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

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 A ddiction 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 ...

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

“…Similarly, we observed no change in ERK signaling in the hippocampus or cingulate cortex at a 5 min time point, likely due to the fact that activation of ERK signaling by morphine in these areas peaks at 20 min post injection (Valjent et al, 2004). Other studies show that inhibition of ERK during place conditioning blocks cocaine CPP (Valjent et al, 2006a). ERK induction at the 5 min time point indicates that stimulation of ERK would occur during exposure to the training chamber during place conditioning.…”

“…A trend for slightly higher levels of ERK1/2 phosphorylation in GKO mice (WT-Mor vs KO-Mor: F(3, 19) ¼ 2.4; p ¼ 0.08) correlates with the tendency for these animals to show increased behavioral sensitivity to morphine. Together with studies showing that ERK activity is necessary for place preference (Girault et al, 2007;Salzmann et al, 2003;Valjent et al, 2001Valjent et al, , 2006aValjent et al, , b, 2004 and that galanin reduces morphine CPP (Zachariou et al, 1999), these data suggest that galanin might regulate morphine reward via regulation of ERK signaling in the VTA. It is also possible that ERK activity in the VTA regulates the ability of galanin to modulate morphineinduced locomotor activation.…”

“…In addition, together with evidence indicating that phosphorylation of ERK is necessary for drug reinforcement (Ozaki et al, 2004;Valjent et al, 2001Valjent et al, , 2006aValjent et al, , b, 2004Valjent et al, , 2005, these data suggest that galanin may modulate drug-dependent behaviors via activation of ERK in brain areas such as the VTA, NAc, and amygdala. Thus, galanin agonists may prove useful in attenuating the rewarding properties of opiates.…”

“…At the molecular level, morphine administration leads to enhanced phosphorylation, and thus activation of extracellularregulated kinase (ERK1/2) in the VTA, hippocampus, NAc, cingulate cortex, and amygdala (Berhow et al, 1996;Valjent et al, 2004). Increased ERK1/2 phosphorylation in the VTA is associated with morphine and psychostimulant reward (Ozaki et al, 2004) and systemic inhibition of ERK1/2 phosphorylation blocks expression of morphine and cocaine CPP (Valjent et al, 2006a). To assess galanin effects on changes in signaling, we measured the effects of morphine administration on levels of total and phosphorylated ERK1/2 in the VTA, NAc, amygdala, cingulate cortex, substantia nigra (SN), LC, caudate putamen, and hippocampus of WT and GKO mice and assessed whether the galanin receptor agonist galnon could reverse these changes.…”

Alcohol Relapse Induced by Discrete Cues Activates Components of AP-1 Transcription Factor and ERK Pathway in the Rat Basolateral and Central Amygdala

“…The inhibition of ERKs in the amygdala has been reported to block the formation of long-term fear memory (Schafe et al, 2000), memory reconsolidation (Duvarci et al, 2005), and extinction (Herry et al, 2006). Furthermore, Valjent et al (2006) have shown that inhibition of the ERK pathway prior to reexposure to cocaine-paired context blocked conditioned place preference on the following trial. Future studies will show whether inhibition of ERKs in the amygdala could also interfere with cue-induced alcohol seeking.…”