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

Department of Neuropharmacology, National Institute on Drug Dependence, Peking University, 38, Xue Yuan Road, Hai Dian District, Beijing, 100083, China.
Cellular and Molecular Neurobiology (Impact Factor: 2.51). 03/2008; 28(2):157-72. DOI: 10.1007/s10571-007-9240-3
Source: PubMed


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, Delta(9)-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.

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Available from: Haifeng Zhai, Feb 14, 2014
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    • "The level of p-ERK was increased after unpaired and paired conditioning in both CDRI-08 and NaB groups, but it was at basal level in control group. The observed results are similar with the earlier studies and supports involvement of the ERK cascade in the formation of hippocampusdependent contextual memories (Ahi et al. 2004; Sweatt 2004; Villarreal and Barea-Rodriguez 2006; Zhai et al. 2008). Further, it has been shown that activation of MAPK/ ERK couples with the phosphorylation of the key transcription factor CREB, which is a positive regulator of memory consolidation (Villarreal and Barea-Rodriguez 2006; Sindreu et al. 2007; Restivo et al. 2009; Suzuki et al. 2011). "
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    ABSTRACT: Contextual fear conditioning is a paradigm for investigating cellular mechanisms involved in hippocampus-dependent memory. Earlier, we showed that standardised extract of Bacopa monniera (CDRI-08) improves hippocampus-dependent learning in postnatal rats by elevating the level of serotonin (5-hydroxytryptamine, 5-HT), activate 5-HT3A receptors, and cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein. In this study, we have further examined the molecular mechanism of CDRI-08 in hippocampus-dependent memory and compared to the histone deacetylase (HDACs) inhibitor sodium butyrate (NaB). To assess the hippocampus-dependent memory, wistar rat pups were subjected to contextual fear conditioning (CFC) following daily (postnatal days 15-29) administration of vehicle solution (0.5 % gum acacia + 0.9 % saline)/CDRI-08 (80 mg/kg, p.o.)/NaB (1.2 g/kg in PBS, i.p.). CDRI-08/NaB treated group showed enhanced freezing behavior compared to control group when re-exposed to the same context. Administration of CDRI-08/NaB resulted in activation of extracellular signal-regulated kinase ERK/CREB signaling cascade and up-regulation of p300, Ac-H3 and Ac-H4 levels, and down-regulation of HDACs (1, 2) and protein phosphatases (PP1α, PP2A) in hippocampus following CFC. This would subsequently result in an increased brain-derived neurotrophic factor (Bdnf) (exon IV) mRNA in hippocampus. Altogether, our results indicate that CDRI-08 enhances hippocampus-dependent contextual memory by differentially regulating histone acetylation and protein phosphatases in hippocampus.
    Cellular and Molecular Neurobiology 03/2014; 34(4). DOI:10.1007/s10571-014-0042-0 · 2.51 Impact Factor
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    • "ERK signaling is also known to be critically linked to DA D1 receptor activation, which couples with Gs proteins leading to cAMP and PKA cascade activation (Valjent et al., 2000; Nagai et al., 2007). Activated ERK can promote the expression of genes associated with memory and learning, in part, by activating transcription factors such as CREB and Elk-1, which in turn activate gene transcription involved in synaptic and neuronal plasticity such as c-Fos, Zif268, etc. (Cammarota et al., 2008; Zhai et al., 2008). Our results indicate that modafinil modulates ERK phosphorylation in mPFC in a dosetreshold manner, which might be related to modafinil's ability to enhance DA neurotransmission and stimulation of D1 receptors (Young and Geyer, 2010). "
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    ABSTRACT: Chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans and in animal models. Modafinil is a wake-promoting compound approved for the treatment of sleeping disorders. It is also prescribed off label to treat METH dependence. In the present study, we investigated whether modafinil could improve cognitive deficits induced by sub-chronic METH treatment in mice by measuring visual retention in a Novel Object Recognition (NOR) task. After sub-chronic METH treatment (1 mg/Kg, once a day for 7 days), mice performed the NOR task, which consisted of habituation to the object recognition arena (5 min a day, 3 consecutive days), training session (2 equal objects, 10 min, day 4), and a retention session (1 novel object, 5 min, day 5). One hour before the training session, mice were given a single dose of modafinil (30 or 90 mg/Kg). METH-treated mice showed impairments in visual memory retention, evidenced by equal preference of familiar and novel objects during the retention session. The lower dose of modafinil (30 mg/Kg) had no effect on visual retention scores in METH-treated mice, while the higher dose (90 mg/Kg) rescued visual memory retention to control values. We also measured ERK phosphorylation in medial prefrontal cortex (mPFC), hippocampus, and nucleus accumbens (NAc) of METH- and vehicle-treated mice that received modafinil 1 hr before exposure to novel objects in the training session, compared to mice placed in the arena without objects. Elevated Extracellular signal-regulated kinase (ERK) phosphorylation was found in the mPFC of vehicle-treated mice, but not in METH-treated mice, exposed to objects (p<0.05). The lower dose of modafinil had no effect on ERK phosphorylation in METH-treated mice, while 90 mg/Kg modafinil treatment restored the ERK phosphorylation induced by novelty in METH-treated mice to values comparable to controls (p<0.05). We found neither a novelty nor treatment effect on ERK phosphorylation in hippocampus or nucleus accumbens (NAc) of vehicle- and METH-treated mice receiving acute 90 mg/Kg modafinil treatment. Our results showed a palliative role of modafinil against METH-induced visual cognitive impairments, possibly by normalizing ERK signaling pathways in mPFC. Modafinil may be a valuable pharmacological tool for the treatment of cognitive deficits observed in human METH abusers as well as in other neuropsychiatric conditions.
    Neuropharmacology 02/2014; 87. DOI:10.1016/j.neuropharm.2014.02.002 · 5.11 Impact Factor
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    • "Both dopamine and glutamate neuronal circuits were proven to contribute to activation of cocaine-induced ERK (the extracellular signal-regulated kinase) phosphorylation [6] [7] [8], an enzyme involved in many cellular processes including the neuronal plasticity [9]. ERK activation triggers a cascade of reactions from the cell membrane to downstream targets in the cytoplasm or nucleus, causing immediate responses or long-lasting adaptations that underlie craving and relapse behaviors [10]. The importance of ERK signaling has been investigated in various animal models that mimic symptoms of drug addiction in humans, like cocaine locomotor sensitization [11] [12] [13], drug conditioned place preference [14] [15] or cocaine-seeking behavior [16] [17]. "
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    ABSTRACT: According to a current hypothesis of learning processes, recent papers pointed out to an important role of the extracellular signal-regulated kinase (ERK), in drug addiction. We employed the Western blotting techniques to examine the ERK activity immediately after cocaine iv self-administration and in different drug-free withdrawal periods in rats. To distinguish motivational vs. pharmacological effects of the psychostimulant intake, a “yoked” procedure was used. Animals were decapitated after 14 daily cocaine self-administration sessions or on the 1st, 3rd or 10th extinction days. At each time point the activity of the ERK was assessed in several brain structures, including the prefrontal cortex, hippocampus, dorsal striatum and nucleus accumbens. Passive, repeated iv cocaine administration resulted in a 45% increase in ERK phosphorylation in the hippocampus while cocaine self-administration did not change brain ERK activity. On the 1st day of extinction, the activity of the ERK in the prefrontal cortex was decreased in rats with a history of cocaine chronic intake: by 66% for “active” cocaine group and by 35% for “yoked” cocaine group. On the 3rd day the reduction in the ERK activity (25–34%) was observed in the hippocampus for both cocaine-treated groups, and also in the nucleus accumbens for “yoked” cocaine group (40%). On the 10th day of extinction there was no significant alteration in ERK activity in any group of rats. Our findings suggest that cortical ERK is involved in cocaine seeking behavior in rats. They also indicate the time and regional adaptations in this enzyme activity after cocaine withdrawal.
    Pharmacological reports: PR 01/2014; 66(4):630–637. DOI:10.1016/S1734-1140(13)71358-6 · 1.93 Impact Factor
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