Cellular and Molecular Neurobiology

, Volume 28, Issue 2, pp 157–172 | Cite as

Drug-induced Alterations in the Extracellular Signal-regulated Kinase (ERK) Signalling Pathway: Implications for Reinforcement and Reinstatement

Review Paper

Abstract

Drug addiction, characterized by high rates of relapse, is recognized as a kind of neuroadaptive disorder. Since the extracellular signal-regulated kinase (ERK) pathway is critical to neuroplasticity in the adult brain, understanding the role this pathway plays is important for understanding the molecular mechanism underlying drug addiction and relapse. Here, we review previous literatures that focus on the effects of exposure to cocaine, amphetamine, Δ9-tetrahydrocannabinol (THC), nicotine, morphine, and alcohol on ERK signaling in the mesocorticolimbic dopamine system; these alterations of ERK signaling have been thought to contribute to the drug’s rewarding effects and to the long-term maladaptation induced by drug abuse. We then discuss the possible upstreams of the ERK signaling pathway activated by exposure of drugs of abuse and the environmental cues previously paired with drugs. Finally, we argue that since ERK activation is a key molecular process in reinstatement of conditioned place preference and drug self-administration, the pharmacological manipulation of the ERK pathway is a potential treatment strategy for drug addiction.

Keywords

Addiction Neuroplasticity Reward Relapse Dopamine Glutamate Contextual cues 

Introduction

Extracellular signal-regulated kinase (ERK) belongs to the family of mitogen-activated protein kinases (MAPKs), which are involved in regulation of many cellular processes including cell proliferation, differentiation, growth, and death (Kyosseva 2004). In mammalian nerve cells, ERK is a collective name for the isoforms of ERK1 (ERK44 or p44 MAPK) and ERK2 (ERK42 or p42 MAPK), two kinases with almost complete structural overlap. In response to extracellular stimuli, ERK is recruited to transfer signals from the cell membrane to downstream targets in the cytoplasm or nucleus, followed by immediate responses or long-lasting adaptive changes. The signal cascade of ERK was first elucidated through the study of neurotrophins and their tyrosine kinase receptors (Trks). Neurotrophins cause activation and autophosphorylation of Trk receptors, followed by sequential activation of the small G-protein Ras and the serine-threonine kinase Raf-1 and MAPK/ERK kinase (MEK). MEK activates ERK by direct phosphorylation on threonine and tyrosine residues in the ERK. The phosphorylation of ERK alters its conformation and turns on kinase activity for downstream targets, such as MSK1 and Elk-1. Phosphorylated ERK is deactivated by protein phosphatases, such as PP2a in neurons (Mansuy and Shenolikar 2006). Besides Trks, ERK is also regulated by G protein-coupled receptor (GPCR) activation and Ca2+ channel opening (Fig. 1).
Fig. 1

ERK signaling cascade. ERK activation is initially recognized as downstream of neurotrophic factors, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and basic fibroblast growth factor (bFGF). By coupling with the G protein-coupled receptor (GPCR)-AC-PKA pathway, ERK directly responds to extracellular dopamine, glutamate, opioids, and cannabinoids. By coupling with NMDA receptors and acetylcholine receptors (nAChR), ERK can respond to glutamate and nicotine. PD98059, U0126, SL327, and PD184161 are used as pharmacological tools to inhibit MEK, and thus down-regulate ERK phosphorylation

Accumulating research indicates an integration of second messenger systems mediating ERK activation, including intracellular Ca2+ store, cyclic adenosine monophosphate (cAMP) with protein kinase A (PKA) (Morozov et al. 2003), protein kinase C (PKC) (Goldin and Segal 2003), and Ca2+/calmodulin-dependent kinase (CaMK) (Schmitt et al. 2005). Actived ERK (phosphorylated ERK, pERK) translocates from the cytoplasm to the nucleus, where it regulates the activity of transcription factors CREB and Elk-1 to control gene expression (Davis et al. 2000). ERK downstream targets also include cytoskeletal proteins, regulatory enzymes, and membrane ion channels (Frodin and Gammeltoft 1999). Accumulating evidence supports ERK-dependency in molecular adaptation, morphological plasticity, and behavioral performance (Lee et al. 2005, Chwang et al. 2006), and even in mood modulation (Einat et al. 2003).

Drug addiction is considered as a neuroadaptive disorder characterized by dis-regulation of the mesocorticolimbic dopamine (DA) reward system (Nestler et al. 1996). This system contains two main components: the mesolimbic and mesocortical circuits. The mesolimbic circuit comprises the ventral tegmental area (VTA), nucleus accumbens (NAc), amygdala and hippocampus, and DA projections from VTA to these areas. The mesocortical circuit involves the VTA, prefrontal cortex (PFC), orbitofrontal cortex (OFC), and anterior cingulate (Acc), as well as DA projections from VTA to other brain regions. These neurocircuits have been implicated in reinforcement and conditioned responses in development of drug dependence, withdrawal distress, craving, and relapse (Cami and Farre 2003). ERK is expressed throughout the brain (Ortiz et al. 1995), and is especially abundant in the mesocorticolimbic DA system. The abundant distribution of ERK in the mesocorticolimbic areas underscores the importance of the ERK signaling cascade in the regulation of the DA reward system. Thus, researchers have increasingly focused on the role of ERK-signaling responses in the development of drug dependence and relapse. Here, we review the ERK alternations induced by cocaine, amphetamine, Δ9-tetrahydrocannabinol (THC), nicotine, morphine, and alcohol in mesocorticolimbic system and the possible role that the ERK pathway plays in drug reinforcement and in relapse/reinstatement after withdrawal.

Drugs Induce Alterations of ERK Signal Transduction in the Mesolimbic Brain Area

ERK activation pattern in mesocorticolimbic areas is responsive specifically to drugs of abuse (Corbille et al. 2007; Valjent et al. 2004). Acute administration of addictive drugs, including cocaine, Δ9-tetrahydrocannabinol (THC), nicotine, and morphine, enhanced ERK phosphorylation in NAc, Bed Nucleus of the Stria Terminalis (BNST), central amygdala, and the deep layers of the PFC. Substances that are not drugs of abuse, like caffeine and scopolamine, did not cause such strong ERK activation, although they also moderately induced ERK activation in a few of these brain areas (Valjent et al. 2004). Not only the acute drug treatment, but also chronic/repeated administration produces specific ERK active pattern in mesocorticolimbic brain regions. The effects of cocaine, amphetamine, THC, nicotine, morphine, and alcohol, the most abused substances or their active components, on ERK signaling in mesocorticolimbic brain regions are summarized in Table 1 and as follows.
Table 1

Effects of drugs on ERK phosphorylation in mesolimbic regions

Drugs

pERK regulation

Treatment

References

Cocaine

(↑) Striatum (m)

Acute (20–30 mg/kg, ip)

Corbille et al. (2007), Valjent et al. (2004, 2005, 2000), Zhang et al. (2004)

(↑) Striatum (m)

Repeated (20 mg/kg, ip)

Valjent et al. (2006b)

(↑) NAc (m)

Acute (20 mg/kg, ip)

Valjent et al. (2004)

(↑) NAc (r)

Repeated (15mg/kg, ip)

Yoon et al. (2007), Mattson et al. (2005)

(↑) VTA (r)

Repeated (15 mg/kg, ip)

Berhow et al. (1996)

(↑) BNST (m)

Acute (20 mg/kg, ip)

Valjent et al. (2004)

(↑) Hippocampus (m)

Acute (20 mg/kg, ip)

Valjent et al. (2004)

(↑) PFC (m)

Acute (20 mg/kg, ip)

Valjent et al. (2004)

(↑) CPu (m)

Acute (30 mg/kg, ip)

Zhang and Xu (2006), Zhang et al. (2004)

(↑) CPu (r)

Acute (20 mg/kg, ip)

Jenab et al. (2005)

(↑) Amygdala (m)

Acute, repeated (20 mg/kg, ip)

Radwanska et al. (2005), Valjent et al. (2004)

Amphetamine

(↑) Striatum (r)

Acute (2.5–5 mg/kg, ip)

Shi and McGinty (2006), Choe et al. (2002), Choe and Wang (2002)

(↑) Striatum (r)

Sensitized by 5 mg/kg, ip, then challenged by 1 mg/kg

Shi and McGinty (2007)

(↑) Striatum (m)

Acute (10 mg/kg, ip)

Valjent et al. (2005)

(↑) NAc (m)

Acute (10 mg/kg, ip)

Valjent et al. (2005)

(↑) VTA (r)

Acute (5 mg/kg, ip)

Rajadhyaksha et al. (2004)

(↑) PFC (r)

Acute (5–10 mg/kg, ip)

Pascoli et al. (2005)

THC

(↑) Striatum (m)

Acute (1 mg/kg, ip)

Valjent et al. (2001b, 2004)

(↑) NAc (m)

Acute (1 mg/kg, ip)

Valjent et al. (2001b, 2004)

(↑) BNST (m)

Acute (1 mg/kg, ip)

Valjent et al. (2004)

(↑) PFC (m)

Acute (1 mg/kg, ip)

Valjent et al. (2004)

(↑) PFC (r)

Repeated (0.075–15 mg/kg, ip)

Rubino et al. (2007)

(↑) Hippocampus (m)

Acute (1 mg/kg, ip)

Derkinderen et al. (2003)

(↑) Hippocampus (r)

Repeated (15 mg/kg, ip)

Rubino et al. (2004)

(↑) CPu (m)

Acute (10 mg/kg, sc)

Rubino et al. (2005)

(↑) CPu (r)

Acute, repeated (15 mg/kg, ip)

Rubino et al. (2004)

(↑) Amygdala (m)

Acute (1 mg/kg, ip)

Valjent et al. (2004)

Nicotine

(↑) Striatum (m)

Acute (0.4 mg/kg, ip)

Valjent et al. (2004)

(↑) NAc (m)

Acute (0.4 mg/kg, ip)

Valjent et al. (2004)

(↑) BNST (m)

Acute (0.4 mg/kg, ip)

Valjent et al. (2004)

(↑) PFC (m)

Acute (0.4 mg/kg, ip)

Valjent et al. (2004)

(↑) PFC (m)

Chronic (0.2 mg/ml in water)

Brunzell et al. (2003)

(↑) Amygdala (m)

Acute (0.4 mg/kg, ip)

Valjent et al. (2004)

(↓) Amygdala (m)

Chronic (0.2 mg/ml in water)

Brunzell et al. (2003)

Morphine

(↑) CPu (r)

Chronic (75 mg pellet, sc)

Ortiz et al. (1995)

(↑VTA (r)

Chronic (75 mg pellet, sc)

Berhow et al. (1996)

(↑) Acc (m)

Acute (10 mg/kg, sc)

Eitan et al. (2003)

(↑) BNST (m)

Acute (5 mg/kg, ip)

Valjent et al. (2004)

(↑) NAc (m)

Acute (5 mg/kg, ip)

Valjent et al. (2004)

(↑) NAc (m)

Repeated (10 mg/kg, sc)

Liu et al. (2007)

(↓) NAc (r)

Acute (50 mg/kg, sc), repeated (10–80 mg/kg, sc)

Muller and Unterwald (2004)

(↓) NAc (m)

Acute (10 mg/kg, sc)

Eitan et al. (2003)

(↓) Amygdala (m)

Acute (10 mg/kg, sc)

Eitan et al. (2003)

(↑) Amygdala (m)

Acute (5 mg/kg, ip)

Valjent et al. (2004)

(↑) PFC (m)

Acute (5 mg/kg, ip)

Valjent et al. (2004)

(↓) PFC (r)

Repeated (10–100 mg/kg, sc)

Ferrer-Alcon et al. (2004)

Alcohol

(↓) Hippocampal (r)

Acute (3.5–4.7 g/kg, ip)

Davis et al. (1999), Chandler and Sutton (2005)

(↓) Hippocampal (r)

Chronic (200 ± 50 mg% Blood)

Sanna et al. (2002)

(↓) NAc (r)

Chronic (200 ± 50 mg% Blood)

Sanna et al. (2002)

(↓) Striatum (r)

Chronic (200 ± 50 mg% Blood)

Sanna et al. (2002)

(↓) Amygdala (r)

Chronic (200 ± 50 mg% Blood)

Sanna et al. (2002)

(↓) Cerebral cortex (r)

Chronic (200 ± 50 mg% Blood)

Sanna et al. (2002)

(↓) Cerebral cortex (m)

Acute (3.5 g/kg, ip)

Kalluri and Ticku (2002a, b)

(↓) Cerebral cortex (r)

Acute (3.5 g/kg, ip)

Chandler and Sutton (2005)

Note: (↑) = up-regulating; (↓) = down-regulating; (r) = rat; (m) = mouse; sc = subcutaneously; ip = intraperitoneally

Cocaine

Both acute and repeated cocaine administration causes consistent up-regulation of ERK phosphorylation in the striatum, NAc, VTA, BNST, hippocampus, PFC, caudate putamen (CPu), and amygdala of mice or rats under various doses (Table 1). Cocaine-induced activations of the ERK pathway are critical to the MSK1, CREB, Elk-1, and activator protein 1 (AP1) activation and expression of immediate early genes (IEGs) in numerous mesocorticolimbic regions (Table 2). In addition, treatment with cocaine also increases the expression of some functional proteins, such as dynorphin, neogenin, and synaptotagmin VII in striatum, NAc, and CPu (Zhang and Xu 2006, Zhang et al. 2004). This increase can be reversed by administration of MEK inhibitor SL327 or U0126, suggesting that these enhanced protein expressions are also dependent on ERK activation.
Table 2

Cocaine-recruited signal molecules with dependence on ERK activation

Molecules

Brain regions

Studies

MSK1

Striatum (m), NAc (m)

Brami-Cherrier et al. (2005)

CREB

Striatum (r, m), NAc (m)

Brami-Cherrier et al. (2005), Mattson et al. (2005)

Elk-1

Striatum (r, m)

Jenab et al. (2005). Valjent et al. (2000)

c-fos, fosB, fra2, junB, ΔfosB

Striatum (r, m), Cpu (r, m), Amygdala (r, m)

Brami-Cherrier et al. (2005). Valjent et al. (2000), Zhang et al. (2004), Zhang and Xu (2006), Radwanska et al. (2005, 2006)

AP1

CPu (m)

Radwanska et al. (2006)

Note: (r) = rat, (m) = mouse

Amphetamine

Amphetamine administration increases ERK phosphorylation in the striatum, NAc, VTA, and PFC of mice or rats (Table 1). ERK phosphorylation is accompanied by phosphorylation of CREB and Elk-1, as well as alteration in the expression of IEGs (Choe et al. 2002; Choe and Wang 2002, Ferguson and Robinson 2004) in the rat striatum. The ERK phosphorylation increase has only been reported in animals receiving acute amphetamine administration. The chronic administration of the amphetamine has no effect on ERK phosphorylation, unless inhibition of the L-type Ca2+ channels (Rajadhyaksha et al. 2004). The increase in ERK phosphorylation after acute amphetamine-treated, but not after chronic amphetamine-treated, is different from findings that have been reported for cocaine (Berhow et al. 1996). The reason for the different results may be attributable to the different drugs used and paradigm of drug administration (Berhow et al. 1996; Rajadhyaksha et al. 2004). ERK activation is also involved in amphetamine-induced preproenkephalin and preprodynorphin mRNA transcription in the striatum as revealed by inhibition by site-injection of U0126 and systemic administration of SL327 (Shi and McGinty 2006).

THC

THC administration consistently enhances ERK phosphorylation in the striatum, NAc, PFC, BNST, hippocampus, CPu, and amygdala of mice or rats (Table 1). THC-induced phosphorylation of Elk-1 (Valjent et al. 2001b) and CREB (Rubino et al. 2004, 2007) are dependent on ERK activation. Moreover, the expression of zif268, c-fos, and fosB is regulated by the ERK signal pathway in striatum, hippocampus, PFC, and CPu (Valjent et al. 2001b, Derkinderen et al. 2003, Rubino et al. 2004). Chronic THC exposure significantly activated specific GRK and β-arrestin subunits in the striatum in mice, and such activation could be prevented by SL327 pretreatment (Rubino et al. 2006), indicating that these changes are ERK-dependent. Moreover, THC treatment induced a significant CREB phosphorylation in PFC with dependency of ERK activation in rats (Rubino et al. 2007).

Nicotine

Nicotine up-regulates ERK phosphorylation in striatum, NAc, BNST, PFC, and amygdala of mice with acute treatment (Table 1) (Valjent et al. 2004). Interestingly, chronic exposure to nicotine down-regulates total ERK protein levels and phosphorylated ERK levels in amygdala, although same treatment up-regulates phosphorylated ERK in PFC (Brunzell et al. 2003). However, there are no reports about nicotine effects on ERK in above brain regions of rats.

Morphine

Chronic morphine administration enhances ERK phosphorylation in VTA, CPu, and locus coeruleus (LC) in rats (Berhow et al. 1996; Ortiz et al. 1995), while it induces increased ERK phosphorylation in BNST, Acc, somato-sensory cortices, and LC in mice (Valjent et al. 2004, Eitan et al. 2003). ERK activation is also involved in TH expression in VTA (Berhow et al. 1996). Regulation of ERK phosphorylation by morphine in NAc, amygdala, and PFC has appeared inconsistent between studies. While two groups reported that acute administration in mice led to up-regulation of ERK phosphorylation in the central amygdala and PFC (Liu et al. 2007; Valjent et al. 2004), another study with mice and a study with rats showed the opposite results in the central amygdala in response to acute morphine administration (Muller and Unterwald 2004, Eitan et al. 2003). Moreover, chronic opiate exposure induces down-regulation of ERK phosphorylation in PFC of rats and human beings (Ferrer-Alcon et al. 2004). In a in vitro model of SH-SY5Y neuroblastoma, it was demonstrated that acute administration of morphine stimulated ERK activity (Ferrer-Alcon et al. 2004; Bilecki et al. 2005), while prolonged morphine treatment decreased the level of phosphorylated ERK (Bilecki et al. 2005). The seeming discrepancy of various findings on morphine’s effects on ERK activation may thus reflect the complexity of the drug’s effect on ERK, due to interaction between neurocircuits or cell-level signaling diversion.

Alcohol

Alcohol decreases ERK phosphorylation with chronic and acute exposure in rats or mice. Snnna et al. studied the effects of ethanol utilizing a continuous and intermittent model of chronic alcohol exposure. In this model, rats were kept in ethanol vapor chambers all over the time or for 12 h to reach blood alcohol level of 200 ± 50 mg%. Continuous exposure to alcohol reduced ERK phosphorylation in amygdala, dorsal striatum, cortex, and hippocampus, while intermittent exposure reduced ERK phosphorylation in dorsal striatum, NAc, and hippocampus (Sanna et al. 2002). Acute alcohol treatment reduces ERK phosphorylation in the cerebral cortex and hippocampus of the neonatal rat pups (postnatal day 5 or 21) (Chandler and Sutton 2005; Davis et al. 1999). In addition, acute alcohol exposures decrease ERK phosphorylation with a dose- and time-dependent manner in mouse cerebral cortex (Kalluri and Ticku 2002a, b).

Drug-induced Activation of ERK Signal Pathway in Mesolimbic System is Mediated by Dopaminergic and Glutamatergic Transmission

The mesolimbic DA system is critically involved in activation of ERK signal pathway by drug exposure. Nearly all drugs of abuse, including cocaine, amphetamine, THC, nicotine, and morphine, act on the mesocorticolimbic DA system. Cocaine and amphetamine, by inhibiting the DA transporter, increase the free DA levels between synapses and prolong DA receptor activation (Everitt and Wolf 2002; Rothman and Baumann 2003). Cocaine-induced ERK phosphorylation in the CPu under acute treatment is enhanced by D1 receptor activation and inhibited by D3 receptor activation (Zhang et al. 2004). Morphine and other opioids inhibit gamma-aminobutyric acid (GABA) neurons in VTA through the mu opioid receptor, and then relieve the control of GABA neurons over DA neurons in VTA and increase DA levels in the NAc (Bontempi and Sharp 1997). Nicotine enhances DA release through nicotine acetylcholine receptors (nAChR) on DA neurons in VTA (Picciotto and Corrigall 2002). THC increases DA neuron firing and burst rate in VTA through CB1cannabinoid receptor activation on glutamatergic and GABAergic terminals in VTA (Lupica et al. 2004). All DA receptors are 7-transmembrane GPCRs coupled with adenylyl cyclase (AC). With the signaling pathway from AC and cAMP to PKA, DA receptors couple with ERK in neurons (Ambrosini et al. 2000). The coupling makes ERK signaling a shared pathway in regulating the functional adaptation of DA nerve-projected brain regions (Sealfon and Olanow 2000) (Fig. 1).

Both ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs) are involved in ERK activation by drugs of abuse. Cocaine-induced ERK phosphorylation in the CPu is mediated by glutamate NMDA receptor activation (Jenab et al. 2005). Amphetamine-induced ERK phosphorylation in the PFC and striatum of mice can be reduced by administration of glutamate NMDA receptor antagonist MK801 and group I mGluRs inhibitor PHCCC, respectively (Pascoli et al. 2005; Choe and Wang 2002; Choe et al. 2002). Chronic morphine-induced ERK hyperphosphorylation in the VTA can also be blocked by MK801 (Berhow et al. 1996). In hippocampal slices, THC-enhanced ERK phosphorylation in hippocampal neurons was found to be dependent on the activity of glutamate NMDA receptors (Derkinderen et al. 2003).

There are at least three plausible relationships between glutamate and dopamine signaling in regulation of ERK phosphorylation in the brain during drug and drug cue exposure. The first possibility is that the glutamate signaling pathway can independently mediate drug-induced ERK activation (Lu et al., 2006). Infusion of NMDA into central amygdala has been evident to increase activation of ERK and enhance the cocaine craving after 1 day withdrawal from cocaine self-administration (Lu et al. 2005b). In one study of amphetamine, blockade of NMDA receptor by MK801 greatly reduced ERK phosphorylation in the mouse PFC, but blockade of DA receptors did not affect phosphorylated ERK level (Pascoli et al. 2005). A second possibility is that glutamate signaling plays a subsidiary role while dopamine signaling is dominant. This scenario is supported by the finding that a progressive activation of ERK in the dorsal striatum and NAc of rats induced by acute THC administration could be partially inhibited by MK801 and totally blocked by the D1 receptor antagonist SCH23390 (Valjent et al. 2001a). A final possibility is that a synergistic interaction exists between NMDA signaling and DA signaling. Amphetamine treatment activates ERK in the dorsal striatum which is not found in mice with pretreatment of NMDA receptor antagonist MK801 or in mice with mutant DA- and cAMP-regulated phosphoprotein (DARPP-32). In this case, both glutamate NMDA and DA receptor activation are essential (Valjent et al. 2005).

Role of ERK Signal Pathway in Drug Reward and Drug-induced Neuroadaptation

ERK in the mesocorticolimbic system mediates drug’s rewarding effects, as assessed by conditioned place preference (CPP) studies. Microinjection of PD98059 or U0126 into NAc was found to impair the acquisition of morphine (Ozaki et al. 2004) and THC (Valjent et al. 2001b) CPP in mice. Cocaine administration activates ERK in the striatum, and ERK activation is required for the acquisition of cocaine-induced CPP (Valjent et al. 2000). These findings indicate that ERK phosphorylation in NAc or striatum mediates morphine, THC, and cocaine’s rewarding effects. Other studies indicate that the role of ERK is MAPK-specific. NAc injections of MEK inhibitor PD98059 impaired amphetamine-induced CPP, while c-Jun-N-terminal kinase (another MAPK member) inhibitor SP600125 failed to block amphetamine CPP (Gerdjikov et al. 2004).

Repeated administration of drugs of abuse such as cocaine increases individual’s response to those drugs, reflecting comprehensive biological alternations in the brain, especially in the mesocorticolimbic regions. Activation of ERK in the brain mesocorticolimbic area is involved in the drug sensitization (Valjent et al. 2000, 2006c). For example, MEK inhibitor SL327 greatly inhibits ERK phosphorylation but does not affect basal spontaneous locomotion. SL327 had virtually no effect on the acute hyperlocomotion induced by cocaine or d-amphetamine (Valjent et al. 2006c). However, pre-treatment with SL327 prior to administration of cocaine or amphetamine prevented the locomotor sensitization induced by repeated injection of these drugs (Valjent et al. 2006c; Shi and McGinty 2006). Further, SL327 has been found to be effective in preventing the tolerance to hypolocomotion produced by THC (Rubino et al. 2005). These findings suggest that blocking the activation of ERK in the mesolimbic areas is of great interest in the prevention of drug-induced abnormal alteration in the brain.

Although most biological functions of ERK1 and ERK2 overlap, studies have revealed some differences in their effects on behavioral plasticity. A functional difference was first supported by the finding of their significantly different distribution in the brain (Ortiz et al. 1995). Gene manipulation enabled researchers to further characterize differences between the roles of ERK1 and ERK2 in drug reward. Mutant mice lacking functional ERK1 displayed stimulus-dependent increase of ERK2 phosphorylation. Correspondingly, sensitivity to morphine’s rewarding properties was increased (Mazzucchelli et al. 2002). Deletion of the ERK1 isoform can increase stimulus-dependent signaling through ERK2, facilitating the development of cocaine-induced hypersensitization and the acquisition of CPP (Ferguson et al. 2006). Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine (Ferguson et al. 2006). Finally, cocaine-evoked gene expression in the mesocorticolimbic brain regions is enhanced in ERK1-deficient mice (Ferguson et al. 2006). Thus, ERK2 appears to be the isoform most important for the behavioral effects of drug abuse (Girault et al. 2007).

Cue-induced ERK Activation and its Implications for Drug Reinstatement

Relapse to drug abuse in humans is often precipitated by exposure to drug-related cues that provoke drug craving even after long periods of abstinence. Accumulating evidence demonstrates that ERK activity is important in both the existence and persistence of incubation of cocaine craving (Lu et al. 2006). In addition to the pharmacological effect of drugs of abuse on ERK activation, drug withdrawal also alters ERK signaling (Sanna et al. 2002; Lu et al. 2005a). Studies have revealed that drug-paired cues also induce ERK phosphorylation in the mesocorticolimbic system (Lu et al. 2005b, 2006, Miller and Marshall 2005). Rats trained for CPP showed ERK, CREB, and Elk-1 activation in the NAc core when reexposed to the drug-paired chambers (Miller and Marshall 2005).

Recently, it has been hypothesized that the major substrates of persistent compulsive drug use share the molecular and cellular mechanisms that underlie long-term associative memories in several forebrain circuits (Hyman et al. 2006). Consolidation, retrieval, and reconsolidation of drug memories can be demonstrated by CPP paradigm (Miller and Marshall 2005; Zhao et al. 2007). There is evidence that the reactivated ‘labile’ memory is susceptible to pharmacological manipulations of ERK (Lu et al. 2006; Miller and Marshall 2005). For example, infusion of U0126 or PD98059 into the NAc core both inhibited ERK phosphorylation and blocked CPP retrieval (Miller and Marshall 2005). After cocaine CPP was established, systemically injecting SL327 plus cocaine, before reexposure to the cocaine-paired chamber abolished the CPP expression 24 h later, which was accompanied with the blockade of ERK phosphorylation in the ventral and dorsal striatum (Valjent et al. 2006b). Erasure of CPP expression by SL327 administration required the combination of cocaine administration and drug-paired context. Similarly, reexposure to morphine in the presence of SL327 abolished response of previously learned morphine-CPP over the long term (Valjent et al. 2006b). These findings showed that an established CPP could be disrupted when reactivation was associated with both the conditioned context and drug administration, in which the ERK pathway was involved (Valjent et al. 2006b, but see Miller and Marshall 2005). Preventing ERK activation during reexposure to context previously associated with the drug erased the previously learned behavioral response (Valjent et al. 2006a, b, c). Moreover, at the dose that did not have effects on spontaneous locomotion, SL327 pre-treatment could prevent the acquisition of cocaine sensitization, and abolish the conditioned locomotor response of mice placed in the context previously paired with cocaine (Valjent et al. 2006c), but could not disrupt the established drug sensitization (Valjent et al. 2006a, c).

In the rat self-administration model, the time-dependency of drug seeking was demonstrated through greater responsiveness to cocaine-paired cues after 30 withdrawal days than that after 1 withdrawal day (Lu et al. 2004a, b, 2005b). Exposure to these cues increased ERK phosphorylation in the central amygdala after 30 days, but not 1 day, of withdrawal (Lu et al. 2005b). After 30 days of withdrawal from cocaine, inhibition of central amygdala ERK phosphorylation significantly decreased the time-dependent enhanced cocaine craving, which revealed a positive correlation between cocaine craving and ERK phosphorylation (Fig. 2). Blocked of glutamate transmission in the central amygdala significantly inhibited ERK activation and decreased the enhanced drug craving (Lu et al. 2006, 2007), which suggest that ERK phosphorylation in central amygdala is critical for time-dependent change of cocaine craving after withdrawal. ERK activation in amygdala has been found to play a key role in Pavlovian fear conditioning, disjoined associative memory consolidation and retrieval (Nader et al. 2000), as demonstrated by the finding that cued fear conditioning could be inhibited by systemic administration of MEK inhibitor SL327. Taken together, these findings indicate the necessity of ERK activation in specific brain regions for cue-induced drug reinstatement. Thus, blocking ERK function may be a way to induce cue-related memory knockout (Hernandez and Kelley 2005).
Fig. 2

Cue-induced reinstatement of drug seeking depending on ERK phosphorylation and NMDA glutamate receptor activation. Rats were first trained for cocaine self-administration. When returned to their training environments for the extinction test, the rats showed higher lever-press responses at withdrawal day 30 (A, left, *P < 0.05 versus withdrawal day 1, accompanied by enhanced ERK phosphorylation in the central amygdala (A, right, *P < 0.05 versus non-extinction test). This higher lever-press response could be inhibited by the MEK inhibitor U0126 (B, left, *P < 0.05 versus active lever in vehicle group) and NMDA receptor antagonist AP-5 (C, left, *P < 0.05 versus active lever in vehicle group). Decreased lever-press response was associated with specific down-regulated ERK phosphorylation in the central amygdala (B and C, right, *P < 0.05 versus vehicle), but not the basolateral amygdala. Adapted from Lu et al. (2005b) with permission from Nature Publishing Group

Concluding Remarks

Drug addiction is a neuroadaptive disorder of the brain. Accumulating evidence indicates that ERK signaling in the mesocorticolimbic DA system is altered by drugs of abuse and conditioned drug-associated stimuli, and that expression of drug reinforcement and reinstatement depends on ERK activation in brain. However, the different roles that ERK signaling plays in the various facets of addiction, such as drug taking, sensitization, tolerance, and incubation of craving, are not known, which should be the future direction of research (Lu et al. 2006; Girault et al. 2007). Moreover, ERK is critical for downstream regulation of DA and glutamate signal transmission in the mesocorticolimbic brain areas that mediate drug reinforcement and reinstatement. Thus, pharmacological agents that inhibit ERK activity and decrease reinstatement of drug seeking in a rat addiction model may be considered for the treatment of addiction in the future.

Notes

Acknowledgments

This work was supported in part by the Program for New Century Excellent Talents in University, the National Basic Research Program of China (973 Program, 2007CB512302 and 2003CB515400), the National High Technology Research and Development Program of China (863 Program, 2006AA02Z4D1), and the Natural Science Foundation of China (Nos. 30570576 and 30670713).

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Neuropharmacology, National Institute on Drug Dependence Peking UniversityHai Dian DistrictChina

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