psychomotor-activating properties of a drug). Indeed, activation of ERK in the brain mesocorticolimbic area has been shown to be involved in sensitization and hence druginduced plasticity (Pierce et al., 1999; X. Shi & McGinty, 2006; Valjent, et al., 2000; Valjent, Corvol, et al., 2006). Thus, pre-treatment with the MEK inhibitor SL327 prior to the repeated administration of cocaine or amphetamine prevents the subsequent expression of sensitization to their locomotor-activating effects upon receiving a challenge dose of the drug (Valjent, Corvol, et al., 2006). In contrast, the expression of sensitization was not affected when SL327 was administered before the challenge (Valjent, Corvol, et al., 2006). Therefore it appears ERK is more critical for the development of sensitization to psychostimulants. ERK activation in the VTA is implicated in this process as intra-VTA infusions of PD98059 attenuate the

ERK in the NAc also appears to be involved in drug-induced plasticity as cocaine sensitized rats display increased phospho-ERK2 during withdrawal from cocaine which is normalized upon cocaine challenge (Boudreau et al., 2007). ERK2 phosphorylation corresponded with accumbens AMPA receptor surface expression (Boudreau, et al., 2007). The authors suggest the possibility that ERK contributes to both rapid (LTP) and slowly induced (cocaine withdrawal) increases in AMPA receptor surface expression, thus contributing to addictionrelated plasticity (Boudreau, et al., 2007). Similarly, withdrawal following development of sensitization to cocaine has been shown to be associated with time-dependent increases in ERK activity which correlate with the increased expression of NMDAR subunits (Schumann & Yaka, 2009). Furthermore, the increase in both GluR1 expression and ERK activity is blocked with intra-NAc infusions of a MEK inhibitor 21 d after withdrawal from cocaine. These data suggest that the development of cocaine psychomotor sensitization triggers a delayed increase in the expression of NMDAR subunits in the NAc, which in turn enhances

The activation of ERK by drugs of abuse in mesocorticolimbic regions has been shown to require both glutamate and dopamine signalling as it is prevented by both dopamine D1 and NMDA receptor antagonists (Berhow et al., 1996; Jenab et al., 2005; Valjent, et al., 2000; Valjent, et al., 2001; Valjent et al., 2005), and in the case of amphetamine, by group I metabotropic glutamate (mGlu) receptor antagonists (Choe et al., 2002). This is not surprising as ERK is found downstream of all these receptors. Thus, the activation of dopamine D1 receptors by dopamine increases cyclic adenosine monophosphate (cAMP) and thus cAMP-dependent protein kinase A (Bilbao et al. 2008). Activated cAMP-dependent protein kinase (Bilbao, et al. 2008) then activates ERK through the the dopamine- and cAMPregulated phosphoprotein 32 kDa (DARPP-32) signaling cascade (Greengard et al., 1999; Svenningsson et al., 2004). In striatal neurons, the mGlu5 receptor activates ERK through Ca2+-dependent and -independent mechanisms, the latter involving the scaffolding protein Homer (L. Mao et al., 2005). Activation of NMDA receptors and the resulting Ca2+ influx activate Ca2+/calmodulin-dependent protein kinase II (CaMKII). CaMKII then activates Ras-GTP, which initiates a number of kinase cascades, including Raf-1, MAPK/ERK kinases and ERK (G. M. Thomas, et al., 2004; Xia et al., 1996). ERK is also activated by opioid receptors most likely via a mechanism involving Ras and beta-gamma subunits of Gi/o proteins (Belcheva et al., 1998). Once activated, ERK translocates to the cell nucleus where it regulates

development of sensitization to cocaine (Pierce, et al., 1999).

the activity of ERK (Schumann, et al., 2009).

**4.4 Drugs of abuse and mechanisms of ERK signalling**

activation has been shown to be required for the acquisition of CPP induced by cocaine (Valjent et al., 2000), MDMA (Salzmann et al., 2003), THC (Valjent et al., 2001), amphetamines (Gerdjikov et al., 2004; Mizoguchi et al., 2004) and morphine (Ozaki et al., 2004), but not ethanol (Groblewski, Ryabinin et al., 2011). It is most likely that the NAc is a site of action, at least for amphetamines, as intra-NAc injections of the MEK inhibitor PD98059 impair both methamphetamine and amphetamine-induced CPP (Gerdjikov, et al., 2004; Mizoguchi, et al., 2004). This is supported by the observation of increased activation of ERK in the NAc and dorsal striatum of mice that have been conditioned to methamphetamine (Mizoguchi, et al., 2004) and the NAc, dorsal striatum and prefrontal cortex of mice that have been conditioned to cocaine (Valjent, Corbille et al., 2006). Another study found that exposing mice to a previously cocaine-paired context increased phosphorylation of ERK in the dorsal hippocampus, but not the NAc. Enhanced CREB and DARPP-32 phosphorylation in the NAc, however, was observed (Tropea et al., 2008). Pre-treatment with the MEK inhibitor SL327 has also been shown to abolish the conditioned locomotor response of mice placed in a context previously paired with cocaine or D-amphetamine (Valjent, Corvol et al., 2006), indicating the role of ERK can be generalised to other contextually-driven behaviors.

It also appears that the NAc mediates consolidation of learned associations between a drug's rewarding effects (US) and the drug-paired context (CS). If rats are injected with a MEK inhibitor either systemically or into the NAc core after the test for the expression of cocaine or morphine CPP, subsequent CPP is abolished (Miller & Marshall, 2005; Valjent, Corbille, et al., 2006). Erasure of CPP expression is accompanied with blockade of ERK phosphorylation in the NAc and dorsal striatum (Valjent, Corbille, et al., 2006). This effect can be mirrored with a protein synthesis inhibitor thus providing evidence that ERK exerts this effect on memory reconsolidation through regulation of protein synthesis, presumably by controlling transcription.

### **4.3 The involvement of MAPK in the actions of drugs of abuse & drug-induced plasticity**

The MAPK signalling cascade has been implicated in responses to most drugs of abuse, supporting the notion that drug-induced plasticity might share common mechanisms with learning and memory processes (Berke & Hyman, 2000; Girault et al., 2007; Hyman, 2005). ERK is expressed abundantly throughout the brain, including mesocorticolimbic regions (Ortiz et al., 1995). Acute and chronic administration of most drugs of abuse such as cocaine, morphine, nicotine and Δ9-tetrahydrocannabinol (THC) has been shown to increase activation of ERK in reward-related areas such as the VTA, NAc, PFC, central and extended amygdala and hippocampus (reviewed in Girault et al., 2007; Zhai et al., 2008). The exception is alcohol, where data are equivocal. Acute administration has actually been shown to decrease phosphorylation of ERK in the cortex and hippocampus (Chandler & Sutton, 2005) but increase phosphorylation in other areas (Bachtell et al., 2002). Chronic ethanol intake has been shown to attenuate ERK phosphorylation in the striatum, whereas withdrawal for one day potentiates ERK phosphorylation in the same region (Cui et al., 2011).

The activation of ERK in response to repeated administration of drugs of abuse suggests that ERK plays a role in drug-induced plasticity. One measure of drug-induced plasticity is the development and expression of behavioral sensitization (an enhancement of the psychomotor-activating properties of a drug). Indeed, activation of ERK in the brain mesocorticolimbic area has been shown to be involved in sensitization and hence druginduced plasticity (Pierce et al., 1999; X. Shi & McGinty, 2006; Valjent, et al., 2000; Valjent, Corvol, et al., 2006). Thus, pre-treatment with the MEK inhibitor SL327 prior to the repeated administration of cocaine or amphetamine prevents the subsequent expression of sensitization to their locomotor-activating effects upon receiving a challenge dose of the drug (Valjent, Corvol, et al., 2006). In contrast, the expression of sensitization was not affected when SL327 was administered before the challenge (Valjent, Corvol, et al., 2006). Therefore it appears ERK is more critical for the development of sensitization to psychostimulants. ERK activation in the VTA is implicated in this process as intra-VTA infusions of PD98059 attenuate the development of sensitization to cocaine (Pierce, et al., 1999).

ERK in the NAc also appears to be involved in drug-induced plasticity as cocaine sensitized rats display increased phospho-ERK2 during withdrawal from cocaine which is normalized upon cocaine challenge (Boudreau et al., 2007). ERK2 phosphorylation corresponded with accumbens AMPA receptor surface expression (Boudreau, et al., 2007). The authors suggest the possibility that ERK contributes to both rapid (LTP) and slowly induced (cocaine withdrawal) increases in AMPA receptor surface expression, thus contributing to addictionrelated plasticity (Boudreau, et al., 2007). Similarly, withdrawal following development of sensitization to cocaine has been shown to be associated with time-dependent increases in ERK activity which correlate with the increased expression of NMDAR subunits (Schumann & Yaka, 2009). Furthermore, the increase in both GluR1 expression and ERK activity is blocked with intra-NAc infusions of a MEK inhibitor 21 d after withdrawal from cocaine. These data suggest that the development of cocaine psychomotor sensitization triggers a delayed increase in the expression of NMDAR subunits in the NAc, which in turn enhances the activity of ERK (Schumann, et al., 2009).

### **4.4 Drugs of abuse and mechanisms of ERK signalling**

350 Advances in Protein Kinases

activation has been shown to be required for the acquisition of CPP induced by cocaine (Valjent et al., 2000), MDMA (Salzmann et al., 2003), THC (Valjent et al., 2001), amphetamines (Gerdjikov et al., 2004; Mizoguchi et al., 2004) and morphine (Ozaki et al., 2004), but not ethanol (Groblewski, Ryabinin et al., 2011). It is most likely that the NAc is a site of action, at least for amphetamines, as intra-NAc injections of the MEK inhibitor PD98059 impair both methamphetamine and amphetamine-induced CPP (Gerdjikov, et al., 2004; Mizoguchi, et al., 2004). This is supported by the observation of increased activation of ERK in the NAc and dorsal striatum of mice that have been conditioned to methamphetamine (Mizoguchi, et al., 2004) and the NAc, dorsal striatum and prefrontal cortex of mice that have been conditioned to cocaine (Valjent, Corbille et al., 2006). Another study found that exposing mice to a previously cocaine-paired context increased phosphorylation of ERK in the dorsal hippocampus, but not the NAc. Enhanced CREB and DARPP-32 phosphorylation in the NAc, however, was observed (Tropea et al., 2008). Pre-treatment with the MEK inhibitor SL327 has also been shown to abolish the conditioned locomotor response of mice placed in a context previously paired with cocaine or D-amphetamine (Valjent, Corvol et al., 2006), indicating the role of ERK

It also appears that the NAc mediates consolidation of learned associations between a drug's rewarding effects (US) and the drug-paired context (CS). If rats are injected with a MEK inhibitor either systemically or into the NAc core after the test for the expression of cocaine or morphine CPP, subsequent CPP is abolished (Miller & Marshall, 2005; Valjent, Corbille, et al., 2006). Erasure of CPP expression is accompanied with blockade of ERK phosphorylation in the NAc and dorsal striatum (Valjent, Corbille, et al., 2006). This effect can be mirrored with a protein synthesis inhibitor thus providing evidence that ERK exerts this effect on memory reconsolidation through regulation of protein synthesis, presumably by controlling

**4.3 The involvement of MAPK in the actions of drugs of abuse & drug-induced**

The MAPK signalling cascade has been implicated in responses to most drugs of abuse, supporting the notion that drug-induced plasticity might share common mechanisms with learning and memory processes (Berke & Hyman, 2000; Girault et al., 2007; Hyman, 2005). ERK is expressed abundantly throughout the brain, including mesocorticolimbic regions (Ortiz et al., 1995). Acute and chronic administration of most drugs of abuse such as cocaine, morphine, nicotine and Δ9-tetrahydrocannabinol (THC) has been shown to increase activation of ERK in reward-related areas such as the VTA, NAc, PFC, central and extended amygdala and hippocampus (reviewed in Girault et al., 2007; Zhai et al., 2008). The exception is alcohol, where data are equivocal. Acute administration has actually been shown to decrease phosphorylation of ERK in the cortex and hippocampus (Chandler & Sutton, 2005) but increase phosphorylation in other areas (Bachtell et al., 2002). Chronic ethanol intake has been shown to attenuate ERK phosphorylation in the striatum, whereas withdrawal for one day potentiates ERK phosphorylation in the same region (Cui et al.,

The activation of ERK in response to repeated administration of drugs of abuse suggests that ERK plays a role in drug-induced plasticity. One measure of drug-induced plasticity is the development and expression of behavioral sensitization (an enhancement of the

can be generalised to other contextually-driven behaviors.

transcription.

**plasticity**

2011).

The activation of ERK by drugs of abuse in mesocorticolimbic regions has been shown to require both glutamate and dopamine signalling as it is prevented by both dopamine D1 and NMDA receptor antagonists (Berhow et al., 1996; Jenab et al., 2005; Valjent, et al., 2000; Valjent, et al., 2001; Valjent et al., 2005), and in the case of amphetamine, by group I metabotropic glutamate (mGlu) receptor antagonists (Choe et al., 2002). This is not surprising as ERK is found downstream of all these receptors. Thus, the activation of dopamine D1 receptors by dopamine increases cyclic adenosine monophosphate (cAMP) and thus cAMP-dependent protein kinase A (Bilbao et al. 2008). Activated cAMP-dependent protein kinase (Bilbao, et al. 2008) then activates ERK through the the dopamine- and cAMPregulated phosphoprotein 32 kDa (DARPP-32) signaling cascade (Greengard et al., 1999; Svenningsson et al., 2004). In striatal neurons, the mGlu5 receptor activates ERK through Ca2+-dependent and -independent mechanisms, the latter involving the scaffolding protein Homer (L. Mao et al., 2005). Activation of NMDA receptors and the resulting Ca2+ influx activate Ca2+/calmodulin-dependent protein kinase II (CaMKII). CaMKII then activates Ras-GTP, which initiates a number of kinase cascades, including Raf-1, MAPK/ERK kinases and ERK (G. M. Thomas, et al., 2004; Xia et al., 1996). ERK is also activated by opioid receptors most likely via a mechanism involving Ras and beta-gamma subunits of Gi/o proteins (Belcheva et al., 1998). Once activated, ERK translocates to the cell nucleus where it regulates

The Role of Mitogen-Activated Protein Kinase in Treatment Strategies for Fear and Drug Addiction 353

The striatum is a key structure which mediates instrumental (action-outcome) learning and it is glutamate-dopamine signaling which appears particularly important (Horvitz, 2002). Dopamine release in the dorsal striatum is thought to enable coding of action-outcome associations facilitating potentiation of corticostriatal synapses during learning (Di Filippo et al., 2009; Reynolds et al., 2001). The induction of corticostriatal LTP is dependent on the coincident activation of D1 and NMDA receptors (Calabresi et al., 1992; Kerr & Wickens, 2001; Reynolds, et al., 2001). Thus, corticostriatal LTP has been shown to require activation of ERK (Ferguson et al., 2006; Mazzucchelli et al., 2002; Sgambato et al., 1998) and indeed, the requirement for coincident activation of NMDA and D1 receptors for ERK activation has led some to propose that ERK functions to selectively induce plasticity at corticostriatal synapses during highly salient learning situations like reward learning, when coordinated dopamine and NMDA receptor activation is likely to occur (Girault, et al., 2007; Shiflett &

The involvement of ERK in instrumental learning and corticostriatal LTP (Shiflett et al., 2010; G. M. Thomas, et al., 2004) suggests that ERK may play a role in the action-outcome learning which occurs with initial drug use. Indeed, a recent study showed that clinically relevant concentrations of ethanol dose-dependently attenuated the high frequency stimulation-induced LTP and ERK activation in the dorsomedial striatum (Xie et al., 2009). Relatively little is understood regarding synaptic plasticity in habit formation, but it may involve corticostriatal LTD (Shiflett, et al., 2011). The induction of LTD in the striatum was recently shown to require ERK activation (Cui, et al., 2011) which matches with findings regarding LTD in other brain regions such as hippocampus (Thiels et al., 2002). This recent study also showed that chronic ethanol intake by rats attenuated both ERK phosphorylation and LTD induction, whereas withdrawal for one day potentiated ERK phosphorylation and LTD induction (Cui, et al., 2011). By showing that chronic ethanol intake and withdrawal differentially altered synaptic plasticity in the dorsolateral striatum through the ERK signaling pathway, these findings suggest that chronic alcohol use may impact on the habitformation process, and this neural maladaptation may consequently lead to habitual drug-

Persistent vulnerability to relapse in addiction is thought to be a result of a specific impairment in LTD at cortico-accumbal synapses (Kasanetz et al. 2010; Martin et al., 2006; Moussawi et al., 2009). In addition to LTD, cortico-accumbal LTP is abolished *in vivo* after withdrawal from cocaine self-administration (Knackstedt et al., 2010; Moussawi, et al., 2009) The loss of both LTP and LTD *in vivo* after cocaine self-administration has led to the hypothesis that the inability of the medium spiny neurons in the NAc core to undergo bidirectional prefrontal-induced neuroplasticity may reduce the capacity of drug addicts to adaptively organize a behavioral response that incorporates environmental contingencies that mediate against relapse (Kalivas, 2009; M. J. Thomas, et al., 2008). The following section will describe the literature supporting a role for ERK in relapse to drug-seeking behavior.

The operant self-administration procedure is a widely accepted model to study drug reinforcement and drug-seeking because it has both face and construct validity (Feltenstein & See, 2008). In the operant paradigm the animal is trained to perform an instrumental task to self-administer a drug (generally by pressing a lever or via a nose-poke) for a period of

Balleine, 2011).

seeking behavior (Cui, et al., 2011).

**4.6 The involvement of MAPK in drug-seeking behavior**

the activity of the transcription factors CREB and Elk-1 which control the transcription of many genes implicated in addiction, such as c-fos, ΔFosB, zif268, Homer and preprodynorphin (Benavides & Bibb, 2004; Choe & McGinty, 2001; S. Davis, Vanhoutte et al., 2000; Girault, et al., 2007; Hurd & Herkenham, 1993; L. Lu, et al., 2006; McClung & Nestler, 2003; Nestler, 2001; Radwanska et al., 2005). Downstream effects of many drugs of abuse on these genes have been shown to be mediated via ERK (Bachtell, et al., 2002; Salzmann, et al., 2003; Valjent, et al., 2000).

Evidence has accumulated which supports a coincident interaction between D1 and NMDA receptors with respect to cocaine-driven ERK signaling in the striatum. Thus, cocaineinduced ERK activation has been shown to require the coincident stimulation of D1 and NMDA receptors (Valjent, et al., 2000; Valjent, et al., 2005) and this appears to be controlled by Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal specific activator of Ras-ERK signaling (Fasano et al., 2009). The relevance of this Ras-GRF1-mediated ERK signaling to reward and drug-induced plasticity is demonstrated by the observation that CPP and locomotor sensitization are significantly attenuated in Ras-GRF1–deficient mice, and conversely heightened in over-expressing transgenic animals (Fasano, et al., 2009).

More recently, the D1 or cocaine-mediated activation of ERK in striatal neurons was shown to depend on a potentiation of NMDA receptor function independent of cAMP (Pascoli et al., 2011). Furthermore, NMDA receptor potentiation involves tyrosine phosphorylation of the NR2B subunit via Src-family kinase (SFKs). This mechanism, demonstrated in cultured striatal neurons, was also observed *in vivo*, as ERK phosphorylation in response to D1 receptor agonism in mice was blocked by pretreatment with an NMDA receptor antagonist (Pascoli, et al., 2011). The observed potentiation by the D1 receptor potentially explains why NMDA receptor stimulation is required for ERK activation by cocaine and other drugs of abuse. As the authors suggest this mechanism has potentially significant functional consequences, providing a possible mechanism for facilitation of long-term potentiation of glutamatergic synapses in D1 receptor-expressing striatal neurons (Andre et al., 2010; Shen et al., 2008). This was evidenced by the attenuation of cocaine-induced sensitization and CPP upon inhibition of this D1R/Src family kinases/NR2B pathway (Pascoli, et al., 2011).

### **4.5 MAPK in reward learning and synaptic plasticity**

As discussed earlier in this chapter, MAPK has been shown to be intimately involved in synaptic plasticity and hence learning and memory processes (for detailed review see G. M. Thomas, et al., 2004). As with fear-related disorders, drug addiction has been proposed by some to be a form of pathological learning (Berke, et al., 2000). Reinforcement as a concept is ultimately defined by learning processes – it is the strengthening of associations through experience. Reinforcement can also be viewed as a process that enhances memory consolidation for the association (Landauer, 1969). Either way, it is the "stamping in" (and hence learning) of associations that ultimately leads to reinforcement. The associations may manifest in a variety of ways: associations between a stimulus and a response (Thorndike, 1898), associations between a US and CS (I.P. Pavlov, 1927), or associations between a response and an outcome (Skinner, 1938). With repeated exposure drugs cause aberrant "stamping in" of associations between drug-taking, the resultant drug high and associated cues and contexts.

the activity of the transcription factors CREB and Elk-1 which control the transcription of many genes implicated in addiction, such as c-fos, ΔFosB, zif268, Homer and preprodynorphin (Benavides & Bibb, 2004; Choe & McGinty, 2001; S. Davis, Vanhoutte et al., 2000; Girault, et al., 2007; Hurd & Herkenham, 1993; L. Lu, et al., 2006; McClung & Nestler, 2003; Nestler, 2001; Radwanska et al., 2005). Downstream effects of many drugs of abuse on these genes have been shown to be mediated via ERK (Bachtell, et al., 2002;

Evidence has accumulated which supports a coincident interaction between D1 and NMDA receptors with respect to cocaine-driven ERK signaling in the striatum. Thus, cocaineinduced ERK activation has been shown to require the coincident stimulation of D1 and NMDA receptors (Valjent, et al., 2000; Valjent, et al., 2005) and this appears to be controlled by Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal specific activator of Ras-ERK signaling (Fasano et al., 2009). The relevance of this Ras-GRF1-mediated ERK signaling to reward and drug-induced plasticity is demonstrated by the observation that CPP and locomotor sensitization are significantly attenuated in Ras-GRF1–deficient mice, and conversely heightened in over-expressing transgenic animals (Fasano, et al., 2009).

More recently, the D1 or cocaine-mediated activation of ERK in striatal neurons was shown to depend on a potentiation of NMDA receptor function independent of cAMP (Pascoli et al., 2011). Furthermore, NMDA receptor potentiation involves tyrosine phosphorylation of the NR2B subunit via Src-family kinase (SFKs). This mechanism, demonstrated in cultured striatal neurons, was also observed *in vivo*, as ERK phosphorylation in response to D1 receptor agonism in mice was blocked by pretreatment with an NMDA receptor antagonist (Pascoli, et al., 2011). The observed potentiation by the D1 receptor potentially explains why NMDA receptor stimulation is required for ERK activation by cocaine and other drugs of abuse. As the authors suggest this mechanism has potentially significant functional consequences, providing a possible mechanism for facilitation of long-term potentiation of glutamatergic synapses in D1 receptor-expressing striatal neurons (Andre et al., 2010; Shen et al., 2008). This was evidenced by the attenuation of cocaine-induced sensitization and CPP upon inhibition of this D1R/Src family kinases/NR2B pathway (Pascoli, et al., 2011).

As discussed earlier in this chapter, MAPK has been shown to be intimately involved in synaptic plasticity and hence learning and memory processes (for detailed review see G. M. Thomas, et al., 2004). As with fear-related disorders, drug addiction has been proposed by some to be a form of pathological learning (Berke, et al., 2000). Reinforcement as a concept is ultimately defined by learning processes – it is the strengthening of associations through experience. Reinforcement can also be viewed as a process that enhances memory consolidation for the association (Landauer, 1969). Either way, it is the "stamping in" (and hence learning) of associations that ultimately leads to reinforcement. The associations may manifest in a variety of ways: associations between a stimulus and a response (Thorndike, 1898), associations between a US and CS (I.P. Pavlov, 1927), or associations between a response and an outcome (Skinner, 1938). With repeated exposure drugs cause aberrant "stamping in" of associations between drug-taking, the resultant drug high and associated

Salzmann, et al., 2003; Valjent, et al., 2000).

**4.5 MAPK in reward learning and synaptic plasticity**

cues and contexts.

The striatum is a key structure which mediates instrumental (action-outcome) learning and it is glutamate-dopamine signaling which appears particularly important (Horvitz, 2002). Dopamine release in the dorsal striatum is thought to enable coding of action-outcome associations facilitating potentiation of corticostriatal synapses during learning (Di Filippo et al., 2009; Reynolds et al., 2001). The induction of corticostriatal LTP is dependent on the coincident activation of D1 and NMDA receptors (Calabresi et al., 1992; Kerr & Wickens, 2001; Reynolds, et al., 2001). Thus, corticostriatal LTP has been shown to require activation of ERK (Ferguson et al., 2006; Mazzucchelli et al., 2002; Sgambato et al., 1998) and indeed, the requirement for coincident activation of NMDA and D1 receptors for ERK activation has led some to propose that ERK functions to selectively induce plasticity at corticostriatal synapses during highly salient learning situations like reward learning, when coordinated dopamine and NMDA receptor activation is likely to occur (Girault, et al., 2007; Shiflett & Balleine, 2011).

The involvement of ERK in instrumental learning and corticostriatal LTP (Shiflett et al., 2010; G. M. Thomas, et al., 2004) suggests that ERK may play a role in the action-outcome learning which occurs with initial drug use. Indeed, a recent study showed that clinically relevant concentrations of ethanol dose-dependently attenuated the high frequency stimulation-induced LTP and ERK activation in the dorsomedial striatum (Xie et al., 2009). Relatively little is understood regarding synaptic plasticity in habit formation, but it may involve corticostriatal LTD (Shiflett, et al., 2011). The induction of LTD in the striatum was recently shown to require ERK activation (Cui, et al., 2011) which matches with findings regarding LTD in other brain regions such as hippocampus (Thiels et al., 2002). This recent study also showed that chronic ethanol intake by rats attenuated both ERK phosphorylation and LTD induction, whereas withdrawal for one day potentiated ERK phosphorylation and LTD induction (Cui, et al., 2011). By showing that chronic ethanol intake and withdrawal differentially altered synaptic plasticity in the dorsolateral striatum through the ERK signaling pathway, these findings suggest that chronic alcohol use may impact on the habitformation process, and this neural maladaptation may consequently lead to habitual drugseeking behavior (Cui, et al., 2011).

Persistent vulnerability to relapse in addiction is thought to be a result of a specific impairment in LTD at cortico-accumbal synapses (Kasanetz et al. 2010; Martin et al., 2006; Moussawi et al., 2009). In addition to LTD, cortico-accumbal LTP is abolished *in vivo* after withdrawal from cocaine self-administration (Knackstedt et al., 2010; Moussawi, et al., 2009) The loss of both LTP and LTD *in vivo* after cocaine self-administration has led to the hypothesis that the inability of the medium spiny neurons in the NAc core to undergo bidirectional prefrontal-induced neuroplasticity may reduce the capacity of drug addicts to adaptively organize a behavioral response that incorporates environmental contingencies that mediate against relapse (Kalivas, 2009; M. J. Thomas, et al., 2008). The following section will describe the literature supporting a role for ERK in relapse to drug-seeking behavior.

### **4.6 The involvement of MAPK in drug-seeking behavior**

The operant self-administration procedure is a widely accepted model to study drug reinforcement and drug-seeking because it has both face and construct validity (Feltenstein & See, 2008). In the operant paradigm the animal is trained to perform an instrumental task to self-administer a drug (generally by pressing a lever or via a nose-poke) for a period of

The Role of Mitogen-Activated Protein Kinase in Treatment Strategies for Fear and Drug Addiction 355

behavioral effects of BDNF were most likely mediated via a TrkB receptor-ERK pathway. This study elucidates a mechanism whereby BDNF/TrkB activates ERK-regulated CREB phosphorylation in the dmPFC to counteract the neuroadaptations induced by cocaine self-

There are no studies as yet which have specifically examined the role of ERK in extinction learning related to operant responding. There is one CPP study that showed heightened ERK activation in the amygdala following extinction of cocaine-induced CPP (Chen & Xu, 2010), which is consistent with fear extinction literature showing a key role for the amygdala (Myers, et al., 2007). In addition, dopamine D3 receptor mutant mice showed delayed CPP extinction compared with wild-type mice and this was associated with sustained ERK activation in the NAc and PFC (Chen, et al., 2010). This suggests that extinction of cocaine conditioning involves dopamine D3 receptor/ERK signaling though this finding is not necessarily readily generalized to other drugs of abuse as the MEK inhibitor SL327 has been shown to have no effect on extinction of an ethanol-induced CPP in mice (Groblewski,

**4.6.2 The role of MAPK in the abstinence model of relapse and incubation of craving**  Of the millions of people suffering from addiction, only a small proportion actually seek treatment in a formal setting. For example, in 2009 out of 23.5 million Americans who were considered to have an illicit drug or alcohol use problem, only 2.6 million (11.2%) received treatment at a specialty facility (SAMHSA, 2010). In this sense then, the reinstatement model of relapse is only relevant to those addicts who engage in new learning to overcome their addiction. The bulk of drug dependent individuals will attempt to overcome their addiction by simply attempting to abstain from drug use (also known as going 'cold turkey'). Therefore another relevant model of relapse is one that measures drug-seeking following a

In 1986 it was suggested that in humans, craving induced by drug cues actually increases over the first several weeks of the withdrawal period and remains elevated over extended periods of abstinence (Gawin & Kleber, 1986). Scientists have since discovered an analogous phenomenon in laboratory animals which has been termed 'incubation of craving'. It has been demonstrated with opiates (Shalev et al., 2001), psychostimulants (Grimm, et al., 2001; Shepard et al., 2004) and ethanol (Bienkowski et al., 2004), that cue-induced drug-seeking increases over time over the first months of withdrawal. This phenomenon has also been observed with the natural reinforcer sucrose (Grimm et al., 2002), though in this case the effect peaks after 1–4 weeks, but decays after 2 months, while for cocaine, the responding peaks after 1 month and persists for up to 3 months in rats (L. Lu et al., 2004). In humans, this incubation of drug craving ultimately results in an increased propensity to relapse as a function of time spent in withdrawal. A more appropriate paradigm for this sort of relapse behavior is a modification of the reinstatement model known as the abstinence model (e.g. Brown et al., 2009; Lu et al., 2009; reviewed in Reichel and Bevins, 2009). After a period of self-administration the animal undergoes withdrawal for a period of time (typically a number of weeks) in the home cage. At the end of this period drug-seeking behavior is measured by re-introducing the subject to the operant chamber and measuring responding

administration and subsequent relapse to cocaine-seeking (Whitfield, et al., 2011).

Franken et al., 2011).

period of abstinence.

under extinction conditions (i.e. in the absence of drug).

time, thereby developing an action-outcome association between the operant task and the ensuing reward (conditioned response). Rodents will readily self-administer most drugs of abuse, including cocaine (R. M. Brown & Lawrence, 2009; McPherson et al., 2010). Accordingly, the abuse potential of a substance in humans can be predicted from selfadministration in rodents (Collins et al., 1984). Moreover, similar to the laboratory model of anxiety disorders, the self-administration paradigm can incorporate a Pavlovian conditioning component by introducing CSs that signal drug delivery to represent cues/contexts that are critically related to relapse of drug-seeking (Adams et al., 2010; Jupp et al., 2011).

### **4.6.1 The role of MAPK in the reinstatement model of drug-seeking**

As with extinction of fear, the reinforced response (e.g. lever press) can be subsequently extinguished whereby no drug is administered despite the animal responding on the drugpaired manipulandum. Responding will typically spike in what has been termed an 'extinction burst' and then gradually decline to a level whereby the behavior is deemed extinguished. Extinction learning is an active process that reduces the value or salience of these conditioned cues and contexts. Longer and repeated cue/contextual re-exposure without the associated fear or drug experience reduces conditioned responding. Extinction learning can be effective for reducing cue- and context-induced symptoms in addiction and anxiety and can improve outcomes in these disorders. Reinstatement of drug-seeking behavior as measured by responding on the drug-paired manipulandum can be precipitated in a number of ways: with non-contingent 'priming' injections of the drug (Stretch et al., 1971), stressors (Carroll, 1985; Shaham & Stewart, 1996), and drug-associated cues (W. M. Davis & Smith, 1976). In humans, drug craving and relapse have shown to be triggered by similar factors (S. A. Brown, et al., 1995; C. O'Brien, et al., 1992), giving this model an element of construct validity. This model also exhibits predictive validity, as drugs such as naltrexone that decrease relapse in abstinent drug users also decrease reinstatement of drug seeking behavior in rats (Comer et al., 2006)

As mentioned previously, drug-associated cues induce ERK phosphorylation in components of the mesocorticolimbic system (L. Lu et al., 2005; Miller, et al., 2005) and ERK has been shown to play a role in drug-induced and synaptic plasticity (G. M. Thomas, et al., 2004; Valjent, Corvol, et al., 2006) thus it is not surprising that evidence exist that support a role for ERK in cue-elicited reinstatement of drug-seeking. Cue-induced reinstatement of alcohol-seeking is associated with enhanced activation of ERK in the BLA and NAc shell (Schroeder et al., 2008). The mGlu5 receptor antagonist 2-Methyl-6-(phenylethynyl)pyridine (MPEP) was shown to block both the cue-induced drug-seeking and the associated increase in phospho-ERK (Schroeder, et al., 2008), indicating that ERK activation is dependent on mGlu5 receptor signalling and plays a key role in the effect of MPEP on drug-seeking.

A recent study demonstrated a critical role for ERK in the ability of BNDF infusions in the dmPFC to attenuate reinstatement of both cue-induced and primed cocaine-seeking, as well as cocaine-seeking following abstinence (Whitfield et al., 2011). Vehicle-infused rats showed significant decreases in phospho-ERK and CREB at the end of the cocaine selfadministration period that were reversed by intra-dmPFC BDNF. This ability of BDNF to reverse cocaine-mediated decreases in ERK and CREB phosphorylation was blocked by both the MEK inhibitor U0126 and the tyrosine kinase inhibitor K252a, thus demonstrating the

time, thereby developing an action-outcome association between the operant task and the ensuing reward (conditioned response). Rodents will readily self-administer most drugs of abuse, including cocaine (R. M. Brown & Lawrence, 2009; McPherson et al., 2010). Accordingly, the abuse potential of a substance in humans can be predicted from selfadministration in rodents (Collins et al., 1984). Moreover, similar to the laboratory model of anxiety disorders, the self-administration paradigm can incorporate a Pavlovian conditioning component by introducing CSs that signal drug delivery to represent cues/contexts that are critically related to relapse of drug-seeking (Adams et al., 2010; Jupp

As with extinction of fear, the reinforced response (e.g. lever press) can be subsequently extinguished whereby no drug is administered despite the animal responding on the drugpaired manipulandum. Responding will typically spike in what has been termed an 'extinction burst' and then gradually decline to a level whereby the behavior is deemed extinguished. Extinction learning is an active process that reduces the value or salience of these conditioned cues and contexts. Longer and repeated cue/contextual re-exposure without the associated fear or drug experience reduces conditioned responding. Extinction learning can be effective for reducing cue- and context-induced symptoms in addiction and anxiety and can improve outcomes in these disorders. Reinstatement of drug-seeking behavior as measured by responding on the drug-paired manipulandum can be precipitated in a number of ways: with non-contingent 'priming' injections of the drug (Stretch et al., 1971), stressors (Carroll, 1985; Shaham & Stewart, 1996), and drug-associated cues (W. M. Davis & Smith, 1976). In humans, drug craving and relapse have shown to be triggered by similar factors (S. A. Brown, et al., 1995; C. O'Brien, et al., 1992), giving this model an element of construct validity. This model also exhibits predictive validity, as drugs such as naltrexone that decrease relapse in abstinent drug users also decrease reinstatement of drug

As mentioned previously, drug-associated cues induce ERK phosphorylation in components of the mesocorticolimbic system (L. Lu et al., 2005; Miller, et al., 2005) and ERK has been shown to play a role in drug-induced and synaptic plasticity (G. M. Thomas, et al., 2004; Valjent, Corvol, et al., 2006) thus it is not surprising that evidence exist that support a role for ERK in cue-elicited reinstatement of drug-seeking. Cue-induced reinstatement of alcohol-seeking is associated with enhanced activation of ERK in the BLA and NAc shell (Schroeder et al., 2008). The mGlu5 receptor antagonist 2-Methyl-6-(phenylethynyl)pyridine (MPEP) was shown to block both the cue-induced drug-seeking and the associated increase in phospho-ERK (Schroeder, et al., 2008), indicating that ERK activation is dependent on mGlu5 receptor signalling and plays a key role in the effect of MPEP on drug-seeking.

A recent study demonstrated a critical role for ERK in the ability of BNDF infusions in the dmPFC to attenuate reinstatement of both cue-induced and primed cocaine-seeking, as well as cocaine-seeking following abstinence (Whitfield et al., 2011). Vehicle-infused rats showed significant decreases in phospho-ERK and CREB at the end of the cocaine selfadministration period that were reversed by intra-dmPFC BDNF. This ability of BDNF to reverse cocaine-mediated decreases in ERK and CREB phosphorylation was blocked by both the MEK inhibitor U0126 and the tyrosine kinase inhibitor K252a, thus demonstrating the

**4.6.1 The role of MAPK in the reinstatement model of drug-seeking**

seeking behavior in rats (Comer et al., 2006)

et al., 2011).

behavioral effects of BDNF were most likely mediated via a TrkB receptor-ERK pathway. This study elucidates a mechanism whereby BDNF/TrkB activates ERK-regulated CREB phosphorylation in the dmPFC to counteract the neuroadaptations induced by cocaine selfadministration and subsequent relapse to cocaine-seeking (Whitfield, et al., 2011).

There are no studies as yet which have specifically examined the role of ERK in extinction learning related to operant responding. There is one CPP study that showed heightened ERK activation in the amygdala following extinction of cocaine-induced CPP (Chen & Xu, 2010), which is consistent with fear extinction literature showing a key role for the amygdala (Myers, et al., 2007). In addition, dopamine D3 receptor mutant mice showed delayed CPP extinction compared with wild-type mice and this was associated with sustained ERK activation in the NAc and PFC (Chen, et al., 2010). This suggests that extinction of cocaine conditioning involves dopamine D3 receptor/ERK signaling though this finding is not necessarily readily generalized to other drugs of abuse as the MEK inhibitor SL327 has been shown to have no effect on extinction of an ethanol-induced CPP in mice (Groblewski, Franken et al., 2011).

### **4.6.2 The role of MAPK in the abstinence model of relapse and incubation of craving**

Of the millions of people suffering from addiction, only a small proportion actually seek treatment in a formal setting. For example, in 2009 out of 23.5 million Americans who were considered to have an illicit drug or alcohol use problem, only 2.6 million (11.2%) received treatment at a specialty facility (SAMHSA, 2010). In this sense then, the reinstatement model of relapse is only relevant to those addicts who engage in new learning to overcome their addiction. The bulk of drug dependent individuals will attempt to overcome their addiction by simply attempting to abstain from drug use (also known as going 'cold turkey'). Therefore another relevant model of relapse is one that measures drug-seeking following a period of abstinence.

In 1986 it was suggested that in humans, craving induced by drug cues actually increases over the first several weeks of the withdrawal period and remains elevated over extended periods of abstinence (Gawin & Kleber, 1986). Scientists have since discovered an analogous phenomenon in laboratory animals which has been termed 'incubation of craving'. It has been demonstrated with opiates (Shalev et al., 2001), psychostimulants (Grimm, et al., 2001; Shepard et al., 2004) and ethanol (Bienkowski et al., 2004), that cue-induced drug-seeking increases over time over the first months of withdrawal. This phenomenon has also been observed with the natural reinforcer sucrose (Grimm et al., 2002), though in this case the effect peaks after 1–4 weeks, but decays after 2 months, while for cocaine, the responding peaks after 1 month and persists for up to 3 months in rats (L. Lu et al., 2004). In humans, this incubation of drug craving ultimately results in an increased propensity to relapse as a function of time spent in withdrawal. A more appropriate paradigm for this sort of relapse behavior is a modification of the reinstatement model known as the abstinence model (e.g. Brown et al., 2009; Lu et al., 2009; reviewed in Reichel and Bevins, 2009). After a period of self-administration the animal undergoes withdrawal for a period of time (typically a number of weeks) in the home cage. At the end of this period drug-seeking behavior is measured by re-introducing the subject to the operant chamber and measuring responding under extinction conditions (i.e. in the absence of drug).

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Numerous cellular and molecular changes are produced by chronic drug use, which are thought to regulate drug-seeking behavior, yet only a small number thus far have been shown to be associated with time-dependent increases in drug-seeking behavior. One of these neuroadaptations is activation of ERK. Studies by Lu and colleagues have revealed that it is ERK phosphorylation in the CeA, but not BLA, that underpins incubation of cocaine and opiate craving as inhibition of CeA, but not BLA, ERK phosphorylation decreases drug-seeking after 30 days of drug withdrawal but not after 1 day of withdrawal (Li et al., 2008; L. Lu, et al., 2005). After 30 withdrawal days, inhibition of CeA ERK phosphorylation by U0126 or the NMDA receptor antagonist AP-5 decreased cue-induced cocaine seeking.

Subsequently, other studies have shown a similar enhancement of ERK phosphorylation in the NAc core (Edwards et al., 2011) and mPFC (Koya et al., 2008) as a result of exposure to a cocaine-paired context after extended abstinence in animals that had previously selfadministered cocaine. In the former study, the activation of ERK was found only in rats that had self-administered cocaine and not their yoked controls, demonstrating the effect was not merely the result of cocaine exposure (Edwards, et al., 2011). Though the precise role of increased ERK activity in the NAc and mPFC in incubation of craving remains to be investigated, a key role for ERK in the amygdala has been found in Pavlovian fear conditioning and memory reconsolidation (Nader et al., 2000). ERK in the amygdala also appears to be critically involved in the long-term neuroadaptations which result in heightened reactivity to drug-associated cues. This is supported by the observation that reexposure to an ethanol-associated context and discrete cues following abstinence increases activation of ERK in the BLA and ventral lateral amygdala (Radwanska et al., 2008). Collectively, these findings indicate that activation of ERK, particularly in the amygdala appears to be a key substrate for incubation of drug craving.

### **5. Concluding remarks**

The studies highlighted in the present chapter clearly demonstrate the learning and memory principles underlying fear and drug-seeking behavior. Additionally, drug addiction has been emphasized as a brain disorder that involves enduring neuroadaptations that alter signal transduction within neurons as well as electrical and chemical communications between neurons and neural structures. Considering the significance of the MAPK cascade in cellular growth, differentiation and neuronal survivability (Ahn & Krebs, 1990; Hoshi et al., 1988; Impey et al., 1999; Kornhauser & Greenberg, 1997), perhaps it is not surprising that MAPK signalling also plays a seemingly important role in both the acquisition and treatment of anxiety and drug-seeking behavior as pointed out in the present chapter. Given the prevalence and financial burden of anxiety disorders and drug addiction, we propose that further research into the MAPK signalling cascade could be a fruitful strategy in finding effective treatments for anxiety disorders and drug addiction.

### **6. References**

Adams, C. L., Short, J. L., & Lawrence, A. J. (2010). Cue-conditioned alcohol seeking in rats following abstinence: Involvement of metabotropic glutamate 5 receptors. *Br J Pharmacol, 159*, 534-542.

Numerous cellular and molecular changes are produced by chronic drug use, which are thought to regulate drug-seeking behavior, yet only a small number thus far have been shown to be associated with time-dependent increases in drug-seeking behavior. One of these neuroadaptations is activation of ERK. Studies by Lu and colleagues have revealed that it is ERK phosphorylation in the CeA, but not BLA, that underpins incubation of cocaine and opiate craving as inhibition of CeA, but not BLA, ERK phosphorylation decreases drug-seeking after 30 days of drug withdrawal but not after 1 day of withdrawal (Li et al., 2008; L. Lu, et al., 2005). After 30 withdrawal days, inhibition of CeA ERK phosphorylation by U0126 or the NMDA receptor antagonist AP-5 decreased cue-induced

Subsequently, other studies have shown a similar enhancement of ERK phosphorylation in the NAc core (Edwards et al., 2011) and mPFC (Koya et al., 2008) as a result of exposure to a cocaine-paired context after extended abstinence in animals that had previously selfadministered cocaine. In the former study, the activation of ERK was found only in rats that had self-administered cocaine and not their yoked controls, demonstrating the effect was not merely the result of cocaine exposure (Edwards, et al., 2011). Though the precise role of increased ERK activity in the NAc and mPFC in incubation of craving remains to be investigated, a key role for ERK in the amygdala has been found in Pavlovian fear conditioning and memory reconsolidation (Nader et al., 2000). ERK in the amygdala also appears to be critically involved in the long-term neuroadaptations which result in heightened reactivity to drug-associated cues. This is supported by the observation that reexposure to an ethanol-associated context and discrete cues following abstinence increases activation of ERK in the BLA and ventral lateral amygdala (Radwanska et al., 2008). Collectively, these findings indicate that activation of ERK, particularly in the amygdala

The studies highlighted in the present chapter clearly demonstrate the learning and memory principles underlying fear and drug-seeking behavior. Additionally, drug addiction has been emphasized as a brain disorder that involves enduring neuroadaptations that alter signal transduction within neurons as well as electrical and chemical communications between neurons and neural structures. Considering the significance of the MAPK cascade in cellular growth, differentiation and neuronal survivability (Ahn & Krebs, 1990; Hoshi et al., 1988; Impey et al., 1999; Kornhauser & Greenberg, 1997), perhaps it is not surprising that MAPK signalling also plays a seemingly important role in both the acquisition and treatment of anxiety and drug-seeking behavior as pointed out in the present chapter. Given the prevalence and financial burden of anxiety disorders and drug addiction, we propose that further research into the MAPK signalling cascade could be a fruitful strategy in finding

Adams, C. L., Short, J. L., & Lawrence, A. J. (2010). Cue-conditioned alcohol seeking in rats

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**5. Concluding remarks**

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## *Edited by Gabriela Da Silva Xavier*

Proteins are the work horses of the cell. As regulators of protein function, protein kinases are involved in the control of cellular functions via intricate signalling pathways, allowing for fine tuning of physiological functions. This book is a collaborative effort, with contribution from experts in their respective fields, reflecting the spirit of collaboration - across disciplines and borders - that exists in modern science. Here, we review the existing literature and, on occasions, provide novel data on the function of protein kinases in various systems. We also discuss the implications of these findings in the context of disease, treatment, and drug development.

Photo by Leonid Andronov / iStock

Advances in Protein Kinases

Advances in Protein Kinases