteration that may be relevant for some aspects of addiction (38). Sensitization is partly dependent on association of the locomotor effects of a drug with the environment in which it has been previously administered (39). Although the mechanisms underlying locomotor sensitization are not fully understood, it is thought to reflect neuronal adaptations in several brain regions, including NAcc, prefrontal cortex, and DA neurons in the mesencephalon (40), that seem different from those of CPP (41). We examined whether inhibition of protein synthesis was capable of altering locomotor sensitization using a single injection protocol (12, 42). We first evaluated whether anisomycin was able to prevent the induction of locomotor sensitization using a single injection paradigm (Fig. 5 A). Mice received a first injection of cocaine (1st inj) and were challenged with a test injection 7 days later (test inj) (Fig. 5 A). As previously reported (12), these mice displayed an increased locomotion in response to the second injection of cocaine (Fig. 5 A). In contrast, mice that received anisomycin either 30 min before or immediately after the first injection of cocaine, did not display any locomotor sensitization a week later (Fig. 5 A), demonstrating that protein synthesis is necessary for induction of this long-lasting effect of cocaine. This result confirms previous findings showing that locomotor sensitization was prevented by local application of anisomycin in the ventral tegmental area (43).

Fig. 5.
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Fig. 5.

Cocaine-induced locomotor sensitization induction is prevented by protein synthesis inhibitors but does not undergo protein synthesis-dependent reconsolidation. (A) Mice received a first injection of cocaine (C, 20 mg/kg), preceded or followed by vehicle (Veh) or anisomycin (Ani, 100 mg/kg) (10–11 mice per group). Locomotor activity was measured during 60 min in response to this first injection (1st inj) of cocaine and to a second injection of cocaine, 7 days later (test inj). Data were analyzed with mixed factor ANOVA (repeated measure over time) (effect of time, F(1,53) = 6.99, P < 0.01; effect of treatment, F(2,53) = 5.36, P < 0.01). Bonferroni test was as follows: ∗, P < 0.01 compared with 1st inj; ○, P < 0.01 Veh vs. Ani. (B) To test possible reconsolidation process, all groups of mice received a 1st injection of cocaine (1st inj). Three days later, they were left untreated (no reexposure) or received a second injection of cocaine in the actimeter, followed by an injection of vehicle (C + Veh) or anisomycin (C + Ani). All mice received a test injection of cocaine at day 7 (test inj) (10 mice per group). Data were analyzed with mixed factor ANOVA (repeated measure over time) (effect of time, F(1,53) = 35.82, P < 0.01; effect of treatment, F(2,53) = 0.26, NS). Bonferroni test was as follows: ∗, P < 0.01 compared with 1st inj.

We then tested whether protein synthesis inhibition after reexposure to cocaine could erase previously induced locomotor sensitization (Fig. 5 B). For this purpose, after the first exposure to cocaine, mice received no treatment on day 3 or were reexposed to cocaine in the drug-associated environment (actimeter) and then received an injection of vehicle or anisomycin (Fig. 5 B). As expected, mice not reexposed, or reexposed to cocaine and treated with vehicle, showed a robust locomotor sensitization (Fig. 5 B). Mice reexposed to cocaine and treated with anisomycin (group III) also developed a significant sensitization (Fig. 5 B). These results demonstrate that, once induced, locomotor sensitization cannot be reversed by cocaine reexposure in the presence of anisomycin. These results contrast with those reported above for CPP and further support that these two behavioral responses depend on different mechanisms.

Role of ERK in Reconsolidation of Drug-Environment Association.

The present study provides strong evidence that mechanisms similar to memory reconsolidation are operating during repeated drug administration in the same environment. Moreover, it demonstrates that these mechanisms can be manipulated by simple systemic pharmacological treatments. These results extend the recent reports on the effects of local manipulation of the ERK pathway in NAcc or of immediate early gene Zif268 in basolateral amygdala (17, 44). Thus, the ERK pathway plays a central role in the effects of drugs of abuse at several stages. This pathway is activated in the NAcc, the extended amygdala, and other brain regions during the first administration of a variety of drugs of abuse (9,45–47). It is also activated in response to repeated administrations of the same drug (7, 9, 47) or, after conditioning, in response to drug-associated cues (16, 29). We found that, when mice are placed in the CPP test conditions, ERK activation was more widespread than previously reported in rats (29), including the DStr and prefrontal cortex. We also found that an important substrate of cAMP-dependent protein kinase (PKA), GluR1, was phosphorylated in NAcc and DStr, an effect that may be important for the behavioral response.

Peripheral administration of a pharmacological inhibitor of MEK, which crosses the blood–brain barrier, prevents the induction (9, 14) and expression (present study) of drug-environment associations, as well as a process similar to reconsolidation (see ref. 48 for a recent discussion of reconsolidation). In contrast to reconsolidation of other types of memory achieved by exposure to the conditioned stimulus alone, inhibitor-sensitive reactivation of drug-related memory seemed to require the association of both unconditioned (drug injection) and conditioned (drug-paired environment) stimuli. When SL327-pretreated mice were injected with saline in the drug-paired compartment or when they received cocaine in their home cage, CPP was not suppressed. Moreover, although the administration of a MEK inhibitor before the test blocked the expression of CPP acutely, it did not prevent its reexpression 2 days later. This observation differs from a recent report in rat (29). However, it is possible that, by acutely blocking the expression of CPP on the test day, SL327 also prevented contextual memory reactivation. Therefore, further exploration is needed to determine to what extent conditioned stimuli are sufficient for reconsolidation in this context. Interestingly, as in reconsolidation of other types of memory (25, 28), that observed in the present study was inhibited by both a MEK inhibitor and a protein synthesis inhibitor. This finding suggests that a major role of ERK in this context is the control of gene expression, although we cannot rule out that the two inhibitors achieve similar effects through unrelated mechanisms.

Our study does not allow identifying in which brain structures inhibitor-sensitive reactivation is important for the maintenance of drug-induced conditioning. It is likely that several brain regions, including basolateral amygdala (44) and NAcc (29), and possibly others, are all necessary for drug-related memory reconsolidation. On the other hand, the present study provides evidence that a unique systemic injection of a kinase inhibitor has long-lasting behavioral effects, if it is specifically administered before reexposure to the drug in the previously drug-paired environment. The resulting erasure of the previously learned CPP lasts for at least 2 weeks and does not seem to be related to an extinction mechanism. It is not known, however, whether well learned drug associations after a long training protocol would be sensitive to inhibitors. Thus, our results provide an incentive for further exploring possible therapeutic strategies using kinase inhibitors in specific conditions to reverse previously acquired drug-induced conditioning.

Materials and Methods

Experiments were in accordance with the guidelines of the French Agriculture and Forestry Ministry for handling animals (decree 87849, license 01499) in 8-week-old male C57BL/6J mice. Cocaine-HCl and morphine sulfate (Sigma-Aldrich) were dissolved in 0.9% (wt/vol) NaCl (saline); SL327 (Biaffin, Kassel, Germany) dissolved in DMSO was diluted twice in water; and anisomycin (Sigma-Aldrich) in 1 M HCl was diluted in saline, and adjusted to pH7. For immunoblotting, microdisks were prepared from sections of rapidly frozen brains at the end of CPP and lysed in a 1% SDS (vol/vol) solution at 100°C as described (12). CPP was done in a two-compartment apparatus (Imetronic, Pessac, France) with different patterns on floors and walls, separated by a central neutral area (41). Preconditioning phase (day 1, pretest, 18 min) was as follows: mice were placed in the central neutral area and allowed to explore both compartments. Mice were randomly assigned to the various experimental groups (unbiased protocol). Conditioning (days 2–7) was as follows: mice were confined to one compartment for 20 min after injection of cocaine (20 mg/kg, i.p.) or morphine (5 mg/kg, s.c.) on days 2, 4, and 6, or to the other compartment after saline injection on days 3, 5, and 7. Control mice always received saline. The conditioning test (day 8, test 1) lasted 18 min. Results were expressed as the difference between postconditioning and preconditioning time spent in the drug-paired compartment. The day following test 1 (day 9), mice were treated with vehicle or SL327 (30 mg/kg, i.p.), injected 1 h later with saline, cocaine, or morphine, and placed as indicated in the various experiments. In some experiments, mice received anisomycin (100 mg/kg, i.p.) or vehicle immediately after reexposure to the drug. CPP was tested the following day (day 10) and 14 days later (day 24). Priming was done with cocaine (20 mg/kg) or morphine (5 mg/kg) just before CPP test (day 11 or 25).

Locomotor activity was measured by consecutive interruption of two adjacent beams (1/4 tour) in a circular corridor with four infrared beams placed at every 90° (Imetronic) in a low luminosity environment (12). Procedures are detailed in Supporting Experimental Procedures, which is published as supporting information on the PNAS web site.

Acknowledgments

A.-G.C. was supported by a scholarship from Ecole de l’INSERM. This work was supported by INSERM and by a grant from Fondation Liliane Bettencourt (to J.-A.G.).

Footnotes

  • *To whom correspondence should be addressed at:
    Institut National de la Santé et de la Recherche Médicale, U536, 17 Rue du Fer à Moulin, F-75005 Paris, France.
    E-mail: girault{at}fer-a-moulin.inserm.fr
  • Author contributions: E.V., D.H., and J.-A.G. designed research; E.V., A.-G.C., J.B.-G., and D.H. performed research; E.V., A.-G.C., J.B.-G., D.H., and J.-A.G. analyzed data; and E.V., D.H., and J.-A.G. wrote the paper.

  • Conflict of interest statement: No conflicts declared.

  • Abbreviations:
    CPP,
    conditioned place preference;
    DA,
    dopamine;
    DStr,
    dorsal striatum;
    ERK,
    extracellular signal-regulated kinase;
    GluR1,
    glutamate receptor-1;
    NAcc,
    nucleus accumbens;
    P-ERK,
    phosphorylated ERK;
    P-GluR1,
    phospho-Ser845 GluR-1;
    MEK,
    mitogen-activated protein kinase/ERK kinase.
  • © 2006 by The National Academy of Sciences of the USA

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Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference
Emmanuel Valjent, Anne-Gaëlle Corbillé, Jesus Bertran-Gonzalez, Denis Hervé, Jean-Antoine Girault
Proceedings of the National Academy of Sciences Feb 2006, 103 (8) 2932-2937; DOI: 10.1073/pnas.0511030103

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Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference
Emmanuel Valjent, Anne-Gaëlle Corbillé, Jesus Bertran-Gonzalez, Denis Hervé, Jean-Antoine Girault
Proceedings of the National Academy of Sciences Feb 2006, 103 (8) 2932-2937; DOI: 10.1073/pnas.0511030103
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